43.
Front Oncol. 2020 Feb 4;10:94. doi: 10.3389/fonc.2020.00094. eCollection 2020.
Dependence and Guidance Receptors-DCC and Neogenin-In Partial EMT and the Actions of Serine Proteases.
Stone TW1.
Abstract
The Epithelial-Mesenchymal Transition (EMT) is an important concept in understanding the processes of oncogenesis, especially with respect to the relationship between cell proliferation and metastatic properties such as spontaneous cell motility, chemotaxic migration and tissue invasion. EMT is now recognized as a more complex phenomenon than an all-or-nothing event, in which different components of the EMT may have distinct roles in the physio-pathological regulation of cell function and which may in turn depend on differential interactions with cell constituents and metabolic products. This mini-review summarizes recent work on the induction of cancer properties in parallel with the presence of EMT activities in the presence of serine proteases, with the focus on those tumor suppressors known as "dependence" receptors such as neogenin and Deleted in Colorectal Cancer (DCC). It is concluded that various forms of partial EMT should be given more detailed investigation and consideration as the results could have valuable implications for the development of disease-specific and patient-specific therapies.
Copyright © 2020 Stone.
KEYWORDS:
DCC; chymotrypsin; neogenin; serine proteases; subtilisin
44.
Front Oncol. 2020 Feb 12;10:93. doi: 10.3389/fonc.2020.00093. eCollection 2020.
The Diagnostic Performance of DCE-MRI in Evaluating the Pathological Response to Neoadjuvant Chemotherapy in Breast Cancer: A Meta-Analysis.
Abstract
Background: Neoadjuvant chemotherapy (NAC) is commonly utilized in preoperative treatment for local breast cancer, and it gives high clinical response rates and can result in pathologic complete response (pCR) in 6-25% of patients. In recent years, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has been increasingly used to assess the pathological response of breast cancer to NAC. In present analysis, we assess the diagnostic performance of DCE-MRI in evaluating the pathological response of breast cancer to NAC. Materials and Methods: A systematic search in PubMed, the Cochrane Library, and Web of Science for original studies was performed. The Quality Assessment of Diagnostic Accuracy Studies-2 tool was used to assess the methodological quality of the included studies. Patient, study, and imaging characteristics were extracted, and sufficient data to reconstruct 2 × 2 tables were obtained. Data pooling, heterogeneity testing, forest plot construction, meta-regression analysis and sensitivity analysis were performed using Stata version 12.0 (StataCorp LP, College Station, TX). Results: Eighteen studies (969 patients with breast cancer) were included in the present meta-analysis. The pooled sensitivity and specificity of DCE-MRI were 0.80 (95% confidence interval [CI]: 0.70, 0.88) and 0.84 (95% [CI]: 0.79, 0.88), respectively. Meta-regression analysis found no significant factors affecting heterogeneity. Sensitivity analysis showed that studies that set pathological complete response (pCR) (n = 14) as a responder showed a tendency for higher sensitivity compared with those that set pCR and near pCR together (n = 5) as a responder (0.83 vs. 0.72), and studies (n = 14) that used DCE-MRI to early predict the pathological response of breast cancer had a higher sensitivity (0.83 vs. 0.71) and equivalent specificity (0.80 vs. 0.86) compared to studies (n = 5) that assessed the response after NAC completion. Conclusion: Our results indicated that DCE-MRI could be considered an important auxiliary method for evaluating the pathological response of breast cancer to NAC and used as an effective method for dynamically monitoring the efficacy during NAC. DCE-MRI also performed well in predicting the pCR of breast cancer to NAC. However, due to the heterogeneity of the included studies, caution should be exercised in applying our results.
Copyright © 2020 Cheng, Huang, Liang, Ma, Ye, Shi and Luo.
KEYWORDS:
breast cancer; dynamic contrast-enhanced magnetic resonance imaging; meta-analysis; neoadjuvant chemotherapy; pathological response
45.
Front Oncol. 2020 Feb 7;10:92. doi: 10.3389/fonc.2020.00092. eCollection 2020.
Invaders Exposed: Understanding and Targeting Tumor Cell Invasion in Diffuse Intrinsic Pontine Glioma.
Abstract
Diffuse Intrinsic Pontine Glioma (DIPG) is a rare, highly aggressive pediatric brain tumor that originates in the pons. DIPG is untreatable and universally fatal, with a median life expectancy of less than a year. Resection is not an option, due to the anatomical location of the tumor, radiotherapy has limited effect and no chemotherapeutic or targeted treatment approach has proven to be successful. This poor prognosis is partly attributed to the tumor's highly infiltrative diffuse and invasive spread. Thus, targeting the invasive behavior of DIPG has the potential to be of therapeutic value. In order to target DIPG invasion successfully, detailed mechanistic knowledge on the underlying drivers is required. Here, we review both DIPG tumor cell's intrinsic molecular processes and extrinsic environmental factors contributing to DIPG invasion. Importantly, DIPG represents a heterogenous disease and through advances in whole-genome sequencing, different subtypes of disease based on underlying driver mutations are now being recognized. Recent evidence also demonstrates intra-tumor heterogeneity in terms of invasiveness and implies that highly infiltrative tumor subclones can enhance the migratory behavior of neighboring cells. This might partially be mediated by "tumor microtubes," long membranous extensions through which tumor cells connect and communicate, as well as through the secretion of extracellular vesicles. Some of the described processes involved in invasion are already being targeted in clinical trials. However, more research into the mechanisms of DIPG invasion is urgently needed and might result in the development of an effective therapy for children suffering from this devastating disease. We discuss the implications of newly discovered invasive mechanisms for therapeutic targeting and the challenges therapy development face in light of disease in the developing brain.
Copyright © 2020 Kluiver, Alieva, van Vuurden, Wehrens and Rios.
KEYWORDS:
diffuse intrinsic pontine glioma (DIPG); driver mutations; invasion; microenvironment; therapeutic targeting; tumor subclones
46.
Front Oncol. 2020 Feb 11;10:91. doi: 10.3389/fonc.2020.00091. eCollection 2020.
Potential Immune-Related Adverse Events Associated With Monotherapy and Combination Therapy of Ipilimumab, Nivolumab, and Pembrolizumab for Advanced Melanoma: A Systematic Review and Meta-Analysis.
Abstract
Background: The use of ipilimumab, nivolumab, and pembrolizumab as monotherapies or in combination has transformed the management of advanced melanoma even though these drugs are associated with a new profile of immune-related adverse events (irAEs). The incidence of irAEs from clinical trials of these agents is an important factor for clinicians when treating patients with advanced melanoma. In the current study, we aimed to profile the incidence of potential irAEs of these agents when used as monotherapy and as combination therapy. Methods: We searched the Medline, Embase, and Cochrane databases; clinicaltrials.gov; and websites of regulatory agencies in the USA, Europe, Australia, and Japan for phase 1-3 trials of ipilimumab, nivolumab, and pembrolizumab for advanced melanoma. Random effect meta-analysis was utilized to profile the incidence of potential irAEs. Results: A total of 58 reports of 35 trials including 6,331 patients with advanced melanoma and reporting irAE data were included in the meta-analyses. We found higher incidences of potential irAEs in combination therapies vs. monotherapies for most of the types of irAEs. Among the monotherapies, ipilimumab users had the most frequent incidence of potential irAEs related to the gastrointestinal system (diarrhea, 29%; and colitis, 8%) and skin (rash, 31%; pruritus, 27%; and dermatitis, 10%), with hypophysitis in 4% of the patients. The most frequent potential irAEs among nivolumab users were maculopapular rash (13%), erythema (4%), hepatitis (3%), and infusion-related reactions (3%), while they were arthralgia (12%), hypothyroidism (8%), and hyperglycemia (6%), among pembrolizumab users. Conclusion: Especially the combination therapies tend to elevate the incidence of potential irAEs. Clinicians should be vigilant about irAEs following combination therapy as well as gastrointestinal and skin irAEs following ipilimumab therapy, in addition to being aware of potential irAEs leading to hyperglycemia, thyroid, hepatic, and musculoskeletal disorders following nivolumab and pembrolizumab therapy.
Copyright © 2020 Almutairi, McBride, Slack, Erstad and Abraham.
KEYWORDS:
advanced; immune checkpoint inhibitors; immune-related adverse events; incidence; ipilimumab; melanoma; nivolumab; pembrolizumab
47.
Front Oncol. 2020 Feb 14;10:90. doi: 10.3389/fonc.2020.00090. eCollection 2020.
Extracellular Vesicles and Chemotherapy Resistance in the AML Microenvironment.
Abstract
Extracellular vesicle (EV) trafficking provides for a constitutive mode of cell-cell communication within tissues and between organ systems. Different EV subtypes have been identified that transfer regulatory molecules between cells, influencing gene expression, and altering cellular phenotypes. Evidence from a range of studies suggests that EV trafficking enhances cell survival and resistance to chemotherapy in solid tumors. In acute myeloid leukemia (AML), EVs contribute to the dynamic crosstalk between AML cells, hematopoietic elements and stromal cells and promote adaptation of compartmental bone marrow (BM) function through transport of protein, RNA, and DNA. Careful analysis of leukemia cell EV content and phenotypic outcomes provide evidence that vesicles are implicated in transferring several known key mediators of chemoresistance, including miR-155, IL-8, and BMP-2. Here, we review the current understanding of how EVs exert their influence in the AML niche, and identify research opportunities to improve outcomes for relapsed or refractory AML patients.
Copyright © 2020 Nehrbas, Butler, Chen and Kurre.
KEYWORDS:
acute myeloid leukemia; bone marrow microenvironment; chemoresistance; extracellular vesicles; stroma
48.
Front Oncol. 2020 Feb 14;10:89. doi: 10.3389/fonc.2020.00089. eCollection 2020.
Impact of Radiochemotherapy on Immune Cell Subtypes in High-Grade Glioma Patients.
Dutoit V1,2, Philippin G1,2, Widmer V1,2, Marinari E1,2, Vuilleumier A3, Migliorini D1,2, Schaller K4, Dietrich PY1,2,3.
Abstract
Glioblastoma is a dreadful disease with very poor prognosis, median overall survival being <2 years despite standard-of-care treatment. This has led to the development of alternative strategies, among which immunotherapy is being actively tested. In particular, many clinical trials of therapeutic vaccination using peptides or tumor cells are ongoing. A major issue in implementing therapeutic vaccines in patients with high-grade glioma is that immune responses have to be elicited in the context of immunosuppressive treatments. Indeed, radiotherapy, chemotherapy, and steroids, which are part of the standard of care for patients with glioblastoma, are known to deplete leukocytes. Whether lymphopenia is beneficial or detrimental to elicitation of efficient immune responses is still debated. Here, in order to determine the impact of standard radiochemotherapy on immune cell subsets, we analyzed the phenotype and function of immune populations in 25 patients with high-grade glioma along concomitant radiochemotherapy and adjuvant chemotherapy with temozolomide. Thirteen healthy individuals were studied along the same period. We show that absolute T and B cell counts are reduced upon concomitant radiochemotherapy. Importantly, T cell counts were not restored long-term after discontinuation of treatment. In addition, the percentage of T regulatory cells among CD4 T cells was increased during the same period and was not decreased upon treatment discontinuation. Finally, we show that the ability of T cells to proliferate is transiently reduced after concomitant radiochemotherapy but is restored at the time of adjuvant TMZ cycles. Although not experimentally validated, transient reduction in proliferation associated with strong lymphopenia during radiochemotherapy may suggest that vaccine-induced T cell stimulation would be suboptimal in that period and that therapeutic vaccination should be performed outside radiochemotherapy administration. In addition, strategies aiming at depleting Treg cells should be implemented in future trials.
Copyright © 2020 Dutoit, Philippin, Widmer, Marinari, Vuilleumier, Migliorini, Schaller and Dietrich.
KEYWORDS:
cancer vaccines; glioma; immune subsets; immunotherapy; lymphopenia; radiotherapy; temozolomide
49.
Front Oncol. 2020 Feb 14;10:88. doi: 10.3389/fonc.2020.00088. eCollection 2020.
Linc00668 Promotes Invasion and Stem Cell-Like Properties of Breast Cancer Cells by Interaction With SND1.
Abstract
Long non-coding RNAs (lncRNAs) are reported to be involved in breast cancer progression. Herein, we observed that the expression of Linc00668 was increased in breast cancer compared to normal tissue. The patients with high Linc00668 expression exhibited an association with a higher metastatic risk. We demonstrated that forced expression of Linc00668 enhanced, whereas depletion of Linc00668 diminished invasion and self-renewal of breast cancer cells as well as resistance to doxorubicin (Dox). Further mechanistic studies revealed that Linc00668 associated with staphylococcal nuclease domain-containing 1 (SND1) and regulated the expression of downstream genes. Linc00668 depletion led to reduced expression of the downstream target of SND1 and further attenuated the self-renewal capacity of breast cancer cells. Our observations suggest that Linc00668 promotes metastasis, and chemotherapeutic resistance in breast cancer by interacting with SND1. Therefore, Linc00668 may serve as a potential therapeutic modulator in breast cancer treatment.
Copyright © 2020 Qian, Zhu, Wu, Guo, Wu, Lobie and Zhu.
KEYWORDS:
SND1; breast cancer; chemotherapy resistance; long non-coding RNA; metastasis
50.
Front Oncol. 2020 Feb 7;10:87. doi: 10.3389/fonc.2020.00087. eCollection 2020.
Systemic Analysis of RNA Alternative Splicing Signals Related to the Prognosis for Head and Neck Squamous Cell Carcinoma.
Li Z1, Chen X2, Wei M1, Liu G3, Tian Y1, Zhang X1, Zhu G4, Chen C1, Liu J5, Wang T6, Lin G7, Wang J1, Cai G7, Lv Y8.
Abstract
Alternative splicing (AS) is an important mechanism that is responsible for the production of protein diversity. An increasing body of evidence has suggested that out-of-control AS is closely related to the genesis and development of cancer. Systematic analysis of genome-wide AS in head and neck squamous cell carcinoma (HNSCC) has not yet been carried out, and consideration of this topic remains at the preliminary stage and requires further investigation. In this study, systemic bioinformatic analysis was carried out on the genome-wide AS events of 555 clinical HNSCC samples from the TCGA database. Firstly, we statistically analyzed the distributions of seven AS event types in HNSCC samples. Then, through univariate survival analysis, we observed the relationship between AS and the prognosis of the disease and found that 437 intersections of AS events were significantly related to overall survival. Among them, 335 cross-genes showed a high degree of consistency in the genes associated with overall survival and recurrence. The overall survival was significantly related to AS events. Besides, the frequency of overall survival-related ES events was evidently reduced, while the AP and the AT events were increased. In addition, AT events accounted for the largest proportion. Further, multiple regression model analysis proved that AS could become a new classification method for HNSCC, and KEGG enrichment analysis proved that most genes and proteins interacting with AS events had different biological functions and were associated with a variety of diseases. Finally, through the selection of characteristic HNSCC genes and the construction of a prognostic model, seven cross-genes related to survival and recurrence were screened out, and these characteristic genes were verified by multivariate survival model analysis so as to classify the prognosis at different splicing times and gene expression levels. These results have laid a solid foundation for our further research and play a decisive role in showing the correlation of AS with the prognosis of HNSCC.
Copyright © 2020 Li, Chen, Wei, Liu, Tian, Zhang, Zhu, Chen, Liu, Wang, Lin, Wang, Cai and Lv.
KEYWORDS:
Alternative Splicing (AS); TCGA database; head and neck squamous cell carcinoma (HNSCC); oncology; prognosis
51.
Front Oncol. 2020 Feb 11;10:86. doi: 10.3389/fonc.2020.00086. eCollection 2020.
Prognostic Significance of Systematic Lymphadenectomy in Patients With Optimally Debulked Advanced Ovarian Cancer: A Meta-Analysis.
Abstract
Background: The effect of systematic lymphadenectomy (SL) on survival in patients with optimally debulked advanced ovarian cancer remains unclear. We evaluated the therapeutic value of SL in advanced ovarian cancer patients who underwent primary optimal debulking surgery. Methods: A meta-analysis was carried out using articles retrieved from the PubMed, Embase, and Cochrane databases. Overall survival (OS) and progression-free survival (PFS) were compared between patients who underwent SL and those who underwent unsystematic lymphadenectomy (USL). Results: Seven studies that included 2,425 patients with advanced ovarian cancer were included in the meta-analysis. The overall analyses indicated significantly improved OS [hazard ratio (HR) = 0.64, 95% confidence interval (CI): 0.49-0.84, P < 0.01] but not PFS (HR = 0.89, 95% CI: 0.69-1.15, P = 0.38) in patients who underwent SL compared to those who underwent USL. Subgroup analyses based on study type, study quality, total numbers of patients, and International Federation of Gynecology and Obstetrics (FIGO) stage provided similar results. However, subgroup analysis of patients with no residual tumor revealed that SL was not associated with improved OS (HR = 0.81, 95% CI: 0.66-1.00, P = 0.05) or PFS (HR = 1.09, 95% CI: 0.91-1.30, P = 0.33). Conclusions: In patients with optimally debulked advanced ovarian cancer, SL may improve OS but not PFS. However, SL does not provide a survival advantage when macroscopically complete resection of all visible tumors is achieved.
Copyright © 2020 Wang, Ren, Song, Wang, Zhang and Ouyang.
KEYWORDS:
advanced ovarian cancer; meta-analysis; optimal debulking surgery; residual tumor; systematic lymphadenectomy
52.
Front Oncol. 2020 Feb 7;10:84. doi: 10.3389/fonc.2020.00084. eCollection 2020.
Advanced Cancer Imaging Applied in the Comparative Setting.
Abstract
The potential for companion (pet) species with spontaneously arising tumors to act as surrogates for preclinical development of advanced cancer imaging technologies has become more apparent in the last decade. The utility of the companion model specifically centers around issues related to body size (including spatial target/normal anatomic characteristics), physical size and spatial distribution of metastasis, tumor heterogeneity, the presence of an intact syngeneic immune system and a syngeneic tumor microenvironment shaped by the natural evolution of the cancer. Companion species size allows the use of similar equipment, hardware setup, software, and scan protocols which provide the opportunity for standardization and harmonization of imaging operating procedures and quality assurance across imaging protocols, imaging hardware, and the imaged species. Murine models generally do not replicate the size and spatial distribution of human metastatic cancer and these factors strongly influence image resolution and dosimetry. The following review will discuss several aspects of comparative cancer imaging in more detail while providing several illustrative examples of investigational approaches performed or currently under exploration at our institutions. Topics addressed include a discussion on interested consortia; image quality assurance and harmonization; image-based biomarker development and validation; contrast agent and radionuclide tracer development; advanced imaging to assess and predict response to cytotoxic and immunomodulatory anticancer agents; imaging of the tumor microenvironment; development of novel theranostic approaches; cell trafficking assessment via non-invasive imaging; and intraoperative imaging to inform surgical oncology decision making. Taken in totality, these comparative opportunities predict that safety, diagnostic and efficacy data generated in companion species with naturally developing and progressing cancers would better recapitulate the human cancer condition than that of artificial models in small rodent systems and ultimately accelerate the integration of novel imaging technologies into clinical practice. It is our hope that the examples presented should serve to provide those involved in cancer investigations who are unfamiliar with available comparative methodologies an understanding of the potential utility of this approach.
Copyright © 2020 Vail, LeBlanc and Jeraj.
KEYWORDS:
PET/CT; biomarkers; cancer; canine; comparative; imaging; radiomics; theranostics
53.
Front Oncol. 2020 Feb 5;10:83. doi: 10.3389/fonc.2020.00083. eCollection 2020.
Long-Term Patient-Reported Quality of Life After Stereotactic Body Radiation Therapy for Recurrent, Previously-Irradiated Head and Neck Cancer.
Abstract
Objectives: Long-term quality-of-life data following stereotactic body radiation therapy (SBRT) for recurrent head and neck cancer (rHNC) is underreported. We report patient-reported quality-of-life (PR-QOL) after at least 1 year post-treatment. Methods and Materials: A retrospective review was performed on 64 patients receiving SBRT for previously-irradiated rHNC. PR-QOL was prospectively evaluated using the University of Washington Quality of Life Questionnaire. The mixed effects proportional odds model was used to assess post-treatment overall PR-QOL changes, as well as the effects of late toxicities, tumor volume > 25 cc, local failure, nodal recurrence, distant failure, prior neck dissection, performance status other than ECOG 0 or Karnofsky 100, sex, age >65, squamous vs. non-squamous primary histology, and specific organ recurrence. Results: SBRT had no significant effect on overall PR-QOL at days 1-90 post-treatment (SBRT effect 0.035, p = 0.93) and days 91-365 (SBRT effect -0.30, p = 0.45). Beyond day 365, overall PR-QOL was significantly worse than baseline (SBRT effect -0.77, p =.03). Grade ≥3 late toxicities (p = 0.0072) and tumor volume > 25 cc (p = 0.032) predicted significantly worse overall PR-QOL. Oral cavity recurrence predicted significant decrements in chewing (p = 0.0006), swallowing (p = 0.0301), and taste PR-QOL (p = 0.02). Nasal recurrence predicted significant decrements in taste PR-QOL (p = 0.030). Grade ≥3 late dysphagia predicted significant decline in chewing (p = 0.039) and swallowing (p = 0.0004). Grade ≥3 late osteonecrosis predicted significant differences in pain PR-QOL (p = 0.0026). Conclusion: PR-QOL across several domains declines immediately after SBRT for previously-irradiated rHNC before returning to baseline levels at 1 year. Long-term PR-QOL declines thereafter. Patients with grade ≥3 late toxicities or tumor volume >25 cc report reduced long-term overall PR-QOL, likely representing late disease progression. Specific organ recurrence and grade ≥3 late toxicities predict decrements in specific PR-QOL domains.
Copyright © 2020 Thomas, Wang, Clump, Ferris, Duvvuri, Ohr and Heron.
KEYWORDS:
SBRT (stereotactic body radiation therapy); disease recurrence; head and neck cancer; quality of life; toxicity
54.
Front Oncol. 2020 Feb 4;10:82. doi: 10.3389/fonc.2020.00082. eCollection 2020.
Carbon Ion Therapy: A Modern Review of an Emerging Technology.
Abstract
Radiation therapy is one of the most widely used therapies for malignancies. The therapeutic use of heavy ions, such as carbon, has gained significant interest due to advantageous physical and radiobiologic properties compared to photon based therapy. By taking advantage of these unique properties, carbon ion radiotherapy may allow dose escalation to tumors while reducing radiation dose to adjacent normal tissues. There are currently 13 centers treating with carbon ion radiotherapy, with many of these centers publishing promising safety and efficacy data from the first cohorts of patients treated. To date, carbon ion radiotherapy has been studied for almost every type of malignancy, including intracranial malignancies, head and neck malignancies, primary and metastatic lung cancers, tumors of the gastrointestinal tract, prostate and genitourinary cancers, sarcomas, cutaneous malignancies, breast cancer, gynecologic malignancies, and pediatric cancers. Additionally, carbon ion radiotherapy has been studied extensively in the setting of recurrent disease. We aim to provide a comprehensive review of the studies of each of these disease sites, with a focus on the current trials using carbon ion radiotherapy.
Copyright © 2020 Malouff, Mahajan, Krishnan, Beltran, Seneviratne and Trifiletti.
KEYWORDS:
carbon; heavy ion; high LET radiation; particle; radiation therapy
55.
Front Oncol. 2020 Feb 6;10:81. doi: 10.3389/fonc.2020.00081. eCollection 2020.
A 6 lncRNA-Based Risk Score System for Predicting the Recurrence of Colon Adenocarcinoma Patients.
Abstract
Colon adenocarcinoma (COAD) is a common type of colon cancer, and post-operative recurrence and metastasis may occur in COAD patients. This study is designed to build a risk score system for COAD patients. The Cancer Genome Atlas (TCGA) dataset of COAD (the training set) was downloaded, and GSE17538 and GSE39582 (the validation sets) from Gene Expression Omnibus database were obtained. The differentially expressed RNAs (DERs) were analyzed by limma package. Using survival package, the independent prognosis-associated long non-coding RNAs (lncRNAs) were selected for constructing risk score system. After the independent clinical prognostic factors were screened out using survival package, a nomogram survival model was constructed using rms package. Furthermore, competitive endogenous RNA (ceRNA) regulatory network and enrichment analyses separately were performed using Cytoscape software and DAVID tool. Totally 404 DERs between recurrence and non-recurrence groups were identified. Based on the six independent prognosis-associated lncRNAs (including H19, KCNJ2-AS1, LINC00899, LINC01503, PRKAG2-AS1, and SRRM2-AS1), the risk score system was constructed. After the independent clinical prognostic factors (Pathologic M, pathologic T, and RS model status) were identified, the nomogram survival model was built. In the ceRNA regulatory network, there were three lncRNAs, four miRNAs, and 77 mRNAs. Additionally, PPAR signaling pathway and hedgehog signaling pathway were enriched for the mRNAs in the ceRNA regulatory network. The risk score system and the nomogram survival model might be used for predicting COAD recurrence. Besides, PPAR signaling pathway and hedgehog signaling pathway might affect the recurrence of COAD patients.
Copyright © 2020 Yang, Lin, Liu, Gan, Jin, Cui, Yan, Qian, Han and Wang.
KEYWORDS:
colon adenocarcinoma; competitive endogenous RNA; differential expression analysis; nomogram survival model; risk score system
56.
Front Oncol. 2020 Feb 6;10:80. doi: 10.3389/fonc.2020.00080. eCollection 2020.
Prognostic Impact of Menopausal Hormone Therapy in Breast Cancer Differs According to Tumor Characteristics and Treatment.
Abstract
This study investigated how a history of menopausal hormone therapy (MHT) impacts clinical outcomes overall and in different subgroups of breast cancer patients. The study included 814 primary breast cancer patients aged ≥50 years in Sweden (2002-2012) with follow-up until 2016. Associations between patient- and tumor characteristics, recurrences, and overall survival were analyzed in relation to MHT. After a median follow-up of 7 years, 119 recurrences, and 111 deaths occurred. Ever MHT (n = 433, 53.2%) was associated with a lower BMI, frequency of alcohol abstinence, and histological grade, higher frequency of oral contraceptive use, and lobular cancer. Overall, MHT was not associated with prognosis, but there were significant effect modifications by estrogen receptor (ER) status, node status, main histological type, and aromatase inhibitor (AI) treatment on recurrence-risk (all P interactions ≤ 0.017). MHT conferred an increased recurrence-risk in patients with ER- tumors, adjusted Hazard Ratio (HRadj) 3.99 (95% Confidence Interval (CI) 1.40-11.33), in node-negative patients HRadj 1.88 (95% CI 1.11-3.17), and in non-AI-treated patients HRadj 1.81 (95% CI 1.01-3.24), but decreased recurrence-risk in AI-treated patients HRadj 0.46 (95% CI 0.25-0.84) and in patients with lobular cancer HRadj 0.15 (95% CI 0.04-0.64). MHT was associated with lower risk of death in node-positive patients HRadj of 0.48 (95% CI 0.27-0.86) and in AI-treated patients HRadj of 0.41 (95% CI 0.22-0.77), but not in other patients (both P interactions ≤ 0.027). A history of MHT may have prognostic value for certain subgroups of breast cancer patients such as AI-treated or node-negative patients.
Copyright © 2020 Godina, Ottander, Tryggvadottir, Borgquist, Isaksson and Jernström.
KEYWORDS:
aromatase inhibitor; breast cancer; cohort; menopausal hormone therapy; prognosis
57.
Front Oncol. 2020 Feb 6;10:79. doi: 10.3389/fonc.2020.00079. eCollection 2020.
LincRNA00494 Suppresses Non-small Cell Lung Cancer Cell Proliferation by Regulating SRCIN1 Expression as a ceRNA.
Dong J1, Li B1, Lin D1, Lu D2, Liu C3, Lu X4, Tang X1, Li L1, Zhu D1, Liu J1, Qiu X1, Tian L1, Zhou Q1.
Abstract
Background: Lung cancer is the most common malignant tumor worldwide. Accumulating results have shown that long non-coding RNAs (lncRNAs) play a key role in tumorigenesis. Patients and Methods: A total of 163 tumor tissues were collected from non-small cell lung cancer (NSCLC) patients from West China Hospital of Sichuan University. LincRNA00494 is a novel lncRNA, and its expression and biological effect in NSCLC were reported in this study. NSCLC cell lines were used in this study. Results: LincRNA00494 is mainly distributed in the cytoplasm. LincRNA00494 was downregulated in the tumor tissues compared with the adjacent non-tumor tissues. LincRNA00494 expression was positively correlated with SRCIN1 expression (R = 0.57, P < 0.05). Silencing of LincRNA00494 in the cell lines substantially decreased SRCIN1 expression at the mRNA and protein levels, whereas overexpression of LincRNA00494 enhanced the SRCIN1 levels. miR-150-3p significantly decreased the luciferase signals of LincRNA00494 and SRCIN1 reporters. After transfection with miR-150-3p mimics and miR-150-3p inhibitor, overexpression of LincRNA00494 decreased the proliferation of the H358 (36%) and H1299 (29%) cell lines compared with that of the control cells, as shown by CCK-8 assays, whereas silencing LincRNA00494 promoted the proliferation of the H358 (47%) and H1299 (35%) cells. Tumor growth from LincRNA00494-overexpressing xenografts was significantly decreased; additionally, LincRNA00494 silencing substantially increased tumor growth compared with that of the control cells. Conclusions: Functional experiments revealed that LincRNA00494 inhibited NSCLC cell proliferation, which might be related to the suppression of SRCIN1, a tumor suppressor gene, by acting as a decoy for miR-150-3p. The data showed that LincRNA00494 might have antineoplastic effects during NSCLC tumorigenesis through its role as a ceRNA.
Copyright © 2020 Dong, Li, Lin, Lu, Liu, Lu, Tang, Li, Zhu, Liu, Qiu, Tian and Zhou.
KEYWORDS:
LincRNA00494; LncRNA; SRCIN1; ceRNA; non-small cell lung cancer
58.
Front Oncol. 2020 Feb 4;10:78. doi: 10.3389/fonc.2020.00078. eCollection 2020.
High Dimensional Mass Cytometry Analysis Reveals Characteristics of the Immunosuppressive Microenvironment in Diffuse Astrocytomas.
Fu W1,2, Wang W3, Li H1,2, Jiao Y1,2, Weng J1,2, Huo R1,2, Yan Z1,2, Wang J1,2, Xu H1,2, Wang S1,2, Wang J1,2, Chen D3, Cao Y1,2, Zhao J1,2.
Abstract
The tumor immune microenvironment (TIME) plays a pivotal role in tumor development, progression, and prognosis. However, the characteristics of the TIME in diffuse astrocytoma (DA) are still unclear. Leveraging mass cytometry with a panel of 33 markers, we analyzed the infiltrating immune cells from 10 DA and 4 oligodendroglioma (OG) tissues and provided a single cell-resolution landscape of the intricate immune microenvironment. Our study profiled the composition of the TIME in DA and confirmed the presence of immune cells, such as glioma-associated microglia/macrophages (GAMs), CD8+ T cells, CD4+ T cells, regulatory T cells (Tregs), and natural killer cells. Increased percentages of PD-1+ CD8+ T cells, TIM-3+ CD4+ T cell subpopulations, Tregs and pro-tumor phenotype GAMs substantially contribute to the local immunosuppressive microenvironment in DA. DAs and OGs share similar compositions in terms of immune cells, while GAMs in DA exhibit more inhibitory characteristics than those in OG.
Copyright © 2020 Fu, Wang, Li, Jiao, Weng, Huo, Yan, Wang, Xu, Wang, Wang, Chen, Cao and Zhao.
KEYWORDS:
CyTOF; diffuse astrocytoma; immune profiling; microenvironment; oligodendroglioma
59.
Front Oncol. 2020 Feb 4;10:77. doi: 10.3389/fonc.2020.00077. eCollection 2020.
Prediction of Response to Preoperative Neoadjuvant Chemotherapy in Locally Advanced Cervical Cancer Using Multicenter CT-Based Radiomic Analysis.
Tian X1, Sun C2,3, Liu Z2,4, Li W1, Duan H1, Wang L1, Fan H1, Li M1, Li P1, Wang L3, Liu P1, Tian J2,4,5, Chen C1.
Abstract
Objective: To investigate whether pre-treatment CT-derived radiomic features could be applied for prediction of clinical response to neoadjuvant chemotherapy (NACT) in locally advanced cervical cancer (LACC). Patients and Methods: Two hundred and seventy-seven LACC patients treated with NACT followed by surgery/radiotherapy were included in this multi-institution retrospective study. One thousand and ninety-four radiomic features were extracted from venous contrast enhanced and non-enhanced CT imaging for each patient. Five combined methods of feature selection were used to reduce dimension of features. Radiomics signature was constructed by Random Forest (RF) method in a primary cohort of 221 patients. A combined model incorporating radiomics signature with clinical factors was developed using multivariable logistic regression. Prediction performance was then tested in a validation cohort of 56 patients. Results: Radiomics signature containing pre- and post-contrast imaging features can adequately distinguish chemotherapeutic responders from non-responders in both primary and validation cohorts [AUCs: 0.773 (95% CI, 0.701-0.845) and 0.816 (95% CI, 0.690-0.942), respectively] and remain relatively stable across centers. The combined model has a better predictive performance with an AUC of 0.803 (95% CI, 0.734-0.872) in the primary set and an AUC of 0.821 (95% CI, 0.697-0.946) in the validation set, compared to radiomics signature alone. Both models showed good discrimination, calibration. Conclusion: Newly developed radiomic model provided an easy-to-use predictor of chemotherapeutic response with improved predictive ability, which might facilitate optimal treatment strategies tailored for individual LACC patients.
Copyright © 2020 Tian, Sun, Liu, Li, Duan, Wang, Fan, Li, Li, Wang, Liu, Tian and Chen.
KEYWORDS:
CT; locally advanced cervical cancer (LACC); neoadjuvant chemotherapy; radiomics; response prediction
60.
Front Oncol. 2020 Feb 6;10:74. doi: 10.3389/fonc.2020.00074. eCollection 2020.
Novel Expression of EGFL7 in Osteosarcoma and Sensitivity to Cisplatin.
Abstract
Epidermal growth factor-like domain 7 (EGFL7) is a protein specifically secreted by blood vessel endothelial cells, which plays an important role in angiogenesis. Considering the aberrant secretion of EGFL7 in osteosarcoma (OS) has not yet been elucidated, this study investigated the secretion of EGFL7 in OS and the changes in its secretion after chemotherapy. We observed increased varying secretion of EGFL7 in OS tissues compared with chondrosarcoma (CS) tissues. OS cell lines and HUVECs showed higher EGFL7 mRNA and protein expression than SW1353, with OS cells expressing the highest levels. In patient samples, EGFL7 was highly expressed in the cytoplasm of OS tumor cells and vascular endothelium cells. This overexpression was abolished in OS cell and tumor tissues when treated with chemotherapy. This study is a pioneering study to investigate EGFL7 expression and localization in human OS tissues and cell. Overexpression of EGFL-7 in response to chemotherapy suggests that it can be used as a therapeutic target for OS.
Copyright © 2020 Liu, He, Yuan, Zeng, Wang and Luo.
KEYWORDS:
angiogenesis; chemotherapy; epidermal growth factor-like domain 7; osteosarcoma; therapeutic target
61.
Front Oncol. 2020 Feb 4;10:73. doi: 10.3389/fonc.2020.00073. eCollection 2020.
The Association Between Cancer and Dementia: A National Cohort Study in Sweden.
Abstract
Background: Previous studies have found that the incidence of dementia is lower in patients with cancer. However, the impact of survival bias, as well as the confounding by medical treatment, have not been fully addressed. We aimed to explore the subsequent risk of dementia in different follow-up intervals among patients with cancer, as well as the risk before the diagnosis of cancer. Methods: By using the Swedish Cancer Register and the Swedish Hospital Discharge Register, we systematically examined the risk of dementia among patients diagnosed with 35 different types of cancer. Standardized incidence ratios (SIRs) were used to calculate the relative risk. Results: The subsequent risk of dementia in patients with cancer decreased by 21% compared to matched cancer-free controls (SIR = 0.79, 95% CI 0.78-0.80). For specific cancer sites, 21 of them had a significantly lower risk of subsequent dementia. The decreased risk of dementia was also significant before the diagnosis of cancer. However, the risk was higher among patients with cancer who survived for more than 10 years' post-diagnosis (SIR = 1.37, 95% CI 1.32-1.41). Conclusions: In this population-based study, we found that the risk of dementia was lower among patients with cancer, and the risk was also lower before the diagnosis of cancer. This suggests that lower dementia risk is not simply due to bias. However, the underlying mechanisms need to be explored further.
Copyright © 2020 Sun, Wang, Sundquist, Sundquist and Ji.
KEYWORDS:
cancer; dementia; incidence; inverse association; nationwide
62.
Front Oncol. 2020 Feb 7;10:72. doi: 10.3389/fonc.2020.00072. eCollection 2020.
Genetic Variants of HOTAIR Associated With Colorectal Cancer Susceptibility and Mortality.
Abstract
In colorectal carcinogenesis, the unique molecular and genetic changes that occur within cells result in specific CRC phenotypes. The involvement of the long non-coding RNA, HOTAIR, in cancer development, progression, and metastasis is well-established. Various studies have reported on the contribution of HOTAIR to cancer pathogenesis. Therefore, we selected four HOTAIR polymorphisms (rs7958904G>C, rs1899663G>T, rs4759314A>G, and rs920778T>C) to evaluate the association of each variant with CRC prevalence and prognosis. We conducted a case-control study of 850 individuals to identify the genotype frequencies of each polymorphism. The study population included 450 CRC patients and 400 control individuals that were randomly selected following a health screening. Notably, rs7958904 and rs1899663, their hetero genotype, and the dominant model were significantly different when compared to the healthy control group (rs7958904; AOR = 1.392, 95% CI = 1.052-1.843, P = 0.021). To evaluate the effect of HOTAIR polymorphisms on the survival rate, we analyzed patient mortality and relapse occurrence within 3 and 5 years with Cox-regression analysis. The rs7958904 CC polymorphism mortality rate was significantly higher than the GG polymorphism mortality rate (adjusted HR = 2.995, 95% CI = 1.189-7.542, P = 0.021). In addition, the rs920778 CC genotype was significantly different than the TT genotype (adjusted HR = 3.639, 95% CI = 1.435-9.230, P = 0.007). In addition, this study confirmed that genetic variants of HOTAIR alter the mRNA expression level (P < 0.01). We suggest that HOTAIR rs7958904G>C which is associated with CRC prevalence and mortality is a potential biomarker for CRC. The association between HOTAIR gene polymorphisms and CRC prevalence were reported for the first time.
Copyright © 2020 Kim, Jun, Kim, Lee, Park, Ryu, Kim, Oh, Kim and Kim.
KEYWORDS:
HOTAIR; case-control study; colorectal cancer; long non-coding RNA; single nucleotide polymorphisms
63.
Front Oncol. 2020 Feb 7;10:71. doi: 10.3389/fonc.2020.00071. eCollection 2020.
Machine Learning Decision Tree Models for Differentiation of Posterior Fossa Tumors Using Diffusion Histogram Analysis and Structural MRI Findings.
Abstract
We applied machine learning algorithms for differentiation of posterior fossa tumors using apparent diffusion coefficient (ADC) histogram analysis and structural MRI findings. A total of 256 patients with intra-axial posterior fossa tumors were identified, of whom 248 were included in machine learning analysis, with at least 6 representative subjects per each tumor pathology. The ADC histograms of solid components of tumors, structural MRI findings, and patients' age were applied to construct decision models using Classification and Regression Tree analysis. We also compared different machine learning classification algorithms (i.e., naïve Bayes, random forest, neural networks, support vector machine with linear and polynomial kernel) for dichotomized differentiation of the 5 most common tumors in our cohort: metastasis (n = 65), hemangioblastoma (n = 44), pilocytic astrocytoma (n = 43), ependymoma (n = 27), and medulloblastoma (n = 26). The decision tree model could differentiate seven tumor histopathologies with terminal nodes yielding up to 90% accurate classification rates. In receiver operating characteristics (ROC) analysis, the decision tree model achieved greater area under the curve (AUC) for differentiation of pilocytic astrocytoma (p = 0.020); and atypical teratoid/rhabdoid tumor ATRT (p = 0.001) from other types of neoplasms compared to the official clinical report. However, neuroradiologists' interpretations had greater accuracy in differentiating metastases (p = 0.001). Among different machine learning algorithms, random forest models yielded the highest accuracy in dichotomized classification of the 5 most common tumor types; and in multiclass differentiation of all tumor types random forest yielded an averaged AUC of 0.961 in training datasets, and 0.873 in validation samples. Our study demonstrates the potential application of machine learning algorithms and decision trees for accurate differentiation of brain tumors based on pretreatment MRI. Using easy to apply and understandable imaging metrics, the proposed decision tree model can help radiologists with differentiation of posterior fossa tumors, especially in tumors with similar qualitative imaging characteristics. In particular, our decision tree model provided more accurate differentiation of pilocytic astrocytomas from ATRT than by neuroradiologists in clinical reads.
Copyright © 2020 Payabvash, Aboian, Tihan and Cha.
KEYWORDS:
MRI; decision tree model; diffusion histogram; machine learning; posterior fossa tumor
64.
Front Oncol. 2020 Feb 14;10:70. doi: 10.3389/fonc.2020.00070. eCollection 2020.
Immunotherapy Potentiates the Effect of Chemotherapy in Metastatic Melanoma-A Retrospective Study.
Hadash-Bengad R1, Hajaj E1, Klein S1, Merims S1, Frank S1, Eisenberg G1, Yakobson A2, Orevi M3, Caplan N4, Peretz T1, Lotem M1, Cohen JE1,5.
Abstract
Melanoma survival increased with targeted- and immunotherapy agents, yet most patients ultimately progress and require salvage therapy. In our experience, some progressive disease patients on immune-checkpoint inhibitors (ICIs) demonstrate deep and sustained responses to chemotherapy. We hypothesized that ICIs improve the response to subsequent chemotherapy in metastatic melanoma. We conducted a retrospective study to compare the efficacy of chemotherapy given with prior immunotherapy, to its efficacy given without it. We measured progression free survival (PFS), overall survival, and response rate. Immune-monitoring was performed on sequential peripheral blood mononuclear cell samples taken from a chemotherapy-responsive patient. The chemotherapy post-immunotherapy group (CpI) included 11 patients, the chemotherapy without prior immunotherapy (CNPI) group included 24 patients. Median PFS was 5.2 months in the CpI vs. 2.5 months in the CNPI groups; HR 0.37 [95% Confidence interval (CI) 0.144-0.983], P = 0.046. Immune-monitoring showed an increased proportion of CD8+ cells, with elevated PD-1 and CD69 expression, while on chemotherapy, as compared with all-time points on ICIs, suggesting immune-activation. Immunotherapy potentiates the effect of chemotherapy in metastatic melanoma possibly through activation of CD8+ T cells.
Copyright © 2020 Hadash-Bengad, Hajaj, Klein, Merims, Frank, Eisenberg, Yakobson, Orevi, Caplan, Peretz, Lotem and Cohen.
KEYWORDS:
chemotherapy; immune checkpoint inhibitors; immune-monitoring; malignant melanoma; salvage therapy
65.
Front Oncol. 2020 Feb 5;10:69. doi: 10.3389/fonc.2020.00069. eCollection 2020.
The CaSR in Pathogenesis of Breast Cancer: A New Target for Early Stage Bone Metastases.
Abstract
The Ca2+-sensing receptor (CaSR) is a class-C G protein-coupled receptor which plays a pivotal role in calciotropic processes, primarily in regulating parathyroid hormone secretion to maintain systemic calcium homeostasis. Among its non-calciotropic roles, where the CaSR sits at the intersection of myriad processes, it has steadily garnered attention as an oncogene or tumor suppressor in different organs. In maternal breast tissues the CaSR promotes lactation but in breast cancer it acts as an oncoprotein and has been shown to drive the pathogenesis of skeletal metastases from breast cancer. Even though research has made great strides in treating primary breast cancer, there is an unmet need when it comes to treatment of metastatic breast cancer. This review focuses on how the CaSR leads to the pathogenesis of breast cancer by contrasting its role in healthy tissues and tumorigenesis, and by drawing brief parallels with the tissues where it has been implicated as an oncogene. A class of compounds called calcilytics, which are CaSR antagonists, have also been surveyed in the instances where they have been used to target the receptor in cancerous tissues and constitute a proof of principle for repurposing them. Current clinical therapies for treating bone metastases from breast cancer are limited to targeting osteoclasts and a deeper understanding of the CaSR signaling nexus in this context can bolster them or lead to novel therapeutic interventions.
Copyright © 2020 Das, Clézardin, Kamel, Brazier and Mentaverri.
KEYWORDS:
CaSR; bone metastasis; breast cancer; calcilytics; calcium-sensing receptor; mammary gland
66.
Front Oncol. 2020 Feb 5;10:68. doi: 10.3389/fonc.2020.00068. eCollection 2020.
Comprehensive Review of Web Servers and Bioinformatics Tools for Cancer Prognosis Analysis.
Zheng H1, Zhang G1, Zhang L1, Wang Q1, Li H1, Han Y1, Xie L1, Yan Z1, Li Y1, An Y1, Dong H1, Zhu W2, Guo X1.
Abstract
Prognostic biomarkers are of great significance to predict the outcome of patients with cancer, to guide the clinical treatments, to elucidate tumorigenesis mechanisms, and offer the opportunity of identifying therapeutic targets. To screen and develop prognostic biomarkers, high throughput profiling methods including gene microarray and next-generation sequencing have been widely applied and shown great success. However, due to the lack of independent validation, only very few prognostic biomarkers have been applied for clinical practice. In order to cross-validate the reliability of potential prognostic biomarkers, some groups have collected the omics datasets (i.e., epigenetics/transcriptome/proteome) with relative follow-up data (such as OS/DSS/PFS) of clinical samples from different cohorts, and developed the easy-to-use online bioinformatics tools and web servers to assist the biomarker screening and validation. These tools and web servers provide great convenience for the development of prognostic biomarkers, for the study of molecular mechanisms of tumorigenesis and progression, and even for the discovery of important therapeutic targets. Aim to help researchers to get a quick learning and understand the function of these tools, the current review delves into the introduction of the usage, characteristics and algorithms of tools, and web servers, such as LOGpc, KM plotter, GEPIA, TCPA, OncoLnc, PrognoScan, MethSurv, SurvExpress, UALCAN, etc., and further help researchers to select more suitable tools for their own research. In addition, all the tools introduced in this review can be reached at http://bioinfo.henu.edu.cn/WebServiceList.html.
Copyright © 2020 Zheng, Zhang, Zhang, Wang, Li, Han, Xie, Yan, Li, An, Dong, Zhu and Guo.
KEYWORDS:
cancer; prognosis; survival; tool; web server
67.
Front Oncol. 2020 Feb 7;10:64. doi: 10.3389/fonc.2020.00064. eCollection 2020.
Tumor Regression Grading Assessment in Locally Advanced Pancreatic Cancer After Neoadjuvant FOLFIRINOX: Interobserver Agreement and Prognostic Implications.
Cacciato Insilla A1, Vivaldi C2, Giordano M1, Vasile E3, Cappelli C4, Kauffmann E5, Napoli N5, Falcone A2, Boggi U5, Campani D1.
Abstract
Neoadjuvant therapy represents an increasingly used strategy in pancreatic cancer, and this means that more pancreatic resections need to be evaluated for therapy effect. Several grading systems have been proposed for the histological assessment of tumor regression in pre-treated patients with pancreatic cancer, but issues like practical application, level of agreement and prognostic significance are still debated. To date, a standardized and widely accepted score has not been established yet. In this study, two pathologists with expertise in pancreatic cancer used 4 of the most frequently reported systems (College of American Pathologists, Evans, MD Anderson, and Hartman) to evaluate tumor regression in 29 locally advanced pancreatic cancers previously treated with modified FOLFIRINOX regimen, to establish the level of agreement between pathologists and to determine their potential prognostic value. Cases were additionally evaluated with a fifth grading system inspired to the Dworak score, normally used for colo-rectal cancer, to identify an alternative, relevant option. Results obtained for current grading systems showed different levels of agreement, and they often proved to be very subjective and inaccurate. In addition, no significant correlation was observed with survival. Interestingly, Dworak score showed a higher degree of concordance and a significant correlation with overall survival in individual assessments. These data reflect the need to re-evaluate grading systems for pancreatic cancer to establish a more reproducible and clinically relevant score.
Copyright © 2020 Cacciato Insilla, Vivaldi, Giordano, Vasile, Cappelli, Kauffmann, Napoli, Falcone, Boggi and Campani.
KEYWORDS:
locally advanced; neoadjuvant therapy; pancreatic cancer; survival; tumor regression grade
68.
Front Oncol. 2020 Feb 4;10:60. doi: 10.3389/fonc.2020.00060. eCollection 2020.
miR-936 Suppresses Cell Proliferation, Invasion, and Drug Resistance of Laryngeal Squamous Cell Carcinoma and Targets GPR78.
Lin XJ1, Liu H2, Li P1, Wang HF1, Yang AK3,4,5, Di JM6, Jiang QW7, Yang Y7, Huang JR7, Yuan ML7, Xing ZH7, Wei MN7, Li Y7, Shi Z7, Ye J1.
Abstract
MicroRNAs (miRs) play important roles in tumor progression. miR-936 has been reported to suppress cell invasion and proliferation of glioma and non-small cell lung cancer. Nevertheless, the function of miR-936 in laryngeal squamous cell carcinoma (LSCC) remains undiscovered. Hence, our study was to investigate the role of miR-936 in LSCC. In our present research, we have testified that miR-936 was substantially downregulated in LSCC tissues compared with adjacent normal tissues. Furthermore, miR-936 could inhibit proliferation, migration and invasion, and improve the sensitivity to doxorubicin and cisplatin of LSCC cells. Additionally, luciferase reporter assays were performed to confirm that GPR78 was a novel target of miR-936, and the protein expression of GPR78 was obviously inhibited by miR-936 in LSCC cells. In summary, our study indicates that the miR-936/GPR78 axis could be both a diagnostic marker and a therapeutic target for LSCC.
Copyright © 2020 Lin, Liu, Li, Wang, Yang, Di, Jiang, Yang, Huang, Yuan, Xing, Wei, Li, Shi and Ye.
KEYWORDS:
GPR78; drug resistance; invasion; laryngeal squamous cell carcinoma; miR-936; proliferation
69.
Front Oncol. 2020 Feb 7;10:58. doi: 10.3389/fonc.2020.00058. eCollection 2020.
7-Methoxy-1-Tetralone Induces Apoptosis, Suppresses Cell Proliferation and Migration in Hepatocellular Carcinoma via Regulating c-Met, p-AKT, NF-κB, MMP2, and MMP9 Expression.
Abstract
This study aimed to determine the anti-proliferative and anti-migratory effects of 7-methoxy-1-tetralone (MT) in hepatocellular carcinoma (HCC) cells. MTT assay assessed HCC cell viability; cell apoptosis of HCC cells was determined by flow cytometry; wound healing assay evaluated HCC cell migratory ability; protein expression levels were assessed using western blot assay; the in vivo antitumor effects of MT were tested in BALB/c nude mice and the pathological changes within the tumor tissues were evaluated by immunohistochemistry. MT treatment significantly suppressed the cell proliferative and migratory potentials of HepG2 cells, and induced HepG2 cell apoptosis. The western blot assay showed that MT treatment caused a suppression on c-Met, phosphorylated AKT (p-AKT), NF-κB, matrix metallopeptidase 2 (MMP2)/MMP9 protein levels in HepG2 cells. Further in vivo animal studies deciphered that MT treatment suppressed tumor growth of HepG2 cells in the nude mice, but had no effect on the body weight and the organ index of liver and spleen. Further immunohistochemistry analysis of the dissected tumor tissues showed that MT treatment significantly suppressed the protein expression levels of NF-κB, MMP9, MMP2, and p-AKT. In summary, the present study demonstrated the anti-tumor effects of MT on the HCC, and MT suppressed HCC progression possibly via regulating proliferation- and migration-related mediators including c-Met, p-AKT, NF-κB, MMP2, and MMP9 in HepG2 cells.
Copyright © 2020 Wen, Cai, Chen, Fu, Chai, Zhang and Zhang.
KEYWORDS:
7-methoxy-1-tetralone; cell apoptosis; cell migration; cell proliferation; hepatocellular carcinoma
70.
Front Oncol. 2020 Feb 6;10:54. doi: 10.3389/fonc.2020.00054. eCollection 2020.
The Emerging Role of the c-MET-HGF Axis in Non-small Lung Cancer Tumor Immunology and Immunotherapy.
Abstract
Study of the c-Met-HGF axis in non-small cell lung cancer (NSCLC) has focused on the roles of c-MET signaling in neoplastic epithelial cells and the secretion of its ligand hepatocyte growth factor (HGF) by tumor stromal cells. However, there is increasing evidence that some leukocyte sub-sets also express c-MET raising the possibility of an immunomodulatory role for this axis. Consequently, the role of the c-MET- HGF axis in immunoncology is an active area of ongoing research. This review summarizes current knowledge of c-MET expression in NSCLC, the prognostic significance of these findings and the mechanisms by which the c-MET-HGF axis might act in NSCLC, focusing on the emerging evidence for an immunoregulatory role.
Copyright © 2020 Titmarsh, O'Connor, Dhaliwal and Akram.
KEYWORDS:
HGF; NSCLC; c-MET; cancer immunology; immunotherapy
71.
Front Oncol. 2020 Feb 3;10:51. doi: 10.3389/fonc.2020.00051. eCollection 2020.
Immunometabolic Network Interactions of the Kynurenine Pathway in Cutaneous Malignant Melanoma.
Rad Pour S1, Morikawa H2, Kiani NA1,3, Gomez-Cabrero D1,4, Hayes A5, Zheng X5, Pernemalm M6, Lehtiö J6, Mole DJ5, Hansson J6,7, Eriksson H6,7, Tegnér J1,2,3.
Abstract
Dysregulation of the kynurenine pathway has been regarded as a mechanism of tumor immune escape by the enzymatic activity of indoleamine 2, 3 dioxygenase and kynurenine production. However, the immune-modulatory properties of other kynurenine metabolites such as kynurenic acid, 3-hydroxykynurenine, and anthranilic acid are poorly understood. In this study, plasma from patients diagnosed with metastatic cutaneous malignant melanoma (CMM) was obtained before (PRE) and during treatment (TRM) with inhibitors of mitogen-activated protein kinase pathway (MAPKIs). Immuno-oncology related protein profile and kynurenine metabolites were analyzed by proximity extension assay (PEA) and LC/MS-MS, respectively. Correlation network analyses of the data derived from PEA and LC/MS-MS identified a set of proteins that modulate the differentiation of Th1 cells, which is linked to 3-hydroxykynurenine levels. Moreover, MAPKIs treatments are associated with alteration of 3-hydroxykynurenine and 3hydroxyanthranilic acid (3HAA) concentrations and led to higher "CXCL11," and "KLRD1" expression that are involved in T and NK cells activation. These findings imply that the kynurenine pathway is pathologically relevant in patients with CMM.
Copyright © 2020 Rad Pour, Morikawa, Kiani, Gomez-Cabrero, Hayes, Zheng, Pernemalm, Lehtiö, Mole, Hansson, Eriksson and Tegnér.
KEYWORDS:
3-hydroxykynurenine; CD4+ T helper (Th) cells; cutaneous malignant melanoma; immune metabolic network interactions; kynurenine pathway
72.
Front Oncol. 2020 Feb 14;10:49. doi: 10.3389/fonc.2020.00049. eCollection 2020.
Upregulated Expression of TUBA1C Predicts Poor Prognosis and Promotes Oncogenesis in Pancreatic Ductal Adenocarcinoma via Regulating the Cell Cycle.
Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant disease and has the worst prognosis and survival rate. TUBA1C is a microtubule component implicated in multiple cancers, however, the clinical significance and biological functions of TUBA1C in the progression of PDAC remain unexplored. Methods: The Cancer Genome Atlas (TCGA) and Gene Expression Profiling Interactive Analysis (GEPIA) data were employed to detect the TUBA1C mRNA expression and the relation between TUBA1C expression and overall survival (OS) in PDAC. Then, bioinformatic analysis was employed to determine the potential pathway and genes related to TUBA1C. Human pancreatic cancer tissue and adjacent non-tumor tissues samples were detected by immunochemistry (IHC) staining, and the correlation between TUBA1C expression and the clinicopathological features were investigated. Meanwhile, TUBA1C expression in PDAC cell lines was evaluated by western blotting. Furthermore, functional assays including cell viability, apoptosis, cell cycle, transwell assay, wound healing assay, and a xenograft tumor model were performed to determine the oncogenic role of TUBA1C in PDAC, respectively. Results: TUBA1C was overexpressed in the PDAC tissues and cells. IHC analysis showed that the TUBA1C overexpression was associated with short OS. Bioinformatic analysis indicated that TUBA1C overexpression was mainly associated with cell cycle regulation. The downregulation of TUBA1C significantly suppressed cell proliferation, induced cell apoptosis and cycle arrest, and inhibited invasion and migration in PDAC cells. Furthermore, TUBA1C downregulation also inhibited tumor growth in vivo. Conclusion: These findings suggested that TUBA1C downregulation suppressed PDAC aggressiveness via cell cycle pathway and that TUBA1C may serve as a potential prognostic marker for PDAC therapy.
Copyright © 2020 Albahde, Zhang, Zhang, Li and Wang.
KEYWORDS:
TUBA1C; cell cycle; pancreatic ductal adenocarcinoma; prognosis; proliferation
73.
Front Oncol. 2020 Feb 3;10:46. doi: 10.3389/fonc.2020.00046. eCollection 2020.
Caveolin-1 Promotes Chemoresistance of Gastric Cancer Cells to Cisplatin by Activating WNT/β-Catenin Pathway.
Abstract
Drug resistance is a major challenge for chemotherapy in treating human gastric cancer (GC), as the underlying molecular mechanism of chemoresistance in GC remains unknown. Caveolin-1 (Cav-1) is a scaffold protein of plasma membrane caveolae that acts as a tumor modulator by interacting with several cell signals. In this research, we showed that the survival rate of GC cells to cisplatin (CDDP) increased in the presence of Cav-1. Moreover, Cav-1 overexpression inhibited cisplatin-induced apoptosis and improved the survival rate of GC cells. Cav-1 overexpression and knock-down experiments indicated that Cav-1 expression stimulated wingless-type MMTV integration site (WNTs) pathway through the phosphorylation of LRP6 and dephosphorylation of β-catenin. Cav-1 was positively associated with the increase of WNT downstream target gene Met, which led to the activation of HER2 signaling. Moreover, our results demonstrated that the expression of Cav-1 and Met were positively associated with the resistance of GC cells to cisplatin. Collectively, Cav-1 enhances the cisplatin-resistance of GC cells by activating the WNT signaling pathway and Met-HER2 crosstalk. Understanding the role of Cav-1 in the chemoresistance of GC would help to develop novel therapies for a better treatment outcome of GC patients.
Copyright © 2020 Wang, Lu, Dai, Fu, Hao, Zhao, Chen and Fu.
KEYWORDS:
Caveolin-1; WNT/β-catenin pathway; chemoresistance; cisplatin; gastric cancer
74.
Front Oncol. 2020 Feb 14;10:45. doi: 10.3389/fonc.2020.00045. eCollection 2020.
Impact of Sirtuin Enzymes on the Altered Metabolic Phenotype of Malignantly Transformed Cells.
Abstract
Sirtuins compose a unique collection of histone deacetylase enzymes that have a wide variety of enzymatic activities and regulate diverse cell functions such as cellular metabolism, longevity and energy homeostasis, mitochondrial function, and biogenesis. Impaired sirtuin functions or alterations of their expression levels may result in several pathological conditions and contribute to the altered metabolic phenotype of malignantly transformed cells in a significant manner. In the twenty-first century, principles of personalized anticancer treatment need to involve not only the evaluation of changes of the genetic material, but also the mapping of epigenetic and metabolic alterations, to both of which the contribution of sirtuin enzymes is fundamental. Since sirtuins are central players in the maintenance of cellular energy and metabolic homeostasis, they are key elements in the development of metabolic transformation of cancer cells referred to as the Warburg effect. Although its most well-known features are enhanced glycolysis and excessive lactate production, Warburg effect has several aspects involving both carbohydrate, lipid, and amino acid metabolism, among which different tumor types have different preferences. Therefore, energy supply of cancer cells can be impaired by a growing number of antimetabolite agents, for which appropriate vectors are strongly needed. However, data are controversial about their tumor suppressor or oncogenic properties, the biological effects of sirtuin enzymes strongly depend on the tissue microenvironment (TME) in which they are expressed. Immune cells are regarded as key players of TME. Sirtuins regulate the survival, activation, metabolism, and mitochondrial function of these cells, therefore, they are not only single elements, but key regulators of the network that determines anticancer immunity. Altered metabolism of tumor cells induces changes in the gene expression pattern of cells in TME, due to altered concentrations of metabolite cofactors of epigenetic modifiers including sirtuins. In summary, epigenetic and metabolic alterations in malignant diseases are influenced by sirtuins in a significant manner, and should be treated in a personalized approach. Since they often develop in early stages of cancer, broad examination of these alterations is required at time of the diagnosis in order to provide a personalized combination of distinct therapeutic agents.
Copyright © 2020 Gaál and Csernoch.
KEYWORDS:
cancer; epigenetics; metabolism; personalized treatment; sirtuin enzymes
75.
Front Oncol. 2020 Feb 4;10:44. doi: 10.3389/fonc.2020.00044. eCollection 2020.
Clinical Significance of Circulating miR-1273g-3p and miR-122-5p in Pancreatic Cancer.
Mazza T1, Gioffreda D2, Fontana A3, Biagini T1, Carella M4, Palumbo O4, Maiello E5, Bazzocchi F6, Andriulli A2, Tavano F2.
Abstract
The burden of pancreatic cancer (PanC) requires innovation in the current diagnostic approach. This study aimed to uncover new circulating microRNAs (miRNAs) that would distinguish patients with PanC from healthy subjects (HS) compared with the cancer antigen 19-9 (CA 19-9), and predict patients' clinical phenotypes and outcomes. MiRNA expression profiles in plasma were investigated by using a two-stage process. In a discovery phase, miRNAs levels were analyzed using the GeneChip™ miRNA 4.0 Affymetrix assay in 10 pools of plasma samples from PanC patients and HS; in a validation phase, significantly altered miRNAs were re-tested in independent cohorts of cancer patients and controls by droplet digital PCR (ddPCR). The diagnostic performance of the resulting miRNAs was compared to CA 19-9 determinations, and the associations of miRNAs plasma levels with patients' clinical phenotypes and outcomes were also taken into account. Bioinformatics selection of miRNAs differentially expressed in plasma uncovered miR-18a-5p, miR-122-5p, miR-1273g-3p, and miR-6126 as candidate oncogenic miRNAs in PanC. The ddPCR technology confirmed the significant over-expression of miR-122-5p, miR-1273g-3p, and miR-6126 in PanC compared to HS, in line with the trend of the CA 19-9 levels. Plasma levels of miR-1273g-3p, in combination with CA 19-9, showed higher power in distinguishing PanC patients from HS compared to the CA 19-9 tested alone, with a gain in both sensitivity and negative predictive value indicating a low false-negative rate (SE = 90.2% and NPV = 92.3% vs. SE = 82.1% and NPV = 87.9%). None of the oncogenic miRNAs were able to distinguish between a neoplastic and a proliferative/inflammatory disease of the pancreas, and were not able to stratify subjects according to the clinical risk for the disease. The only valuable association in PanC patients was found between miR-1273g-3p and tumor stage, and increased miR-122-5p levels emerged as independent negative prognostic factor for PanC patients (HR = 1.58, 95% CI = 1.03-2.43, p = 0.037). Our data highlighted a role for circulating miR-1273g-3p and miR-122-5p as new diagnostic and prognostic biomarkers for PanC.
Copyright © 2020 Mazza, Gioffreda, Fontana, Biagini, Carella, Palumbo, Maiello, Bazzocchi, Andriulli and Tavano.
KEYWORDS:
circulating microRNA; diagnostic performance; expression profile; pancreatic cancer; prognosis
76.
Front Oncol. 2020 Feb 3;10:42. doi: 10.3389/fonc.2020.00042. eCollection 2020.
Comparison of Survival and Risk Factors of Differentiated Thyroid Cancer in the Geriatric Population.
Abstract
Purpose: The incidence rate of differentiated thyroid cancer (DTC), the most common type of thyroid cancer, has increased in the past two decades. The present study analyzed the clinical and pathological characteristics of DTC, and discussed the risk factors for survival in elderly age-risk DTC patients. Methods: Elderly patients who were diagnosed with DTC, and subsequently underwent surgery for DTC, were identified from the SEER database (1988-2008). Based on histology, these patients were divided into C-PTC, FV-PTC, and FTC. The clinical characteristics, pathological features, and treatments undertaken were compared among these patients. Cox proportional hazards analysis was performed to evaluate the risk factors to disease-specific survival (DSS). Results: In elderly DTC patients, FV-PTC shows intermediate tumor features compared to C-PTC and FTC, but presented a better outcome. Being male, African-American, tumors sized bigger than 4 cm, extrathyroidal extension, lymph node metastasis, and distant metastasis, were all strong risk factors for DSS in elderly DTC patients (all p < 0.05). No difference was found between lobectomy and total thyroidectomy with respect to DSS, and radiation therapy conferred no apparent advantage with respect to DSS (both p > 0.05). Discussion: Patients with FV-PTC needed more specific histology cataloging and risk assessment, suggesting conservative therapy. Risk stratification should be paid attention to, and treatment should be individualized for elderly patients.
Copyright © 2020 Yu, Hong, Han, Leng, Zhang and Yan.
KEYWORDS:
Disease-specific survival; SEER database; differentiated thyroid carcinoma; elderly people; risk factor
77.
Front Oncol. 2020 Feb 4;10:40. doi: 10.3389/fonc.2020.00040. eCollection 2020.
Vascular Resection for Pancreatic Cancer: 2019 French Recommendations Based on a Literature Review From 2008 to 6-2019.
Abstract
Introduction: Vascular resection remains a subject of debate in the management of Pancreatic Ductal Adenocarcinoma (PDAC). These French recommendations were drafted on behalf of the French National Institute of Cancer (INCA-2019). Material and Methods: A systematic literature search, with PubMed, Medline® (OvidSP), EMBASE, the Cochrane Library, was performed for abstracts published in English from January 2008 to June 2019, and identified systematic reviews/metaanalyses, retrospective analyses and case series dedicated to vascular resections in the setting of PDAC. All selected articles were graded for level of evidence and strength of recommendation was given according to the GRADE system. Results: Neoadjuvant treatment should be performed rather than direct surgery in borderline and locally advanced non-metastatic PDAC with venous and/or arterial infiltration (T4 stage). Patients who respond or those with stable disease and good performance status should undergo surgical exploration to assess resectability because cross-sectional imaging often fails to identify the extent of the remaining viable tumor. Combining vascular resection with pancreatectomy in these cases increases the feasibility of curative resection which is still the only option to improve long-term survival. Venous resection (VR) is recommended if resection is possible in the presence of limited lateral or circumferential involvement but without venous occlusion and in the absence of arterial contact with the celiac axis (CA; cephalic tumors) or the superior mesenteric artery (SMA; all tumor locations) (Grade B). The patients should be in good general condition because mortality and morbidity are higher than following pancreatectomy without VR (Grade B). In case of planned VR, neoadjuvant treatment is recommended since it improves both rate of R0 resections and survival compared to upfront surgery (Grade B). Due to their complexity and specificities, arterial resection (AR; mainly the hepatic artery (HA) or the CA) must be discussed in selected patients, in multidisciplinary team meetings in tertiary referral centers, according to the tumor location and the type of arterial extension. In case of invasion of a short segment of the common HA, resection with arterial reconstruction may be proposed after neoadjuvant therapy. In case of SMA invasion, neoadjuvant therapy may be followed by laparotomy with dissection and biopsy of peri-arterial tissues. A pancreaticoduodenectomy (PD) with SMA-resection is not recommended if the frozen section examination is positive (Grade C). In case of distal PDAC with invasion of the CA, a distal pancreatectomy with CA-resection without arterial reconstruction may be proposed after neoadjuvant therapy and radiologic embolization of the CA branches (expert opinion). Conclusion: For PDAC with vascular involvement, neoadjuvant treatment followed by pancreatectomy with venous resection or even arterial resection can be proposed as a curative option in selected patients with selected vascular involvement.
Copyright © 2020 Delpero and Sauvanet.
KEYWORDS:
French recommendations; arterial resection; pancreatic adenocarcinoma; recommendations (guidelines); venous resection
78.
Front Oncol. 2020 Feb 14;10:37. doi: 10.3389/fonc.2020.00037. eCollection 2020.
Genomic Identification of RNA Editing Through Integrating Omics Datasets and the Clinical Relevance in Hepatocellular Carcinoma.
Abstract
RNA editing is a widespread post-transcriptional mechanism to introduce single nucleotide changes to RNA in human cancers. Here, we characterized the global RNA editing profiles of 373 hepatocellular carcinoma (HCC) and 50 adjacent normal liver samples from The Cancer Genome Atlas (TCGA) and revealed that most editing events tend to occur in minor percentage of samples with moderate editing degrees (20-30%). Moreover, these RNA editing prefer to be A-to-I RNA editing in protein coding genes, especially in 3'UTR regions. Considering the association between DNA mutation and RNA editing, our analysis found that RNA editing maybe a complementary event for DNA mutation of HCC risk genes in HCC patients. We next identified 454 HCC-related editing sites, and many locate on the same genes with the same editing patterns. The functional consequences of editing revealed 2,086 functional editing sites and demonstrated that most editing in coding regions are non-synonymous variations. Furthermore, our results showed that editing in the 3'UTR regions tend to influence miRNA-target binding, and the editing degree seems to be negatively correlated with gene expression. Finally, we found that 46 HCC-related editing sites with consequence are able to distinguish the prognosis differences of HCC patients, suggesting their clinical relevance. Together, our results highlight RNA editing as a valuable molecular resource for investigating HCC mechanisms and clinical treatments.
Copyright © 2020 Chen, Wang, Wang, Liu and Bai.
KEYWORDS:
RNA editing; bioinformatics; hepatocellular carcinoma; post-transcriptional regulation; prognosis
79.
Front Oncol. 2020 Feb 14;10:36. doi: 10.3389/fonc.2020.00036. eCollection 2020.
High Expression of Integrin α3 Predicts Poor Prognosis and Promotes Tumor Metastasis and Angiogenesis by Activating the c-Src/Extracellular Signal-Regulated Protein Kinase/Focal Adhesion Kinase Signaling Pathway in Cervical Cancer.
Abstract
Background: Cervical cancer remains a leading cause of death in women due to metastasis to distant tissues and organs. Integrins are involved in cancer metastasis. However, whether integrin α3 participates in cervical cancer metastasis is under investigation. In this study, we explored the effect and detailed mechanism through which integrin α3 regulates cervical cell migration, invasion, and angiogenesis. Methods: First, we explored the mRNA and protein expression levels of integrin α3 in cervical cancer cell lines and tissue samples obtained from patients. After knocking down the expression of integrin α3 using shRNA, the proliferation, migration, and invasion of cervical cancer cells, as well as the possible signaling pathways involved, were investigated in vitro. In addition, tube formation, proliferation, and migration of human umbilical vein endothelial cells were tested to identify their effect on angiogenesis. Zebrafish tumor migration and nude mouse lung metastasis models were utilized for the in vivo analysis. Results: We examined samples from 142 patients with cervical cancer and 20 normal cervixes. Integrin α3 was highly expressed in patients and predicted poor overall survival and disease-free survival. In SiHa cells, treatment with integrin α3 shRNA induced the phosphorylation of protein focal adhesion kinase and enhanced focal adhesion. These events were mediated by the activation of c-Src and extracellular signal-regulated protein kinase cascades. Consequently, integrin α3 increased the migratory ability of SiHa cells. In addition, knockdown of integrin α3 decreased the tube formation, proliferation, and migration of human umbilical vein endothelial cells, as well as the levels of matrix metalloproteinase-9, indicating its effect on angiogenesis. Stable transfection with integrin α3 shRNA reduced the migratory ability of SiHa cells in the zebrafish model and diminished lung metastasis in the xenograft mouse model. Conclusion: Integrin α3 recruits the c-Src/extracellular signal-regulated protein kinase cascade, leading to phosphorylation of focal adhesion kinase. Moreover, it regulates focal adhesion, endowing cervical cancer cells with potentiated migratory and invasive ability, and promotes angiogenesis via matrix metalloproteinase-9. Our findings may shed light on the mechanism involved in cervical cancer metastasis and highlight integrin α3 as a candidate prognostic biomarker and therapeutic target in patients with cervical cancer.
Copyright © 2020 Du, Wang, Liu, Shang, Huang, Liao, Qin, Chen, Liu, Liu and Yao.
KEYWORDS:
angiogenesis; cervical cancer; focal adhesion kinase; integrin α3; metastasis
80.
Front Oncol. 2020 Feb 14;10:35. doi: 10.3389/fonc.2020.00035. eCollection 2020.
Long Non-coding Wilms Tumor 1 Antisense RNA in the Development and Progression of Malignant Tumors.
Abstract
A growing number of studies have shown that long non-coding RNAs (lncRNAs) play an important role in tumor development and progression and are key molecules affecting tumor progression. The lncRNA Wilms tumor 1 antisense RNA (WT1-AS) is specifically expressed in various malignant tumors. In particular, WT1-AS expression is upregulated in colon cancer and breast cancer but is significantly downregulated in cervical cancer, liver cancer, and kidney cancer. The level of WT1-AS expression is closely related to the size, stage, and patient survival rate of these cancers. In this article, we review the modes of action, expression, function, and mechanisms of WT1-AS in different tumors to provide new targets for tumor diagnosis and treatment.
Copyright © 2020 Zhang, Fan, Zhang, Jiang and Qi.
KEYWORDS:
Wilms tumor 1 antisense RNA; expression; function; long non-coding RNA; tumor
81.
Front Oncol. 2020 Feb 4;10:33. doi: 10.3389/fonc.2020.00033. eCollection 2020.
PLXNC1 Enhances Carcinogenesis Through Transcriptional Activation of IL6ST in Gastric Cancer.
Abstract
Background: Transcriptional factors (TFs) are responsible for orchestrating gene transcription during cancer progression. However, their roles in gastric cancer (GC) remain unclear. Methods: We analyzed the differential expressions of TFs and, using GC cells and tissues, investigated plexin C1 (PLXNC1) RNA levels, as well as PLXNC1's clinical relevance and functional mechanisms. The molecular function of PLXNC1 was evaluated in vitro and in vivo. Kaplan-Meier curves and the log-rank test were used to analyze overall survival (OS) and disease-free survival (DFS). Results: PLXNC1 was frequently up-regulated in GC and associated with poor prognosis. The expression level of PLXNC1 could serve as an independent biomarker to predict a patient's overall survival. Notably, knockdown of PLXNC1 significantly abolished GC cell proliferation, and migration, and overexpression of PLXNC1 accelerated carcinogenesis in GC. The gene set enrichment analysis (GSEA) indicated that high-expression of PLXNC1 was positively correlated with the activation of epithelial-mesenchymal transition (EMT), TNF-α, and IL-6/STAT3 signaling pathways. PLXNC1 promoted proliferation and migration of GC cells through transcriptional activation of the interleukin 6 signal transducer (IL6ST), which could rescue the malignant behavior of PLXNC1-deficient GC cells. Conclusions: Our study demonstrated that the PLXNC1 plays an oncogenic role in GC patients. The PLXNC1-IL6ST axis represents a novel potential therapeutic target for GC.
Copyright © 2020 Chen, Liu, Chen, Sun, Wu and Du.
KEYWORDS:
IL6ST; PLXNC1; carcinogenesis; gastric cancer; transcriptional factor
82.
Front Oncol. 2020 Feb 5;10:29. doi: 10.3389/fonc.2020.00029. eCollection 2020.
Thermal Intravesical Chemotherapy Reduce Recurrence Rate for Non-muscle Invasive Bladder Cancer Patients: A Meta-Analysis.
Abstract
Background: Non-muscle invasive bladder cancer accounts for nearly 80% of newly diagnosed bladder cancer cases, which often recur and progress. This meta-analysis was evaluated by the adverse events and recurrence rate of thermal intravesical chemotherapy vs. normal temperature intravesical chemotherapy in the treatment of non-muscle invasive bladder cancer. Methods: A systematic review and cumulative analysis of studies reporting adverse events and recurrence rate of thermal intravesical chemotherapy vs. normal temperature intravesical chemotherapy was performed through a comprehensive search of Pubmed, Embase, Cochranelibrary.com, CNKI, Wanfang Med Online database and VIP database. All analyses were performed using the Revman manager 5. Result: Twelve studies (11 randomized controlled trials and 1 retrospective study) including 888 patients, 445 in the thermal intravesical chemotherapy group, and 443 in the normal temperature intravesical chemotherapy group, met the eligibility criteria. Patients in the thermal intravesical chemotherapy group had a lower risk of disease recurrence than those who had normal temperature intravesical chemotherapy (24 months follow-up group: RR = 0.30, 95% CI: 0.21-0.43, P < 0.00001, I 2 = 0%; 36 months follow-up group: RR = 0.27, 95% CI: 0.14-0.54, P = 0.0002, I 2 = 0%) while no significant difference in adverse events rate (RR = 0.89, 95% CI = 0.53-1.52; P = 0.67, I 2 = 78%). Conclusions: When compared with normal temperature intravesical chemotherapy, thermal intravesical chemotherapy can reduce the recurrence rate without increasing incidence of adverse events in patients with non-muscle invasive bladder cancer.
Copyright © 2020 Liu, Zhu, Song, Wang, Zhou, Lu and Liu.
KEYWORDS:
external thermal field thermotherapy; hyperthermic intravesical chemotherapy; meta-analysis; non-muscle invasive bladder cancer; normal temperature intravesical chemotherapy; thermal intravesical chemotherapy
83.
Front Oncol. 2020 Feb 11;10:27. doi: 10.3389/fonc.2020.00027. eCollection 2020.
Concordance of Hormone Receptor Status and BRCA1/2 Mutation Among Women With Synchronous Bilateral Breast Cancer.
Abstract
Goals: BRCA1/2 mutations are associated with bilateral breast cancer. The extent of concordance between synchronous bilateral breast cancer (SBBC) tumors with respect to hormone receptor expression and BRCA1/2 mutations is unknown. We investigated the distribution of BRCA1/2 mutations and bilateral estrogen receptor (ER) status in SBBC. Methods: A retrospective analysis was performed on 15,337 patients with primary breast cancer who underwent surgical treatment at the Fudan University Shanghai Cancer Center between 2007 and 2014. We included 163 patients with synchronous bilateral breast cancer who had germline BRCA1/2 mutations testing. BRCA1/2 pathogenic/likely pathogenic mutations and other clinicopathological characteristics were studied in further analyses. Results: Patients with SBBC developed breast cancer at an older age and had a higher rate of ER positivity than patients with UBC (p < 0.001, separately). In contrast, 14.1% of SBBC patients had carcinomas with a lobular component in either breast based on pathological reports (p < 0.001). Twelve patients had BRCA1 mutations, and 14 patients had BRCA2 mutations, while no patients had mutations in both genes. The BRCA1/2 mutation rate was higher in younger patients (23.4 vs. 11.1%, p = 0.036). SBBC patients with a family history of breast cancer or bilateral ER-negative disease had a higher frequency of BRCA1/2 mutations than the cohort without a history of these conditions. SBBC with a bilateral ER-discordant status had a very low frequency of BRCA1/2 mutations (5.6%). Patients with an ER-positive (concordant or discordant) status had better 3-year disease-free survival than patients with a concordant ER-negative status (HR = 0.324, 95% CI: 0.126-0.837, P = 0.020). However, the outcomes were similar during long-term follow-up. Pathological lymph node stage was the only prognostic factor for SBBC in both univariate and multivariate Cox analyses. Conclusions: Our study shows that Chinese women with SBBC have different characteristics from their UBC counterparts. SBBC patients with a younger age, family history of breast cancer, or bilateral ER-negative disease are more likely to have BRCA1/2 mutations. SBBC patients with a concordant ER-negative status had worse early outcomes. Our results suggest that there may be additional factors underlying the tumor biology and genetics of SBBC.
Copyright © 2020 Huang, Liu, Lang, Cao and Shao.
KEYWORDS:
BRCA1/2 mutation; DFS; concordance; hormone receptor status; synchronous bilateral breast cancer
84.
Front Oncol. 2020 Feb 7;10:20. doi: 10.3389/fonc.2020.00020. eCollection 2020.
SPECT-CT Imaging of Dog Spontaneous Diffuse Large B-Cell Lymphoma Targeting CD22 for the Implementation of a Relevant Preclinical Model for Human.
Etienne F1,2, Berthaud M1, Nguyen F1,2, Bernardeau K1,3, Maurel C1, Bodet-Milin C1,4, Diab M1, Abadie J1,2, Gouilleux-Gruart V5, Vidal A6, Bourgeois M1,6, Chouin N1,2, Ibisch C1,2, Davodeau F1.
Abstract
Antibodies directed against CD22 have been used in radioimmunotherapy (RIT) clinical trials to treat patients with diffuse large B-cell lymphoma (DLBCL) with promising results. However, relevant preclinical models are needed to facilitate the evaluation and optimization of new protocols. Spontaneous DLBCL in dogs is a tumor model that may help accelerate the development of new methodologies and therapeutic strategies for RIT targeting CD22. Seven murine monoclonal antibodies specific for canine CD22 were produced by the hybridoma method and characterized. The antibodies' affinity and epitopic maps, their internalization capability and usefulness for diagnosis in immunohistochemistry were determined. Biodistribution and PET imaging on a mouse xenogeneic model of dog DLBCL was used to choose the most promising antibody for our purposes. PET-CT results confirmed biodistribution study observations and allowed tumor localization. The selected antibody, 10C6, was successfully used on a dog with spontaneous DLBCL for SPECT-CT imaging in the context of disease staging, validating its efficacy for diagnosis and the feasibility of future RIT assays. This first attempt at phenotypic imaging on dogs paves the way to implementing quantitative imaging methodologies that would be transposable to humans in a theranostic approach. Taking into account the feedback of existing human radioimmunotherapy clinical trials targeting CD22, animal trials are planned to investigate protocol improvements that are difficult to consider in humans due to ethical concerns.
Copyright © 2020 Etienne, Berthaud, Nguyen, Bernardeau, Maurel, Bodet-Milin, Diab, Abadie, Gouilleux-Gruart, Vidal, Bourgeois, Chouin, Ibisch and Davodeau.
KEYWORDS:
CD22; SPECT-CT imaging; comparative oncology; diffuse large B-cell lymphoma; dog; internalization; monoclonal antibody
85.
Front Oncol. 2020 Jan 24;10:18. doi: 10.3389/fonc.2020.00018. eCollection 2020.
Endothelial Phosphatase VE-PTP Participates in Vasculogenic Mimicry by Preventing Autophagic Degradation of VE-Cadherin.
Abstract
Aberrant extra-vascular expression of VE-cadherin has been observed in metastasis associated with Vasculogenic Mimicry (VM); we have recently shown that in VM prone cells VE-cadherin is mainly in the form of phospho-VE-cadherin in Y658 allowing increased plasticity that potentiates VM development in malignant cells. In the current study, we present results to show that human malignant melanoma cells VM+, express the VE-cadherin phosphatase VE-PTP. VE-PTP forms a complex with VE-Cadherin and p120-catenin and the presence of this complex act as a safeguard to prevent VE-Cadherin protein degradation by autophagy. Indeed, VE-PTP silencing results in complete degradation of VE-cadherin with the features of autophagy. In summary, this study shows that VE-PTP is involved in VM formation and disruption of VE-PTP/VE-Cadherin/p120 complex results in enhanced autophagy in aggressive VM+ cells. Thus, we identify VE-PTP as a key player in VM development by regulating VE-cadherin protein degradation through autophagy.
Copyright © 2020 Delgado-Bellido, Bueno-Galera, López-Jiménez, Garcia-Diaz and Oliver.
KEYWORDS:
VE-PTP; VE-cadherin; autophagy; melanoma; vascular endothelial receptor protein tyrosine phosphatase; vasculogenic mimicry (VM)
86.
Front Oncol. 2020 Feb 4;10:17. doi: 10.3389/fonc.2020.00017. eCollection 2020.
Oncogenic Role of PVT1 and Therapeutic Implications.
Abstract
PVT1, a long non-coding RNA has been implicated in a variety of human cancers. Recent advancements have led to increasing discovery of the critical roles of PVT1 in cancer initiation and progression. Novel insight is emerging about PVT1's mechanism of action in different cancers. Identifying and understanding the variety of activities of PVT1 involved in cancers is a necessity for the development of PVT1 as a diagnostic biomarker or therapeutic target in cancers where PVT1 is dysregulated. PVT1's varied activities include overexpression, modulation of miRNA expression, protein interactions, targeting of regulatory genes, formation of fusion genes, functioning as a competing endogenous RNA (ceRNA), and interactions with MYC, among many others. Furthermore, bioinformatic analysis of PVT1 interactions in cancers has aided understanding of the numerous pathways involved in PVT1 contribution to carcinogenesis in a cancer type-specific manner. However, these recent findings show that there is much more to be learned to be able to fully exploit PVT1 for cancer prognostication and therapy. In this review, we summarize some of the latest findings on PVT1's oncogenic activities, signaling networks and how targeting these networks can be a strategy for cancer therapy.
Copyright © 2020 Onagoruwa, Pal, Ochu and Ogunwobi.
KEYWORDS:
PVT1; cell cycle; molecular signaling; oncogene; therapeutic target
87.
Front Oncol. 2020 Feb 11;10:12. doi: 10.3389/fonc.2020.00012. eCollection 2020.
Tyrosine Kinase Inhibitor Resistance Increased the Risk of Cerebral Radiation Necrosis After Stereotactic Radiosurgery in Brain Metastases of Non-small-Cell Lung Cancer: A Multi-Institutional Retrospective Case-Control Study.
Abstract
Objective: This study aimed to investigate the relationship between the timing of stereotactic radiosurgery (SRS) intervention and the complications of cerebral radiation necrosis (CRN) in patients with brain metastases of lung adenocarcinoma who received tyrosine kinase inhibitor (TKI) treatment. Methods: A total of 361 targets from 257 patients with brain oligometastases of lung adenocarcinoma who received CyberKnife treatment between 2010 and 2017 were retrospectively collected from three CyberKnife centers. The difference in brain necrosis between patients with or without TKI application was statistically counted. Logistic regression analysis was used to analyze the effect of applying TKI on the occurrence of CRN in patients and the effect of SRS before and after TKI resistance on CRN. Results: The rate of CRN in the TKI group was significantly higher than that in the non-TKI group. The incidence of brain necrosis in patients undergoing SRS after drug resistance was significantly higher than that in patients undergoing SRS before drug resistance. Regression analysis showed that combination of TKI with SRS, and SRS after TKI resistance were important influencing factors for CRN. Conclusion: Performing the SRS for brain metastases after TKI resistance worsened the occurrence of CRN of patients treated with TKI. Clinical Trial Registration: Chinese clinical trial registry, http://www.chictr.org.cn/edit.aspx?pid=38395&htm=4, Registration number: ChiCTR1900022750.
Copyright © 2020 Zhuang, Tao, Wang, Shi, Yuan, Wang and Chang.
KEYWORDS:
brain metastasis; cerebral radiation necrosis; epidermal growth factor receptor; stereotactic radiosurgery; tyrosine kinase inhibitor
88.
Front Oncol. 2020 Feb 11;10:8. doi: 10.3389/fonc.2020.00008. eCollection 2020.
CDX2: A Prognostic Marker in Metastatic Colorectal Cancer Defining a Better BRAF Mutated and a Worse KRAS Mutated Subgroup.
Aasebø K1, Dragomir A2,3, Sundström M2,3, Mezheyeuski A3, Edqvist PH3, Eide GE4,5, Ponten F3,6, Pfeiffer P7, Glimelius B3, Sorbye H1,8.
Abstract
Background: Survival of metastatic colorectal cancer (mCRC) patients has improved, but mainly for trial patients. New predictive and prognostic biomarkers validated in the general mCRC population are needed. Caudal-type homeobox 2 (CDX2) is an intestine-specific transcription factor with potential prognostic and predictive effect, but the importance in mCRC has not been fully investigated. Methods: Immunohistochemistry analysis of CDX2 was performed in a Scandinavian population-based cohort of mCRC (n = 796). Frequency, clinical and tumor characteristics, response rate, progression-free survival, and overall survival (OS) were estimated. Results: Loss of CDX2 expression was found in 87 (19%) of 452 stained cases, in 53% if BRAF mutated (BRAFmut) and in 9% if KRAS mutated (KRASmut). CDX2 loss was associated with microsatellite instability, BRAFmut, and poor differentiation and inversely associated with KRASmut. Patients with CDX2 loss received less first-line (53 vs. 64%, p = 0.050) and second-line (23 vs. 39%, p = 0.006) chemotherapy and secondary surgery (1 vs. 9%, p = 0.019). Median progression-free survival and OS for patients given first-line combination chemotherapy was 4 and 10 months if CDX2 loss vs. 9 and 24 months if CDX2 expressed (p = 0.001, p < 0.001). Immediate progression on first-line combination chemotherapy was seen in 35% of patients with CDX2 loss vs. 10% if CDX2 expressed (p = 0.003). Median OS in patients with BRAFmut or KRASmut and CDX2 expressed in tumor (both 21 months) was comparable to wild-type patients (27 months). However, if CDX2 loss, median OS was only 8 and 11 months in BRAFmut and KRASmut cases, respectively, and 10 months in double wild-type patients. In multivariate analysis, CDX2 loss (hazard ratio: 1.50, p = 0.027) and BRAFmut (hazard ratio: 1.62, p = 0.012) were independent poor prognostic markers for OS. Conclusion: In a population-based cohort of mCRC patients, CDX2 loss is an independent poor prognostic marker. Expression of CDX2 defines a new subgroup of BRAFmut cases with a much better prognosis. Loss of CDX2 defines a small group of KRASmut cases with a worse prognosis. Patients with CDX2 loss receive less palliative chemotherapy with less benefit and rarely reach secondary surgery.
Copyright © 2020 Aasebø, Dragomir, Sundström, Mezheyeuski, Edqvist, Eide, Ponten, Pfeiffer, Glimelius and Sorbye.
KEYWORDS:
CDX2; caudal type homeobox transcription factor; colorectal cancer; metastatic disease; population based; prognosis; stage 4 colorectal cancer
89.
Front Oncol. 2020 Feb 11;10:4. doi: 10.3389/fonc.2020.00004. eCollection 2020.
Hypofractionated Irradiation Suppressed the Off-Target Mouse Hepatocarcinoma Growth by Inhibiting Myeloid-Derived Suppressor Cell-Mediated Immune Suppression.
Chen J1,2, Wang Z1,2, Ding Y1,2, Huang F1,2, Huang W1,2, Lan R1,2, Chen R1,2, Wu B1,2, Fu L1,2, Yang Y3, Liu J1,2, Hong J1,2, Zhang W1,2, Zhang L4.
Abstract
Background: Stereotactic radiotherapy treats hepatocellular carcinoma (HCC) at different stages effectively and safely. Besides its direct killing of cancer cells, radiotherapy stimulates host immunity against hepatoma. However, the role of myeloid-derived suppressor cells (MDSCs) in on-target and off-target anti-HCC effects induced by hypofractionated irradiation (IR) is unclear. Methods and Materials: Hepa1-6 and H22 allogeneic transplanted tumors on hind limbs of C57BL/6 and Institute of Cancer Research (ICR) mice, respectively, were irradiated with 0, 2.5, 4, 6, or 8 Gy/fraction until the total dose reached 40 Gy. The off-target effect induced by the IR was investigated by subsequently inoculating the same HCC cells subcutaneously on the abdomen. MDSCs in peripheral blood and tumor tissues were measured by flow cytometry or immunofluorescence microscopy analysis. IL-6, regulated on activation normal T cell expressed and secreted (RANTES), and granulocyte colony-stimulating factor (G-CSF) in irradiated mouse plasma and hepatoma cell cultures were measured with ELISA kits. Conditioned media (CM) from irradiated HCC cell cultures on bone marrow cell differentiation and MDSC proliferation were examined by co-culture and flow cytometry. Results: Our study showed that the IR of primarily inoculated HCC on hind limbs created an "in situ tumor vaccine" and triggered the antitumor immunity. The immunity was capable of suppressing the growth of the same type of HCC subcutaneously implanted on the abdomen, accompanied with reduced MDSCs in both blood and tumors. The decreased MDSCs were associated with low plasma levels of IL-6, RANTES, and G-CSF. The cytokines IL-6 and RANTES in the CM were lower in the high single IR dose group than in the control groups, but G-CSF was higher. The CM from high single-dose IR-Hepa1-6 cell culture reduced the differentiation of C57BL/6 mouse bone marrow cells into MDSCs, whereas CM from high single-dose IR-H22 cells reduced the proliferation of MDSCs, which might be due to the decreased p-STAT3 in bone marrow cells. Conclusions: The hypofractionated IR on transplanted tumors at the primary location exerted a strong antitumor effect on the same tumor at a different location (off target). This abscopal effect is most likely through the reduction of MDSCs and decrease of IL-6, RANTES, and G-CSF.
Copyright © 2020 Chen, Wang, Ding, Huang, Huang, Lan, Chen, Wu, Fu, Yang, Liu, Hong, Zhang and Zhang.
KEYWORDS:
hepatocellular carcinoma; high-dose low-fraction radiation; in situ tumor vaccine; myeloid-derived suppressor cells; negative immune breaker
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