1
Review Front Oncol
. 2020 Jun 11;10:935. doi: 10.3389/fonc.2020.00935. eCollection 2020.
Shp1 in Solid Cancers and Their Therapy
Alessia Varone 1, Daniela Spano 1, Daniela Corda 1 2
Affiliations expand
PMID: 32596156 PMCID: PMC7300250 DOI: 10.3389/fonc.2020.00935
Free PMC article
Abstract
Shp1 is a cytosolic tyrosine phosphatase that regulates a broad range of cellular functions and targets, modulating the flow of information from the cell membrane to the nucleus. While initially studied in the hematopoietic system, research conducted over the past years has expanded our understanding of the biological role of Shp1 to other tissues, proposing it as a novel tumor suppressor gene functionally involved in different hallmarks of cancer. The main mechanism by which Shp1 curbs cancer development and progression is the ability to attenuate and/or terminate signaling pathways controlling cell proliferation, survival, migration, and invasion. Thus, alterations in Shp1 function or expression can contribute to several human diseases, particularly cancer. In cancer cells, Shp1 activity can indeed be affected by mutations or epigenetic silencing that cause failure of Shp1-mediated homeostatic maintenance. This review will discuss the current knowledge of the cellular functions controlled by Shp1 in non-hematopoietic tissues and solid tumors, the mechanisms that regulate Shp1 expression, the role of its mutation/expression status in cancer and its value as potential target for cancer treatment. In addition, we report information gathered from the public available data from The Cancer Genome Atlas (TCGA) database on Shp1 genomic alterations and correlation with survival in solid cancers patients.
Keywords: Shp1; TCGA; cancer; cancer therapy; signaling; tyrosine phosphatase.
Copyright © 2020 Varone, Spano and Corda.
104 references1 figure
supplementary info
Publication typesexpand
full-text links
full-text provider logo
Proceed to details Cite
Share
2
Review Front Oncol
. 2020 Jun 12;10:957. doi: 10.3389/fonc.2020.00957. eCollection 2020.
The Roles of Glycans in Bladder Cancer
Yuli Jian 1, Zhongyang Xu 1, Chunyan Xu 1, Lin Zhang 1, Xiaoxin Sun 1, Deyong Yang 2, Shujing Wang 1
Affiliations expand
PMID: 32596162 PMCID: PMC7303958 DOI: 10.3389/fonc.2020.00957
Free PMC article
Abstract
Bladder cancer is one of the most common malignant tumors of the urogenital system with high morbidity and mortality worldwide. Early diagnosis and personalized treatment are the keys to successful bladder cancer treatment. Due to high postoperative recurrence rates and poor prognosis, it is urgent to find suitable therapeutic targets and biomarkers. Glycans are one of the four biological macromolecules in the cells of an organism, along with proteins, nucleic acids, and lipids. Glycans play important roles in nascent peptide chain folding, protein processing, and translation, cell-to-cell adhesion, receptor-ligand recognition, and binding and cell signaling. Glycans are mainly divided into N-glycans, O-glycans, proteoglycans, and glycosphingolipids. The focus of this review is the discussion of glycans related to bladder cancer. Additionally, this review also addresses the clinical value of glycans in the diagnosis and treatment of bladder cancer. Abnormal glycans are likely to be potential biomarkers for bladder cancer.
Keywords: abnormal glycosylation; biomarkers; bladder cancer; glycans; glycosyltransferases.
Copyright © 2020 Jian, Xu, Xu, Zhang, Sun, Yang and Wang.
75 references2 figures
supplementary info
Publication typesexpand
full-text links
full-text provider logo
Proceed to details Cite
Share
3
Review Front Oncol
. 2020 Jun 12;10:819. doi: 10.3389/fonc.2020.00819. eCollection 2020.
Integrating Loco-Regional Hyperthermia Into the Current Oncology Practice: SWOT and TOWS Analyses
Niloy R Datta 1, H Petra Kok 2, Hans Crezee 2, Udo S Gaipl 3, Stephan Bodis 1
Affiliations expand
PMID: 32596144 PMCID: PMC7303270 DOI: 10.3389/fonc.2020.00819
Free PMC article
Abstract
Moderate hyperthermia at temperatures between 40 and 44°C is a multifaceted therapeutic modality. It is a potent radiosensitizer, interacts favorably with a host of chemotherapeutic agents, and, in combination with radiotherapy, enforces immunomodulation akin to "in situ tumor vaccination." By sensitizing hypoxic tumor cells and inhibiting repair of radiotherapy-induced DNA damage, the properties of hyperthermia delivered together with photons might provide a tumor-selective therapeutic advantage analogous to high linear energy transfer (LET) neutrons, but with less normal tissue toxicity. Furthermore, the high LET attributes of hyperthermia thermoradiobiologically are likely to enhance low LET protons; thus, proton thermoradiotherapy would mimic 12C ion therapy. Hyperthermia with radiotherapy and/or chemotherapy substantially improves therapeutic outcomes without enhancing normal tissue morbidities, yielding level I evidence reported in several randomized clinical trials, systematic reviews, and meta-analyses for various tumor sites. Technological advancements in hyperthermia delivery, advancements in hyperthermia treatment planning, online invasive and non-invasive MR-guided thermometry, and adherence to quality assurance guidelines have ensured safe and effective delivery of hyperthermia to the target region. Novel biological modeling permits integration of hyperthermia and radiotherapy treatment plans. Further, hyperthermia along with immune checkpoint inhibitors and DNA damage repair inhibitors could further augment the therapeutic efficacy resulting in synthetic lethality. Additionally, hyperthermia induced by magnetic nanoparticles coupled to selective payloads, namely, tumor-specific radiotheranostics (for both tumor imaging and radionuclide therapy), chemotherapeutic drugs, immunotherapeutic agents, and gene silencing, could provide a comprehensive tumor-specific theranostic modality akin to "magic (nano)bullets." To get a realistic overview of the strength (S), weakness (W), opportunities (O), and threats (T) of hyperthermia, a SWOT analysis has been undertaken. Additionally, a TOWS analysis categorizes future strategies to facilitate further integration of hyperthermia with the current treatment modalities. These could gainfully accomplish a safe, versatile, and cost-effective enhancement of the existing therapeutic armamentarium to improve outcomes in clinical oncology.
Keywords: SWOT analysis; chemotherapy; clinical trials; hyperthermia; hyperthermia treatment planning; immunotherapy; radiation therapy; radiosensitizer.
Copyright © 2020 Datta, Kok, Crezee, Gaipl and Bodis.
343 references9 figures
supplementary info
Publication typesexpand
full-text links
full-text provider logo
Proceed to details Cite
Share
4
Review Front Oncol
. 2020 Jun 12;10:930. doi: 10.3389/fonc.2020.00930. eCollection 2020.
Quality of Life, Toxicity and Unmet Needs in Nasopharyngeal Cancer Survivors
Lachlan McDowell 1 2, June Corry 3 4, Jolie Ringash 5, Danny Rischin 2 6
Affiliations expand
PMID: 32596155 PMCID: PMC7303258 DOI: 10.3389/fonc.2020.00930
Free PMC article
Abstract
Concerted research efforts over the last three decades have resulted in improved survival and outcomes for patients diagnosed with nasopharyngeal carcinoma (NPC). The evolution of radiotherapy techniques has facilitated improved dose delivery to target volumes while reducing dose to the surrounding normal tissue, improving both disease control and quality of life (QoL). In parallel, clinical trials focusing on determining the optimal systemic therapy to use in conjunction with radiotherapy have been largely successful, resulting in improved locoregional, and distant control. As a consequence, neoadjuvant chemotherapy (NACT) prior to definitive chemoradiotherapy has recently emerged as the preferred standard for patients with locally advanced NPC. Two of the major challenges in interpreting toxicity and QoL data from the published literature have been the reliance on: (1) clinician rather than patient reported outcomes; and (2) reporting statistical rather than clinical meaningful differences in measures. Despite the lower rates of toxicity that have been achieved with highly conformal radiotherapy techniques, survivors remain at moderate risk of persistent and long-lasting treatment effects, and the development of late radiation toxicities such as hearing loss, cranial neuropathies and cognitive impairment many years after successful treatment can herald a significant decline in QoL. Future approaches to reduce long-term toxicity will rely on: (1) identifying individual patients most likely to benefit from NACT; (2) development of response-adapted radiation strategies following NACT; and (3) anticipated further dose reductions to organs at risk with proton and particle therapy. With increasing numbers of survivors, many in the prime of their adult life, research to identify, and strategies to address the unmet needs of NPC survivors are required. This contemporary review will summarize our current knowledge of long-term toxicity, QoL and unmet needs of this survivorship group.
Keywords: chemotherapy; nasopharyngeal carcinoma; quality of life; radiotherapy; survivorship; toxicity; unmet needs.
Copyright © 2020 McDowell, Corry, Ringash and Rischin.
128 references
supplementary info
Publication typesexpand
full-text links
full-text provider logo
Proceed to details Cite
Share
5
Review Front Oncol
. 2020 Jun 11;10:928. doi: 10.3389/fonc.2020.00928. eCollection 2020.
A Potential Role of YAP/TAZ in the Interplay Between Metastasis and Metabolic Alterations
Hirohito Yamaguchi 1, Ghina M Taouk 1
Affiliations expand
PMID: 32596154 PMCID: PMC7300268 DOI: 10.3389/fonc.2020.00928
Free PMC article
Abstract
Yes-Associated Protein (YAP) and Transcriptional Co-activator with PDZ-binding Motif (TAZ) are the downstream effectors of the Hippo signaling pathway that play a crucial role in various aspects of cancer progression including metastasis. Metastasis is the multistep process of disseminating cancer cells in a body and responsible for the majority of cancer-related death. Emerging evidence has shown that cancer cells reprogram their metabolism to gain proliferation, invasion, migration, and anti-apoptotic abilities and adapt to various environment during metastasis. Moreover, it has increasingly been recognized that YAP/TAZ regulates cellular metabolism that is associated with the phenotypic changes, and recent studies suggest that the YAP/TAZ-mediated metabolic alterations contribute to metastasis. In this review, we will introduce the latest knowledge of YAP/TAZ regulation and function in cancer metastasis and metabolism, and discuss possible links between the YAP/TAZ-mediated metabolic reprogramming and metastasis.
Keywords: TAZ; YAP; cancer; metabolism; metastasis.
Copyright © 2020 Yamaguchi and Taouk.
189 references6 figures
supplementary info
Publication typesexpand
full-text links
full-text provider logo
Proceed to details Cite
Share
6
Front Oncol
. 2020 Jun 12;10:807. doi: 10.3389/fonc.2020.00807. eCollection 2020.
Lactic Acidosis in the Presence of Glucose Diminishes Warburg Effect in Lung Adenocarcinoma Cells
Heriberto Prado-Garcia 1, Andrea Campa-Higareda 1, Susana Romero-Garcia 1
Affiliations expand
PMID: 32596143 PMCID: PMC7303336 DOI: 10.3389/fonc.2020.00807
Free PMC article
Abstract
Lactic acidosis (3 to 40 mM, pH < 6.9) is a condition found in solid tumors because tumor cells have a high rate of glucose consumption and lactate production even in the presence of oxygen; nevertheless, the microenvironment might still provide a sufficient glucose supply. Lactic acidosis has been proposed to shift metabolism from aerobic glycolysis toward oxidative phosphorylation (OXPHOS). We tested if lung tumor cells cultured under lactic acidosis shift their metabolism from glycolysis to OXPHOS by consuming extracellular lactate, increasing growth rate. We analyzed lung adenocarcinoma (A-549, A-427) cell lines and non-transformed fibroblast cells (MRC-5), which were cultured using RPMI-1640 medium initially containing lactate (2 mM) and glucose (10 mM), at pH 7.2 or 6.2 and oxygen tension 21% O2 (normoxia) or 2% O2 (hypoxia). We obtained growth curves, as well as glucose consumption and lactate production rates (measured during exponential growth) for each cell line. HIF-1α (Hypoxia-inducible factor 1 α), CS (citrate synthase) and AMPK (AMP-activated protein kinase) transcript levels were analyzed using RT-qPCR. By flow cytometry, we determined: (a) expression of glucose transporters (GLUT)1 and 4; (b) lactate transporters (MCT)1 and 4; (c) cell cycle profile, and (d) protein levels of HIF-1α, total and phosphorylated AMPK (pAMPK). Mitochondrial functionality was evaluated by measuring O2 consumption in tumor cells using polarography and a Clark-type electrode. Tumor and non-transformed cells used both aerobic glycolysis and OXPHOS for obtaining energy. As of 48 h of culture, lactate levels ranged from (4.5-14 mM), thus forming a lactic environment. Lactic acidosis diminished GLUT1/GLUT4 expression and glucose consumption in A-549, but not in A-427 cells, and induced differential expression of HIF-1α, AMPK, and CS transcripts. A-427 cells increased pAMPK and HIF-1α levels and shifted their metabolism increasing OXPHOS; thus supporting cell growth. Conversely, A-549 cells increased HIF-1α protein levels, but did not activate AMPK and diminished OXPHOS. A-549 cells survived by arresting cells in G1-phase. Our findings show that lactic acidosis diminishes Warburg effect in tumor cells, but this change does not necessarily promote a shift to OXPHOS. Hence, lung adenocarcinomas show a differential metabolic response even when they are under the same microenvironmental conditions.
Keywords: aerobic glycolysis; mitochondrial function; oxidative metabolism; tumor metabolic shift; tumor metabolic symbiosis.
Copyright © 2020 Prado-Garcia, Campa-Higareda and Romero-Garcia.
30 references6 figures
full-text links
full-text provider logo
Proceed to details Cite
Share
7
Front Oncol
. 2020 Jun 11;10:855. doi: 10.3389/fonc.2020.00855. eCollection 2020.
Early Detection of Non-Small Cell Lung Cancer by Using a 12-microRNA Panel and a Nomogram for Assistant Diagnosis
Weidong Wang 1 2 3, Dongni Chen 1 2, Weiwei Chen 1 2, Ziya Xin 1 2, Zirui Huang 1 2, Xuewen Zhang 2 4, Kexing Xi 5, Gongming Wang 1 2, Rusi Zhang 1 2, Dechang Zhao 1 2, Li Liu 1 2, Lanjun Zhang 1 2
Affiliations expand
PMID: 32596148 PMCID: PMC7301755 DOI: 10.3389/fonc.2020.00855
Free PMC article
Abstract
Background: We previously identified a 12-microRNA (miRNA) panel (miRNA-17, miRNA-146a, miRNA-200b, miRNA-182, miRNA-155, miRNA-221, miRNA-205, miRNA-126, miRNA-7, miRNA-21, miRNA-145, and miRNA-210) that aided in the early diagnosis of non-small cell lung cancer (NSCLC). We validated the diagnostic value of this miRNA panel and compared it with that of traditional tumor markers and radiological diagnosis. We constructed a nomogram based on the miRNA panel's results to predict the risk of NSCLC. Methods: Eighty-two participants with pulmonary nodules on a CT scan and who underwent a pathological examination and surgical treatment were enrolled in our study. Patients were randomly divided into a training group or a validation group. The miRNA concentrations were quantified by RT-PCR and log-transformed for analysis. The cutoff value was determined in the training group and then applied in the validation group. A comparison between the miRNAs and traditional tumor markers [CEA, NSE, and cytokeratin 19 fragment 21-1 (Cyfra21-1)] and radiological diagnosis was performed. A nomogram based on the miRNA panel's results to predict the risk of NSCLC was constructed. Results: The expression level of these 12 miRNAs was significantly higher in NSCLC patients than in benign patients. In the validation group, the specificity and positive predictive value were 96.4 and 95.8%, respectively, which were significantly higher than those using traditional tumor markers or radiological diagnosis. The sensitivity was 42.6%, which was also higher than that using tumor markers. Moreover, the sensitivity increased to 63.6% when the nodule diameters were larger than 2 cm. The miRNAs and seven clinical factors were integrated into the nomogram, and the calibration curves showed optimal agreement between the predicted and actual probabilities. Conclusions: Our miRNA panel has clinical value for the early detection of NSCLC. A nomogram was constructed and internally validated, and the results indicate that it can assist clinicians in making treatment recommendations in the clinic.
Keywords: early diagnosis; liquid biopsy; miRNA; nomogram; non-small cell lung cancer.
Copyright © 2020 Wang, Chen, Chen, Xin, Huang, Zhang, Xi, Wang, Zhang, Zhao, Liu and Zhang.
38 references6 figures
full-text links
full-text provider logo
Proceed to details Cite
Share
8
Front Oncol
. 2020 Jun 11;10:875. doi: 10.3389/fonc.2020.00875. eCollection 2020.
Gene Signatures and Prognostic Values of M 6 A Genes in Nasopharyngeal Carcinoma
Shanshan Lu 1 2 3, Zhengzheng Yu 1 2, Zhiqiang Xiao 1 2, Yiya Zhang 3 4
Affiliations expand
PMID: 32596151 PMCID: PMC7300221 DOI: 10.3389/fonc.2020.00875
Free PMC article
Abstract
Nasopharyngeal carcinoma (NPC) is a malignant tumor with a high rate of local invasion and early distant metastasis. Accumulating studies suggest that N6-methyladenosine methylation (m6A) is closely related to tumorigenesis. However, the relationship between m6A-related genes and prognosis of NPC is poorly understood. Our research aims to discover the prognostic value of m6A RNA methylation genes in NPC. In this study, we analyzed the differentially expressed m6A-related genes between NPC samples and normal control samples and found that two upregulated genes (YTHDF3 and IGF2BP2) and one downregulated gene (METTL3) were overlapped in GSE68799 and GSE53819. Next, we found that high expression of IGF2BP1 and low expression of METTL3 and YTHDF3 in NPC patients showed poor progression-free survival (PFS). Subsequently, the four m6A genes were selected for consensus cluster analysis, and risk models were established. The risk signature, using three genes (GF2BP1 + IGF2BP2 + METTL3), was an independent prognostic factor and predicts the clinicopathological features of NPC. Additionally, the GO, KEGG analysis, and CIBERSORT algorithm revealed that the risk signature was closely associated to immune infiltration in NPC. Finally, the expression and clinical significance of METTL3 were successfully validated in NPC tissues using immunohistochemical techniques. In conclusion, our finding revealed the potential role of m6A modification in NPC, providing novel insight into NPC prognosis and therapeutic strategies.
Keywords: METTL3; immune infiltration; m6A; nasopharyngeal carcinoma; prognostic factors.
Copyright © 2020 Lu, Yu, Xiao and Zhang.
47 references7 figures
full-text links
full-text provider logo
Proceed to details Cite
Share
9
Front Oncol
. 2020 Jun 11;10:865. doi: 10.3389/fonc.2020.00865. eCollection 2020.
Ubiquitin C-Terminal Hydrolase L5 (UCHL5) Accelerates the Growth of Endometrial Cancer via Activating the Wnt/β-Catenin Signaling Pathway
Da Liu 1, Zixuan Song 1, Xiaoying Wang 1, Ling Ouyang 1
Affiliations expand
PMID: 32596150 PMCID: PMC7300206 DOI: 10.3389/fonc.2020.00865
Free PMC article
Abstract
Endometrial cancer (EC) is the most prevalent gynecological malignancy with high mortality. Chemotherapy plays a pivotal role both in an adjuvant setting and in exclusive treatment. However, current pharmacotherapies are limited and not ideal for improving the overall survival of EC patients. Thus, identification of the underlying molecular mechanisms responsible for initiation and progression of EC is imperative for developing novel therapeutic strategies. Ubiquitin C-terminal hydrolase L5 (UCHL5) has been found to aggravate tumor growth and metastasis in several different types of tumor models such as esophageal squamous cell carcinoma, hepatocellular carcinoma, and epithelial ovarian cancer. However, whether UCHL5 influences the growth of EC has not been elucidated. To expose the role of UCHL5 on EC, bioinformatics analysis was conducted, and it hinted that UCHL5 was overexpressed in EC tissues and associated with lower overall survival. Consistently, the overexpression of UCHL5 in EC tissues and cell lines was further confirmed by western blot (WB) and polymerase chain reaction (PCR) compared with non-tumor control. Lentivirus vectors carrying UCHL5 shRNA or CD sequences were used to reduce or overexpress the UCHL5 gene, respectively. Cell proliferation and cycle were facilitated, and cell apoptosis was decreased when the UCHL5 gene was overexpressed in EC cell lines. These results were opposite in UCHL5 knockdown EC cells. Additionally, the expression of β-catenin is positively related to UCHL5 levels and the tumorigenic effects of UCHL5 overexpression were reversed by the Wnt/β-catenin pathway inhibitor XAV939. Thus, Wnt/β-catenin pathway activation may be a partial mechanism responsible for the promoting effects of UCHL5 on EC growth. In conclusion, UCHL5 accelerated the growth of EC via the Wnt/β-catenin pathway and was expected to be an attractive target for EC treatment.
Keywords: UCHL5; Wnt/β-catenin pathway; XAV939; endometrial cancer; lentivirus vectors.
Copyright © 2020 Liu, Song, Wang and Ouyang.
39 references7 figures
full-text links
full-text provider logo
Proceed to details Cite
Share
10
Review Front Oncol
. 2020 Jun 11;10:942. doi: 10.3389/fonc.2020.00942. eCollection 2020.
The Role of Aberrant Metabolism in Cancer: Insights Into the Interplay Between Cell Metabolic Reprogramming, Metabolic Syndrome, and Cancer
Yina Yu 1, Liang Gong 2, Jun Ye 1
Affiliations expand
PMID: 32596159 PMCID: PMC7301691 DOI: 10.3389/fonc.2020.00942
Free PMC article
Abstract
Metabolic syndrome (MetS) is characterized by hyperglycemia, hypertension, dyslipidemia and abdominal obesity. Patients with MetS or other metabolic disorders are more susceptible to cancer development and recurrence and have a worse long-term prognosis. Moreover, the metabolic reprogramming observed in cancer cells has also been described as one of the new hallmarks of cancer. Thus, aberrant metabolism has been proposed as an important risk factor for cancer. Chronic inflammation, reactive oxygen species (ROS), and oncogenic signaling pathways are considered as main potential triggers. Considering the strong association between metabolism and cancer, metabolism-modulating drugs, including metformin and statins, as well as adopting a healthy lifestyle, have been extensively investigated as strategies to combat cancer. Furthermore, strategies that interfere with the metabolic rewiring of cells may also have potent anti-cancer effects. In this article, we provide a comprehensive review of current knowledge on the relationship between aberrant metabolism and cancer and discuss the potential use of metabolism-targeting strategy for the treatment of cancer.
Keywords: cancer; metabolic reprogramming; metabolic syndrome; metabolism-targeting therapy; metastasis.
Copyright © 2020 Yu, Gong and Ye.
110 references1 figure
supplementary info
Publication typesexpand
full-text links
full-text provider logo
Proceed to details Cite
Share
11
Front Oncol
. 2020 Jun 12;10:853. doi: 10.3389/fonc.2020.00853. eCollection 2020.
An Integrative Analysis Reveals the Underlying Association Between CTNNB1 Mutation and Immunotherapy in Hepatocellular Carcinoma
Zhuomao Mo 1, Yongdan Wang 1, Zhirui Cao 1, Pan Li 1, Shijun Zhang 1
Affiliations expand
PMID: 32596147 PMCID: PMC7304048 DOI: 10.3389/fonc.2020.00853
Free PMC article
Abstract
Background: Tumor mutational burden (TMB) was verified to be closely associated with immune checkpoint inhibitors, but it is unclear whether gene mutation has an effect on immunotherapy of hepatocellular carcinoma (HCC). This research aimed to investigate the underlying correlation between gene mutation and immunotherapy in HCC. Methods: The somatic gene mutation data and gene expression data were retrieved from International Cancer Genome Consortium database and The Cancer Genome Atlas (TCGA) database. The mutational genes were selected by the intersection of three cohorts and further identified using survival analysis and TMB correlation analysis. After the identification of key mutational gene, we explored the correlation between gene mutation and both the immune cell infiltration and immune inhibitors. The signaling pathways associated with gene mutation were confirmed through gene set enrichment analysis. Furthermore, the survival analysis and mutational analysis based on TCGA cohort were performed for the validation of included gene. Results: As one of the frequently mutational genes in HCC, CTNNB1 was finally included in our research, for which it showed the significant result in survival analysis and the positive association with TMB of the three cohorts. Meanwhile, the validation of TCGA showed the significant results. Furthermore, natural killer (NK) cells and neutrophil were found to significantly infiltrate CTNNB1 mutation group from two cohorts. Besides, further analysis demonstrated that four types of immune inhibitors (CD96, HAVCR2, LGALS9, and TGFB1) were downregulated in CTNNB1 mutation group. Conclusion: Our research firstly revealed the underlying association between CTNNB1 mutation and immunotherapy, and we speculated that CTNNB1 mutation may modulate NK cells by affecting CD96. However, more functional experiments should be performed for verification.
Keywords: CTNNB1; gene mutation; hepatocellular carcinoma; immune inhibitor; immunotherapy.
Copyright © 2020 Mo, Wang, Cao, Li and Zhang.
34 references8 figures
full-text links
full-text provider logo
Proceed to details Cite
Share
12
Front Oncol
. 2020 Jun 12;10:856. doi: 10.3389/fonc.2020.00856. eCollection 2020.
Identification of Potential Key Genes Associated With the Pathogenesis, Metastasis, and Prognosis of Triple-Negative Breast Cancer on the Basis of Integrated Bioinformatics Analysis
Bin Zhao 1, Yali Xu 1, Yang Zhao 2, Songjie Shen 1, Qiang Sun 1
Affiliations expand
PMID: 32596149 PMCID: PMC7304260 DOI: 10.3389/fonc.2020.00856
Free PMC article
Abstract
Objective: Breast cancer is the most common solid tumor affecting women and the second leading cause of cancer-related death worldwide, and triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer. We aimed to identify potential TNBC-specific therapeutic targets by performing an integrative analysis on previously published TNBC transcriptome microarray data. Methods: Differentially expressed genes (DEGs) between TNBC and normal breast tissues were screened using six Gene Expression Omnibus (GEO) datasets, and DEGs between metastatic TNBC and non-metastatic TNBC were screened using one GEO dataset. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses were performed on the overlapping DEGs. The Cancer Genome Atlas (TCGA) TNBC data were used to identify candidate genes that were strongly associated with survival. Expression of the candidate genes in TNBC cell lines was blocked or augmented using a lentivirus system, and transwell assays were used to determine their effect on TNBC migration. Results: Eight upregulated genes and nine downregulated genes were found to be differentially expressed both between TNBC and normal breast tissues and between metastatic TNBC and non-metastatic TNBC. Among them, S100P and SDC1 were identified as poor prognostic genes. Furthermore, compared with control cells, SDC1-overexpressing TNBC cells showed enhanced migration ability, whereas SDC1 knockdown markedly reduced the migration of TNBC cells. Conclusion: Our study determined that S100P and SDC1 may be potential treatment targets as well as prognostic biomarkers of TNBC.
Keywords: Gene Expression Omnibus; S100P; SDC1; The Cancer Genome Atlas; bioinformatics; triple-negative breast cancer.
Copyright © 2020 Zhao, Xu, Zhao, Shen and Sun.
31 references5 figures
full-text links
full-text provider logo
Proceed to details Cite
Share
13
Front Oncol
. 2020 Jun 12;10:956. doi: 10.3389/fonc.2020.00956. eCollection 2020.
LncRNA NBR2 Inhibits the Malignancy of Thyroid Cancer, Associated With Enhancing the AMPK Signaling
Wen Yang 1, Zhikun Zheng 2, Pengfei Yi 1, Shi Wang 1, Ning Zhang 1, Jie Ming 1, Jie Tan 1, Hui Guo 1
Affiliations expand
PMID: 32596161 PMCID: PMC7304297 DOI: 10.3389/fonc.2020.00956
Free PMC article
Abstract
Long non-coding RNA NBR2 is a transcript of the neighbor of BRCA1 gene 2 and can regulate tumor development. However, there is little information on the role of NBR2 in the progression of thyroid cancers (TC). Here, we show that NBR2 expression is down-regulated in TC tissues and associated with histologic subtypes of TC. NBR2 expression was variably reduced in different TC cells. While NBR2 silencing significantly enhanced the malignancy of BCPAP cells by increasing cell proliferation, clonogenicity, wound healing, and invasion as well as tumor growth in vivo, and decreasing spontaneous apoptosis, NBR2 over-expression had opposite effects in BHT101 cells. Furthermore, treatment with A-769662 (a specific AMPK activator), like NBR2 over-expression, significantly attenuated the malignancy of BHT101 cells while treatment with Compound C (a specific AMPK inhibitor) significantly rescued that NBR2-reduced malignancy of BHT101 cells. In comparison with non-tumor thyroid epithelial Nthy-ori 3-1 cells, obviously increased GLUT-1 expression, but decreased AMPK and ACC phosphorylation were detected in TC cells. While NBR2 silencing further enhanced GLUT-1 expression and reduced AMPK and ACC phosphorylation as well as the EMT process in BCPAP cells. NBR2 over-expression also had opposite effects in BHT101 cells. Similar patterns of GLUT-1 expression and AMPK and ACC phosphorylation were detected in the different types of xenograft TC tumors in vivo. Therefore, such data indicated that NBR2 acted as a tumor suppressor of thyroid cancers associated with enhancing the AMPK signaling and NBR2 may be a potential biomarker and therapeutic target for thyroid cancers.
Keywords: AMPK; EMT; LncRNA NBR2; malignancy; thyroid cancer.
Copyright © 2020 Yang, Zheng, Yi, Wang, Zhang, Ming, Tan and Guo.
28 references6 figures
full-text links
full-text provider logo
Proceed to details Cite
Share
14
Front Oncol
. 2020 Jun 12;10:839. doi: 10.3389/fonc.2020.00839. eCollection 2020.
Triple Immunotherapy Overcomes Immune Evasion by Tumor in a Melanoma Mouse Model
Mary-Ann N Jallad 1, Abdo R Jurjus 2, Elias A Rahal 1, Alexander M Abdelnoor 1
Affiliations expand
PMID: 32596146 PMCID: PMC7304320 DOI: 10.3389/fonc.2020.00839
Free PMC article
Abstract
Background: Melanoma is a malignancy with increasing incidence that underlies most skin cancer-related deaths. Advanced melanoma patients still have poor prognosis despite recently developed immunotherapies. This study devises a triple immunotherapy to treat melanoma in a mouse model. The combination includes anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) antibodies, Monophosphoryl-lipid-A (MPLA), and an Indolamine-Dioxygenase-1 (IDO1) inhibitor. The aim of the study is, first, to rule out any major toxic effects related to this therapy and, second, to assess its antitumor effects. Methods: Cancer-free C57BL/6 mice were randomized into control groups and groups receiving single, dual, or triple therapies of the defined treatments. Clinical signs, weight gain, and histological sections from their main organs were assessed. Then, melanoma-bearing mice were segregated into similar groups, monitored for survival, and their tumor size was measured repeatedly. Finally, flow cytometry was used to analyze immune cell populations in the tumor masses including CD4+, CD8+, and regulatory T cells in addition to natural killer cells. Results: No adverse effects were detected in any of the treated groups. Survival analysis indicated that the groups receiving dual or triple therapies had prolonged survival compared to the controls. However, the group receiving triple therapy was the only group to show statistically significant increase in survival compared to the controls. Tumor size progression paralleled the survival outcome. The group receiving the triple therapy showed statistically significant smaller tumor sizes compared to all the other groups throughout the whole monitoring period. Flow cytometry used to analyze immune cell populations in the tumor mass indicated that the triple immune therapy was capable of significantly enhancing the natural killer cell counts as well as the CD3+CD4+/Treg and CD3+CD8+/Treg ratios possibly enhancing the anti-tumorigenic environment. Conclusions: Generated data rule out any major adverse events pertaining to the triple immunotherapy and reveal its enhanced effectiveness in thwarting melanoma progression over all other tested treatments.
Keywords: 1-MT; IDO; MPLA; anti-CTLA-4 antibodies; immunotherapy; melanoma.
Copyright © 2020 Jallad, Jurjus, Rahal and Abdelnoor.
38 references6 figures
full-text links
full-text provider logo
Proceed to details Cite
Share
15
Front Oncol
. 2020 Jun 11;10:910. doi: 10.3389/fonc.2020.00910. eCollection 2020.
External Validation of a Predictive Model of Urethral Strictures for Prostate Patients Treated With HDR Brachytherapy Boost
Vanessa Panettieri 1 2, Tiziana Rancati 3, Eva Onjukka 4, Martin A Ebert 5 6 7, David J Joseph 7 8 9, James W Denham 10, Allison Steigler 10, Jeremy L Millar 1 11
Affiliations expand
PMID: 32596153 PMCID: PMC7300245 DOI: 10.3389/fonc.2020.00910
Free PMC article
Abstract
Purpose: For prostate cancer treatment, comparable or superior biochemical control was reported when using External-Beam-Radiotherapy (EBRT) with High-Dose-Rate-Brachytherapy (HDRB)-boost, compared to dose-escalation with EBRT alone. The conformal doses produced by HDRB could allow further beneficial prostate dose-escalation, but increase in dose is limited by normal tissue toxicity. Previous works showed correlation between urethral dose and incidence of urinary toxicity, but there is a lack of established guidelines on the dose constraints to this organ. This work aimed at fitting a Normal-Tissue-Complication-Probability model to urethral stricture data collected at one institution and validating it with an external cohort, looking at neo-adjuvant androgen deprivation as dose-modifying factor. Materials and Methods: Clinical and dosimetric data of 258 patients, with a toxicity rate of 12.8%, treated at a single institution with a variety of prescription doses, were collected to fit the Lyman-Kutcher-Burman (LKB) model using the maximum likelihood method. Due to the different fractionations, doses were converted into 2 Gy-equivalent doses (α/β = 5 Gy), and urethral stricture was used as an end-point. For validation, an external cohort of 187 patients treated as part of the TROG (Trans Tasman Radiation Oncology Group) 03.04 RADAR trial with a toxicity rate of 8.7%, was used. The goodness of fit was assessed using calibration plots. The effect of neo-adjuvant androgen deprivation (AD) was analyzed separating patients who had received it prior to treatment from those who did not receive it. Results: The obtained LKB parameters were TD50 = 116.7 Gy and m = 0.23; n was fixed to 0.3, based on numerical optimization of the likelihood. The calibration plot showed a good agreement between the observed toxicity and the probability predicted by the model, confirmed by bootstrapping. For the external validation, the calibration plot showed that the observed toxicity obtained with the RADAR patients was well-represented by the fitted LKB model parameters. When patients were stratified by the use of AD TD50 decreased when AD was not present. Conclusions: Lyman-Kutcher-Burman model parameters were fitted to the risk of urethral stricture and externally validated with an independent cohort, to provide guidance on urethral tolerance doses for patients treated with a HDRB boost. For patients that did not receive AD, model fitting provided a lower TD50 suggesting a protective effect on urethra toxicity.
Keywords: HDR brachytherapy; NTCP; predictive modeling; prostate cancer; urethra.
Copyright © 2020 Panettieri, Rancati, Onjukka, Ebert, Joseph, Denham, Steigler and Millar.
45 references5 figures
full-text links
full-text provider logo
Proceed to details Cite
Share
16
Review Front Oncol
. 2020 Jun 11;10:941. doi: 10.3389/fonc.2020.00941. eCollection 2020.
The Role of Long Non-Coding RNAs in Thyroid Cancer
Xuejiao Peng 1, Kun Zhang 2, Li Ma 1, Junfeng Xu 1, Weiqin Chang 1
Affiliations expand
PMID: 32596158 PMCID: PMC7300266 DOI: 10.3389/fonc.2020.00941
Free PMC article
Abstract
Thyroid cancer, the most common endocrine malignancy, has become the most commonly diagnosed malignant solid tumor. Moreover, some cases have poor prognosis, and the survival period is only 3-5 months. Long noncoding RNAs (lncRNAs) are a group of functional RNA molecules more than 200 nucleotides in length that lack the ability to encode protein but participate in all aspects of gene regulation. Functionally, many lncRNAs play essential roles in epigenetic regulation at transcriptional and post-transcriptional levels via various molecular mechanisms. Recent studies have discovered important roles for lncRNAs during the complex process of carcinogenesis in thyroid cancer. In this review, we focus on lncRNAs dysregulated in thyroid cancer and summarize recently reported associations between lncRNAs and thyroid cancer in order to demonstrate the significant value of lncRNAs in diagnosis and treatment.
Keywords: biomarker; long non-coding RNAs; molecular mechanism; thyroid cancer; tumorigenesis.
Copyright © 2020 Peng, Zhang, Ma, Xu and Chang.
127 references
supplementary info
Publication typesexpand
full-text links
full-text provider logo
Proceed to details Cite
Share
17
Review Front Oncol
. 2020 Jun 12;10:782. doi: 10.3389/fonc.2020.00782. eCollection 2020.
PARP Inhibitors in First-Line Therapy of Ovarian Cancer: Are There Any Doubts?
Elisena Franzese 1, Anna Diana 1, Sara Centonze 1, Sandro Pignata 2, Ferdinando De Vita 1, Fortunato Ciardiello 1, Michele Orditura 1
Affiliations expand
PMID: 32596142 PMCID: PMC7303974 DOI: 10.3389/fonc.2020.00782
Free PMC article
Abstract
The standard of care for newly diagnosed advanced ovarian cancer (NADOC) is represented by surgical debulking followed by systemic platinum-taxanes combination chemotherapy. At the last European Society for Medical Oncology (ESMO) Congress, results from three trials testing three different poly-adenosine-diphosphate-ribose-polymerase (PARP) inhibitors (olaparib, niraparib, veliparib) in first-line therapy of OC have been presented. For the first time, these studies evaluated the efficacy of PARP inhibitors in this setting and the relative predictive biomarkers for patients' selection. The use of a PARP inhibitor is related with prolonged progression free survival (PFS) in the whole population of NADOC, although the magnitude of benefit varies widely among subgroups, highlighting the need to identify specific biological subtypes into clinical practice. In this minireview, we discuss the updated data available from clinical studies in this scenario.
Keywords: BRCA 1/2 mutation carriers; PARP inhibitor (PARPi); first line; homologous recombination; ovarian cancer.
Copyright © 2020 Franzese, Diana, Centonze, Pignata, De Vita, Ciardiello and Orditura.
14 references
supplementary info
Publication typesexpand
full-text links
full-text provider logo
Proceed to details Cite
Share
18
Editorial Front Oncol
. 2020 Jun 12;10:939. doi: 10.3389/fonc.2020.00939. eCollection 2020.
Editorial: Emerging Therapies for Malignant Mesothelioma
Nico van Zandwijk 1, Glen Reid 2, Paul Baas 3
Affiliations expand
PMID: 32596157 PMCID: PMC7304317 DOI: 10.3389/fonc.2020.00939
Free PMC article
Abstract
No abstract available
Keywords: angiogenesis inhibitors; chemotherapy; immune environment; immunotherapy; malignant mesothelioma; microRNA; preclinical models; tumor biology.
Comment on
Editorial on the Research Topic Emerging Therapies for Malignant Mesothelioma
14 references
supplementary info
Publication typesexpand
full-text links
full-text provider logo
Proceed to details Cite
Share
19
Front Oncol
. 2020 Jun 12;10:949. doi: 10.3389/fonc.2020.00949. eCollection 2020.
Broad Spectrum Deubiquitinase Inhibition Induces Both Apoptosis and Ferroptosis in Cancer Cells
Li Yang 1 2, Xin Chen 2, Qianqian Yang 2, Jinghong Chen 2 3, Qingtian Huang 2, Leyi Yao 2, Ding Yan 2, Jiawen Wu 2, Peiquan Zhang 2, Daolin Tang 4, Nanshan Zhong 2, Jinbao Liu 2
Affiliations expand
PMID: 32596160 PMCID: PMC7304060 DOI: 10.3389/fonc.2020.00949
Free PMC article
Abstract
Proteasomal deubiquitinase (DUB) inhibition has been found to be effective in experimental cancer therapy by inducing proteasome inhibition and apoptosis. Ferroptosis is a form of regulated cell death characterized by an iron-dependent lipid peroxidation. Antioxidant enzyme glutathione peroxidase 4 (GPX4) plays a key role in blocking ferroptosis through directly reducing phospholipid hydroperoxides production. Since cytoplasmic DUB inhibition can promote protein degradation in the cell, we hypothesize that DUB inhibition induces GPX4 degradation. Here we used palladium pyrithione complex (PdPT), a broad spectrum deubiquitinase inhibitor, to explore its cell death induction and anti-cancer effect in vitro, ex vivo, and in vivo. Mechanically, caspase activation and GPX4 protein degradation are required for PdPT-induced apoptosis and ferroptosis, respectively. Notably, PdPT-induced multiple deubiquitinase inhibition is essential for proteasomal degradation of GPX4. These findings not only identify a novel mechanism of post-translational modification of GPX4 in ferroptosis, but also suggest a potential anti-caner therapeutic strategy using Pan-DUB inhibition.
Keywords: GPX4; apoptosis; cancer; deubiquitinase; ferroptosis.
Copyright © 2020 Yang, Chen, Yang, Chen, Huang, Yao, Yan, Wu, Zhang, Tang, Zhong and Liu.
53 references7 figures
full-text links
full-text provider logo
Proceed to details Cite
Share
20
Front Oncol
. 2020 Jun 11;10:896. doi: 10.3389/fonc.2020.00896. eCollection 2020.
Activation of STING by cGAMP Regulates MDSCs to Suppress Tumor Metastasis via Reversing Epithelial-Mesenchymal Transition
Hao Cheng 1 2, Qiming Xu 1 2, Xing Lu 1 2, Hong Yuan 1 2, Tiejun Li 3, Yuefan Zhang 4, Xiangshi Tan 1 2
Affiliations expand
PMID: 32596152 PMCID: PMC7300176 DOI: 10.3389/fonc.2020.00896
Free PMC article
Abstract
The role of cGAMP stimulating cGAS-cGAMP-STING-IRF3 pathway to inhibit tumor growth was well-established. Herein, the efficiency and pharmacological mechanism of cGAMP on regulating tumor metastasis was investigated. The effects of cGAMP regulating CD8+ T cells and myeloid-derived suppressor cells (MDSCs) in tumor microenvironment was explored. In this study, we found that cGAMP boosted STING signaling pathway to activate the production of IFN-γ from CD8+ T cells, and decreased the population of MDSCs in vivo. The metastasis in CT26 tumor bearing mice was inhibited by cGAMP via regulating EMT process. cGAMP played an important role in suppressing the production of reactive oxygen species (ROS) and nitric oxide (NO) from MDSCs, abolished the suppressive function of MDSCs to the T cells. All in all, the results indicated that the STING agonist cGAMP activated the production of IFN-γ from CD8+ T cells to suppress MDSCs in vivo.
Keywords: STING; cGAMP; epithelial-mesenchymal transition; metastasis; myeloid-derived suppressor cells.
Copyright © 2020 Cheng, Xu, Lu, Yuan, Li, Zhang and Tan.
45 references7 figures
full-text links
full-text provider logo
Proceed to details Cite
Share
21
Front Oncol
. 2020 Jun 12;10:824. doi: 10.3389/fonc.2020.00824. eCollection 2020.
GATA6 Exerts Potent Lung Cancer Suppressive Function by Inducing Cell Senescence
Wensheng Chen 1, Zhipeng Chen 1, Miaomiao Zhang 1, Yahui Tian 1, Lu Liu 1, Ruirui Lan 2, Guandi Zeng 1, Xiaolong Fu 3, Guoqing Ru 4, Wanting Liu 1, Liang Chen 1, Zhenzhen Fan 1
Affiliations expand
PMID: 32596145 PMCID: PMC7304445 DOI: 10.3389/fonc.2020.00824
Free PMC article
Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide. Tumor suppressor genes (TSGs) play a critical role in restricting tumorigenesis and impact the therapeutic effect of various treatments. However, TSGs remain to be systemically determined in lung cancer. Here, we identified GATA6 as a potent lung cancer TSG. GATA6 inhibited lung cancer cell growth in vitro and tumorigenesis in vivo. Mechanistically, GATA6 upregulated p53 and p21 mRNA while it inhibited AKT activation to stabilize p21 protein, thus inducing lung cancer cell senescence. Furthermore, we showed that ectopic expression of GATA6 led to dramatic slowdown of growth rate of established lung tumor xenograft in vivo.
Keywords: AKT; GATA6; lung cancer; p21; tumor suppressor genes.
Copyright © 2020 Chen, Chen, Zhang, Tian, Liu, Lan, Zeng, Fu, Ru, Liu, Chen and Fan.
43 references4 figures
full-text links
full-text provider logo
Proceed to details Cite
Share
Review Front Oncol
. 2020 Jun 11;10:935. doi: 10.3389/fonc.2020.00935. eCollection 2020.
Shp1 in Solid Cancers and Their Therapy
Alessia Varone 1, Daniela Spano 1, Daniela Corda 1 2
Affiliations expand
PMID: 32596156 PMCID: PMC7300250 DOI: 10.3389/fonc.2020.00935
Free PMC article
Abstract
Shp1 is a cytosolic tyrosine phosphatase that regulates a broad range of cellular functions and targets, modulating the flow of information from the cell membrane to the nucleus. While initially studied in the hematopoietic system, research conducted over the past years has expanded our understanding of the biological role of Shp1 to other tissues, proposing it as a novel tumor suppressor gene functionally involved in different hallmarks of cancer. The main mechanism by which Shp1 curbs cancer development and progression is the ability to attenuate and/or terminate signaling pathways controlling cell proliferation, survival, migration, and invasion. Thus, alterations in Shp1 function or expression can contribute to several human diseases, particularly cancer. In cancer cells, Shp1 activity can indeed be affected by mutations or epigenetic silencing that cause failure of Shp1-mediated homeostatic maintenance. This review will discuss the current knowledge of the cellular functions controlled by Shp1 in non-hematopoietic tissues and solid tumors, the mechanisms that regulate Shp1 expression, the role of its mutation/expression status in cancer and its value as potential target for cancer treatment. In addition, we report information gathered from the public available data from The Cancer Genome Atlas (TCGA) database on Shp1 genomic alterations and correlation with survival in solid cancers patients.
Keywords: Shp1; TCGA; cancer; cancer therapy; signaling; tyrosine phosphatase.
Copyright © 2020 Varone, Spano and Corda.
104 references1 figure
supplementary info
Publication typesexpand
full-text links
full-text provider logo
Proceed to details Cite
Share
2
Review Front Oncol
. 2020 Jun 12;10:957. doi: 10.3389/fonc.2020.00957. eCollection 2020.
The Roles of Glycans in Bladder Cancer
Yuli Jian 1, Zhongyang Xu 1, Chunyan Xu 1, Lin Zhang 1, Xiaoxin Sun 1, Deyong Yang 2, Shujing Wang 1
Affiliations expand
PMID: 32596162 PMCID: PMC7303958 DOI: 10.3389/fonc.2020.00957
Free PMC article
Abstract
Bladder cancer is one of the most common malignant tumors of the urogenital system with high morbidity and mortality worldwide. Early diagnosis and personalized treatment are the keys to successful bladder cancer treatment. Due to high postoperative recurrence rates and poor prognosis, it is urgent to find suitable therapeutic targets and biomarkers. Glycans are one of the four biological macromolecules in the cells of an organism, along with proteins, nucleic acids, and lipids. Glycans play important roles in nascent peptide chain folding, protein processing, and translation, cell-to-cell adhesion, receptor-ligand recognition, and binding and cell signaling. Glycans are mainly divided into N-glycans, O-glycans, proteoglycans, and glycosphingolipids. The focus of this review is the discussion of glycans related to bladder cancer. Additionally, this review also addresses the clinical value of glycans in the diagnosis and treatment of bladder cancer. Abnormal glycans are likely to be potential biomarkers for bladder cancer.
Keywords: abnormal glycosylation; biomarkers; bladder cancer; glycans; glycosyltransferases.
Copyright © 2020 Jian, Xu, Xu, Zhang, Sun, Yang and Wang.
75 references2 figures
supplementary info
Publication typesexpand
full-text links
full-text provider logo
Proceed to details Cite
Share
3
Review Front Oncol
. 2020 Jun 12;10:819. doi: 10.3389/fonc.2020.00819. eCollection 2020.
Integrating Loco-Regional Hyperthermia Into the Current Oncology Practice: SWOT and TOWS Analyses
Niloy R Datta 1, H Petra Kok 2, Hans Crezee 2, Udo S Gaipl 3, Stephan Bodis 1
Affiliations expand
PMID: 32596144 PMCID: PMC7303270 DOI: 10.3389/fonc.2020.00819
Free PMC article
Abstract
Moderate hyperthermia at temperatures between 40 and 44°C is a multifaceted therapeutic modality. It is a potent radiosensitizer, interacts favorably with a host of chemotherapeutic agents, and, in combination with radiotherapy, enforces immunomodulation akin to "in situ tumor vaccination." By sensitizing hypoxic tumor cells and inhibiting repair of radiotherapy-induced DNA damage, the properties of hyperthermia delivered together with photons might provide a tumor-selective therapeutic advantage analogous to high linear energy transfer (LET) neutrons, but with less normal tissue toxicity. Furthermore, the high LET attributes of hyperthermia thermoradiobiologically are likely to enhance low LET protons; thus, proton thermoradiotherapy would mimic 12C ion therapy. Hyperthermia with radiotherapy and/or chemotherapy substantially improves therapeutic outcomes without enhancing normal tissue morbidities, yielding level I evidence reported in several randomized clinical trials, systematic reviews, and meta-analyses for various tumor sites. Technological advancements in hyperthermia delivery, advancements in hyperthermia treatment planning, online invasive and non-invasive MR-guided thermometry, and adherence to quality assurance guidelines have ensured safe and effective delivery of hyperthermia to the target region. Novel biological modeling permits integration of hyperthermia and radiotherapy treatment plans. Further, hyperthermia along with immune checkpoint inhibitors and DNA damage repair inhibitors could further augment the therapeutic efficacy resulting in synthetic lethality. Additionally, hyperthermia induced by magnetic nanoparticles coupled to selective payloads, namely, tumor-specific radiotheranostics (for both tumor imaging and radionuclide therapy), chemotherapeutic drugs, immunotherapeutic agents, and gene silencing, could provide a comprehensive tumor-specific theranostic modality akin to "magic (nano)bullets." To get a realistic overview of the strength (S), weakness (W), opportunities (O), and threats (T) of hyperthermia, a SWOT analysis has been undertaken. Additionally, a TOWS analysis categorizes future strategies to facilitate further integration of hyperthermia with the current treatment modalities. These could gainfully accomplish a safe, versatile, and cost-effective enhancement of the existing therapeutic armamentarium to improve outcomes in clinical oncology.
Keywords: SWOT analysis; chemotherapy; clinical trials; hyperthermia; hyperthermia treatment planning; immunotherapy; radiation therapy; radiosensitizer.
Copyright © 2020 Datta, Kok, Crezee, Gaipl and Bodis.
343 references9 figures
supplementary info
Publication typesexpand
full-text links
full-text provider logo
Proceed to details Cite
Share
4
Review Front Oncol
. 2020 Jun 12;10:930. doi: 10.3389/fonc.2020.00930. eCollection 2020.
Quality of Life, Toxicity and Unmet Needs in Nasopharyngeal Cancer Survivors
Lachlan McDowell 1 2, June Corry 3 4, Jolie Ringash 5, Danny Rischin 2 6
Affiliations expand
PMID: 32596155 PMCID: PMC7303258 DOI: 10.3389/fonc.2020.00930
Free PMC article
Abstract
Concerted research efforts over the last three decades have resulted in improved survival and outcomes for patients diagnosed with nasopharyngeal carcinoma (NPC). The evolution of radiotherapy techniques has facilitated improved dose delivery to target volumes while reducing dose to the surrounding normal tissue, improving both disease control and quality of life (QoL). In parallel, clinical trials focusing on determining the optimal systemic therapy to use in conjunction with radiotherapy have been largely successful, resulting in improved locoregional, and distant control. As a consequence, neoadjuvant chemotherapy (NACT) prior to definitive chemoradiotherapy has recently emerged as the preferred standard for patients with locally advanced NPC. Two of the major challenges in interpreting toxicity and QoL data from the published literature have been the reliance on: (1) clinician rather than patient reported outcomes; and (2) reporting statistical rather than clinical meaningful differences in measures. Despite the lower rates of toxicity that have been achieved with highly conformal radiotherapy techniques, survivors remain at moderate risk of persistent and long-lasting treatment effects, and the development of late radiation toxicities such as hearing loss, cranial neuropathies and cognitive impairment many years after successful treatment can herald a significant decline in QoL. Future approaches to reduce long-term toxicity will rely on: (1) identifying individual patients most likely to benefit from NACT; (2) development of response-adapted radiation strategies following NACT; and (3) anticipated further dose reductions to organs at risk with proton and particle therapy. With increasing numbers of survivors, many in the prime of their adult life, research to identify, and strategies to address the unmet needs of NPC survivors are required. This contemporary review will summarize our current knowledge of long-term toxicity, QoL and unmet needs of this survivorship group.
Keywords: chemotherapy; nasopharyngeal carcinoma; quality of life; radiotherapy; survivorship; toxicity; unmet needs.
Copyright © 2020 McDowell, Corry, Ringash and Rischin.
128 references
supplementary info
Publication typesexpand
full-text links
full-text provider logo
Proceed to details Cite
Share
5
Review Front Oncol
. 2020 Jun 11;10:928. doi: 10.3389/fonc.2020.00928. eCollection 2020.
A Potential Role of YAP/TAZ in the Interplay Between Metastasis and Metabolic Alterations
Hirohito Yamaguchi 1, Ghina M Taouk 1
Affiliations expand
PMID: 32596154 PMCID: PMC7300268 DOI: 10.3389/fonc.2020.00928
Free PMC article
Abstract
Yes-Associated Protein (YAP) and Transcriptional Co-activator with PDZ-binding Motif (TAZ) are the downstream effectors of the Hippo signaling pathway that play a crucial role in various aspects of cancer progression including metastasis. Metastasis is the multistep process of disseminating cancer cells in a body and responsible for the majority of cancer-related death. Emerging evidence has shown that cancer cells reprogram their metabolism to gain proliferation, invasion, migration, and anti-apoptotic abilities and adapt to various environment during metastasis. Moreover, it has increasingly been recognized that YAP/TAZ regulates cellular metabolism that is associated with the phenotypic changes, and recent studies suggest that the YAP/TAZ-mediated metabolic alterations contribute to metastasis. In this review, we will introduce the latest knowledge of YAP/TAZ regulation and function in cancer metastasis and metabolism, and discuss possible links between the YAP/TAZ-mediated metabolic reprogramming and metastasis.
Keywords: TAZ; YAP; cancer; metabolism; metastasis.
Copyright © 2020 Yamaguchi and Taouk.
189 references6 figures
supplementary info
Publication typesexpand
full-text links
full-text provider logo
Proceed to details Cite
Share
6
Front Oncol
. 2020 Jun 12;10:807. doi: 10.3389/fonc.2020.00807. eCollection 2020.
Lactic Acidosis in the Presence of Glucose Diminishes Warburg Effect in Lung Adenocarcinoma Cells
Heriberto Prado-Garcia 1, Andrea Campa-Higareda 1, Susana Romero-Garcia 1
Affiliations expand
PMID: 32596143 PMCID: PMC7303336 DOI: 10.3389/fonc.2020.00807
Free PMC article
Abstract
Lactic acidosis (3 to 40 mM, pH < 6.9) is a condition found in solid tumors because tumor cells have a high rate of glucose consumption and lactate production even in the presence of oxygen; nevertheless, the microenvironment might still provide a sufficient glucose supply. Lactic acidosis has been proposed to shift metabolism from aerobic glycolysis toward oxidative phosphorylation (OXPHOS). We tested if lung tumor cells cultured under lactic acidosis shift their metabolism from glycolysis to OXPHOS by consuming extracellular lactate, increasing growth rate. We analyzed lung adenocarcinoma (A-549, A-427) cell lines and non-transformed fibroblast cells (MRC-5), which were cultured using RPMI-1640 medium initially containing lactate (2 mM) and glucose (10 mM), at pH 7.2 or 6.2 and oxygen tension 21% O2 (normoxia) or 2% O2 (hypoxia). We obtained growth curves, as well as glucose consumption and lactate production rates (measured during exponential growth) for each cell line. HIF-1α (Hypoxia-inducible factor 1 α), CS (citrate synthase) and AMPK (AMP-activated protein kinase) transcript levels were analyzed using RT-qPCR. By flow cytometry, we determined: (a) expression of glucose transporters (GLUT)1 and 4; (b) lactate transporters (MCT)1 and 4; (c) cell cycle profile, and (d) protein levels of HIF-1α, total and phosphorylated AMPK (pAMPK). Mitochondrial functionality was evaluated by measuring O2 consumption in tumor cells using polarography and a Clark-type electrode. Tumor and non-transformed cells used both aerobic glycolysis and OXPHOS for obtaining energy. As of 48 h of culture, lactate levels ranged from (4.5-14 mM), thus forming a lactic environment. Lactic acidosis diminished GLUT1/GLUT4 expression and glucose consumption in A-549, but not in A-427 cells, and induced differential expression of HIF-1α, AMPK, and CS transcripts. A-427 cells increased pAMPK and HIF-1α levels and shifted their metabolism increasing OXPHOS; thus supporting cell growth. Conversely, A-549 cells increased HIF-1α protein levels, but did not activate AMPK and diminished OXPHOS. A-549 cells survived by arresting cells in G1-phase. Our findings show that lactic acidosis diminishes Warburg effect in tumor cells, but this change does not necessarily promote a shift to OXPHOS. Hence, lung adenocarcinomas show a differential metabolic response even when they are under the same microenvironmental conditions.
Keywords: aerobic glycolysis; mitochondrial function; oxidative metabolism; tumor metabolic shift; tumor metabolic symbiosis.
Copyright © 2020 Prado-Garcia, Campa-Higareda and Romero-Garcia.
30 references6 figures
full-text links
full-text provider logo
Proceed to details Cite
Share
7
Front Oncol
. 2020 Jun 11;10:855. doi: 10.3389/fonc.2020.00855. eCollection 2020.
Early Detection of Non-Small Cell Lung Cancer by Using a 12-microRNA Panel and a Nomogram for Assistant Diagnosis
Weidong Wang 1 2 3, Dongni Chen 1 2, Weiwei Chen 1 2, Ziya Xin 1 2, Zirui Huang 1 2, Xuewen Zhang 2 4, Kexing Xi 5, Gongming Wang 1 2, Rusi Zhang 1 2, Dechang Zhao 1 2, Li Liu 1 2, Lanjun Zhang 1 2
Affiliations expand
PMID: 32596148 PMCID: PMC7301755 DOI: 10.3389/fonc.2020.00855
Free PMC article
Abstract
Background: We previously identified a 12-microRNA (miRNA) panel (miRNA-17, miRNA-146a, miRNA-200b, miRNA-182, miRNA-155, miRNA-221, miRNA-205, miRNA-126, miRNA-7, miRNA-21, miRNA-145, and miRNA-210) that aided in the early diagnosis of non-small cell lung cancer (NSCLC). We validated the diagnostic value of this miRNA panel and compared it with that of traditional tumor markers and radiological diagnosis. We constructed a nomogram based on the miRNA panel's results to predict the risk of NSCLC. Methods: Eighty-two participants with pulmonary nodules on a CT scan and who underwent a pathological examination and surgical treatment were enrolled in our study. Patients were randomly divided into a training group or a validation group. The miRNA concentrations were quantified by RT-PCR and log-transformed for analysis. The cutoff value was determined in the training group and then applied in the validation group. A comparison between the miRNAs and traditional tumor markers [CEA, NSE, and cytokeratin 19 fragment 21-1 (Cyfra21-1)] and radiological diagnosis was performed. A nomogram based on the miRNA panel's results to predict the risk of NSCLC was constructed. Results: The expression level of these 12 miRNAs was significantly higher in NSCLC patients than in benign patients. In the validation group, the specificity and positive predictive value were 96.4 and 95.8%, respectively, which were significantly higher than those using traditional tumor markers or radiological diagnosis. The sensitivity was 42.6%, which was also higher than that using tumor markers. Moreover, the sensitivity increased to 63.6% when the nodule diameters were larger than 2 cm. The miRNAs and seven clinical factors were integrated into the nomogram, and the calibration curves showed optimal agreement between the predicted and actual probabilities. Conclusions: Our miRNA panel has clinical value for the early detection of NSCLC. A nomogram was constructed and internally validated, and the results indicate that it can assist clinicians in making treatment recommendations in the clinic.
Keywords: early diagnosis; liquid biopsy; miRNA; nomogram; non-small cell lung cancer.
Copyright © 2020 Wang, Chen, Chen, Xin, Huang, Zhang, Xi, Wang, Zhang, Zhao, Liu and Zhang.
38 references6 figures
full-text links
full-text provider logo
Proceed to details Cite
Share
8
Front Oncol
. 2020 Jun 11;10:875. doi: 10.3389/fonc.2020.00875. eCollection 2020.
Gene Signatures and Prognostic Values of M 6 A Genes in Nasopharyngeal Carcinoma
Shanshan Lu 1 2 3, Zhengzheng Yu 1 2, Zhiqiang Xiao 1 2, Yiya Zhang 3 4
Affiliations expand
PMID: 32596151 PMCID: PMC7300221 DOI: 10.3389/fonc.2020.00875
Free PMC article
Abstract
Nasopharyngeal carcinoma (NPC) is a malignant tumor with a high rate of local invasion and early distant metastasis. Accumulating studies suggest that N6-methyladenosine methylation (m6A) is closely related to tumorigenesis. However, the relationship between m6A-related genes and prognosis of NPC is poorly understood. Our research aims to discover the prognostic value of m6A RNA methylation genes in NPC. In this study, we analyzed the differentially expressed m6A-related genes between NPC samples and normal control samples and found that two upregulated genes (YTHDF3 and IGF2BP2) and one downregulated gene (METTL3) were overlapped in GSE68799 and GSE53819. Next, we found that high expression of IGF2BP1 and low expression of METTL3 and YTHDF3 in NPC patients showed poor progression-free survival (PFS). Subsequently, the four m6A genes were selected for consensus cluster analysis, and risk models were established. The risk signature, using three genes (GF2BP1 + IGF2BP2 + METTL3), was an independent prognostic factor and predicts the clinicopathological features of NPC. Additionally, the GO, KEGG analysis, and CIBERSORT algorithm revealed that the risk signature was closely associated to immune infiltration in NPC. Finally, the expression and clinical significance of METTL3 were successfully validated in NPC tissues using immunohistochemical techniques. In conclusion, our finding revealed the potential role of m6A modification in NPC, providing novel insight into NPC prognosis and therapeutic strategies.
Keywords: METTL3; immune infiltration; m6A; nasopharyngeal carcinoma; prognostic factors.
Copyright © 2020 Lu, Yu, Xiao and Zhang.
47 references7 figures
full-text links
full-text provider logo
Proceed to details Cite
Share
9
Front Oncol
. 2020 Jun 11;10:865. doi: 10.3389/fonc.2020.00865. eCollection 2020.
Ubiquitin C-Terminal Hydrolase L5 (UCHL5) Accelerates the Growth of Endometrial Cancer via Activating the Wnt/β-Catenin Signaling Pathway
Da Liu 1, Zixuan Song 1, Xiaoying Wang 1, Ling Ouyang 1
Affiliations expand
PMID: 32596150 PMCID: PMC7300206 DOI: 10.3389/fonc.2020.00865
Free PMC article
Abstract
Endometrial cancer (EC) is the most prevalent gynecological malignancy with high mortality. Chemotherapy plays a pivotal role both in an adjuvant setting and in exclusive treatment. However, current pharmacotherapies are limited and not ideal for improving the overall survival of EC patients. Thus, identification of the underlying molecular mechanisms responsible for initiation and progression of EC is imperative for developing novel therapeutic strategies. Ubiquitin C-terminal hydrolase L5 (UCHL5) has been found to aggravate tumor growth and metastasis in several different types of tumor models such as esophageal squamous cell carcinoma, hepatocellular carcinoma, and epithelial ovarian cancer. However, whether UCHL5 influences the growth of EC has not been elucidated. To expose the role of UCHL5 on EC, bioinformatics analysis was conducted, and it hinted that UCHL5 was overexpressed in EC tissues and associated with lower overall survival. Consistently, the overexpression of UCHL5 in EC tissues and cell lines was further confirmed by western blot (WB) and polymerase chain reaction (PCR) compared with non-tumor control. Lentivirus vectors carrying UCHL5 shRNA or CD sequences were used to reduce or overexpress the UCHL5 gene, respectively. Cell proliferation and cycle were facilitated, and cell apoptosis was decreased when the UCHL5 gene was overexpressed in EC cell lines. These results were opposite in UCHL5 knockdown EC cells. Additionally, the expression of β-catenin is positively related to UCHL5 levels and the tumorigenic effects of UCHL5 overexpression were reversed by the Wnt/β-catenin pathway inhibitor XAV939. Thus, Wnt/β-catenin pathway activation may be a partial mechanism responsible for the promoting effects of UCHL5 on EC growth. In conclusion, UCHL5 accelerated the growth of EC via the Wnt/β-catenin pathway and was expected to be an attractive target for EC treatment.
Keywords: UCHL5; Wnt/β-catenin pathway; XAV939; endometrial cancer; lentivirus vectors.
Copyright © 2020 Liu, Song, Wang and Ouyang.
39 references7 figures
full-text links
full-text provider logo
Proceed to details Cite
Share
10
Review Front Oncol
. 2020 Jun 11;10:942. doi: 10.3389/fonc.2020.00942. eCollection 2020.
The Role of Aberrant Metabolism in Cancer: Insights Into the Interplay Between Cell Metabolic Reprogramming, Metabolic Syndrome, and Cancer
Yina Yu 1, Liang Gong 2, Jun Ye 1
Affiliations expand
PMID: 32596159 PMCID: PMC7301691 DOI: 10.3389/fonc.2020.00942
Free PMC article
Abstract
Metabolic syndrome (MetS) is characterized by hyperglycemia, hypertension, dyslipidemia and abdominal obesity. Patients with MetS or other metabolic disorders are more susceptible to cancer development and recurrence and have a worse long-term prognosis. Moreover, the metabolic reprogramming observed in cancer cells has also been described as one of the new hallmarks of cancer. Thus, aberrant metabolism has been proposed as an important risk factor for cancer. Chronic inflammation, reactive oxygen species (ROS), and oncogenic signaling pathways are considered as main potential triggers. Considering the strong association between metabolism and cancer, metabolism-modulating drugs, including metformin and statins, as well as adopting a healthy lifestyle, have been extensively investigated as strategies to combat cancer. Furthermore, strategies that interfere with the metabolic rewiring of cells may also have potent anti-cancer effects. In this article, we provide a comprehensive review of current knowledge on the relationship between aberrant metabolism and cancer and discuss the potential use of metabolism-targeting strategy for the treatment of cancer.
Keywords: cancer; metabolic reprogramming; metabolic syndrome; metabolism-targeting therapy; metastasis.
Copyright © 2020 Yu, Gong and Ye.
110 references1 figure
supplementary info
Publication typesexpand
full-text links
full-text provider logo
Proceed to details Cite
Share
11
Front Oncol
. 2020 Jun 12;10:853. doi: 10.3389/fonc.2020.00853. eCollection 2020.
An Integrative Analysis Reveals the Underlying Association Between CTNNB1 Mutation and Immunotherapy in Hepatocellular Carcinoma
Zhuomao Mo 1, Yongdan Wang 1, Zhirui Cao 1, Pan Li 1, Shijun Zhang 1
Affiliations expand
PMID: 32596147 PMCID: PMC7304048 DOI: 10.3389/fonc.2020.00853
Free PMC article
Abstract
Background: Tumor mutational burden (TMB) was verified to be closely associated with immune checkpoint inhibitors, but it is unclear whether gene mutation has an effect on immunotherapy of hepatocellular carcinoma (HCC). This research aimed to investigate the underlying correlation between gene mutation and immunotherapy in HCC. Methods: The somatic gene mutation data and gene expression data were retrieved from International Cancer Genome Consortium database and The Cancer Genome Atlas (TCGA) database. The mutational genes were selected by the intersection of three cohorts and further identified using survival analysis and TMB correlation analysis. After the identification of key mutational gene, we explored the correlation between gene mutation and both the immune cell infiltration and immune inhibitors. The signaling pathways associated with gene mutation were confirmed through gene set enrichment analysis. Furthermore, the survival analysis and mutational analysis based on TCGA cohort were performed for the validation of included gene. Results: As one of the frequently mutational genes in HCC, CTNNB1 was finally included in our research, for which it showed the significant result in survival analysis and the positive association with TMB of the three cohorts. Meanwhile, the validation of TCGA showed the significant results. Furthermore, natural killer (NK) cells and neutrophil were found to significantly infiltrate CTNNB1 mutation group from two cohorts. Besides, further analysis demonstrated that four types of immune inhibitors (CD96, HAVCR2, LGALS9, and TGFB1) were downregulated in CTNNB1 mutation group. Conclusion: Our research firstly revealed the underlying association between CTNNB1 mutation and immunotherapy, and we speculated that CTNNB1 mutation may modulate NK cells by affecting CD96. However, more functional experiments should be performed for verification.
Keywords: CTNNB1; gene mutation; hepatocellular carcinoma; immune inhibitor; immunotherapy.
Copyright © 2020 Mo, Wang, Cao, Li and Zhang.
34 references8 figures
full-text links
full-text provider logo
Proceed to details Cite
Share
12
Front Oncol
. 2020 Jun 12;10:856. doi: 10.3389/fonc.2020.00856. eCollection 2020.
Identification of Potential Key Genes Associated With the Pathogenesis, Metastasis, and Prognosis of Triple-Negative Breast Cancer on the Basis of Integrated Bioinformatics Analysis
Bin Zhao 1, Yali Xu 1, Yang Zhao 2, Songjie Shen 1, Qiang Sun 1
Affiliations expand
PMID: 32596149 PMCID: PMC7304260 DOI: 10.3389/fonc.2020.00856
Free PMC article
Abstract
Objective: Breast cancer is the most common solid tumor affecting women and the second leading cause of cancer-related death worldwide, and triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer. We aimed to identify potential TNBC-specific therapeutic targets by performing an integrative analysis on previously published TNBC transcriptome microarray data. Methods: Differentially expressed genes (DEGs) between TNBC and normal breast tissues were screened using six Gene Expression Omnibus (GEO) datasets, and DEGs between metastatic TNBC and non-metastatic TNBC were screened using one GEO dataset. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses were performed on the overlapping DEGs. The Cancer Genome Atlas (TCGA) TNBC data were used to identify candidate genes that were strongly associated with survival. Expression of the candidate genes in TNBC cell lines was blocked or augmented using a lentivirus system, and transwell assays were used to determine their effect on TNBC migration. Results: Eight upregulated genes and nine downregulated genes were found to be differentially expressed both between TNBC and normal breast tissues and between metastatic TNBC and non-metastatic TNBC. Among them, S100P and SDC1 were identified as poor prognostic genes. Furthermore, compared with control cells, SDC1-overexpressing TNBC cells showed enhanced migration ability, whereas SDC1 knockdown markedly reduced the migration of TNBC cells. Conclusion: Our study determined that S100P and SDC1 may be potential treatment targets as well as prognostic biomarkers of TNBC.
Keywords: Gene Expression Omnibus; S100P; SDC1; The Cancer Genome Atlas; bioinformatics; triple-negative breast cancer.
Copyright © 2020 Zhao, Xu, Zhao, Shen and Sun.
31 references5 figures
full-text links
full-text provider logo
Proceed to details Cite
Share
13
Front Oncol
. 2020 Jun 12;10:956. doi: 10.3389/fonc.2020.00956. eCollection 2020.
LncRNA NBR2 Inhibits the Malignancy of Thyroid Cancer, Associated With Enhancing the AMPK Signaling
Wen Yang 1, Zhikun Zheng 2, Pengfei Yi 1, Shi Wang 1, Ning Zhang 1, Jie Ming 1, Jie Tan 1, Hui Guo 1
Affiliations expand
PMID: 32596161 PMCID: PMC7304297 DOI: 10.3389/fonc.2020.00956
Free PMC article
Abstract
Long non-coding RNA NBR2 is a transcript of the neighbor of BRCA1 gene 2 and can regulate tumor development. However, there is little information on the role of NBR2 in the progression of thyroid cancers (TC). Here, we show that NBR2 expression is down-regulated in TC tissues and associated with histologic subtypes of TC. NBR2 expression was variably reduced in different TC cells. While NBR2 silencing significantly enhanced the malignancy of BCPAP cells by increasing cell proliferation, clonogenicity, wound healing, and invasion as well as tumor growth in vivo, and decreasing spontaneous apoptosis, NBR2 over-expression had opposite effects in BHT101 cells. Furthermore, treatment with A-769662 (a specific AMPK activator), like NBR2 over-expression, significantly attenuated the malignancy of BHT101 cells while treatment with Compound C (a specific AMPK inhibitor) significantly rescued that NBR2-reduced malignancy of BHT101 cells. In comparison with non-tumor thyroid epithelial Nthy-ori 3-1 cells, obviously increased GLUT-1 expression, but decreased AMPK and ACC phosphorylation were detected in TC cells. While NBR2 silencing further enhanced GLUT-1 expression and reduced AMPK and ACC phosphorylation as well as the EMT process in BCPAP cells. NBR2 over-expression also had opposite effects in BHT101 cells. Similar patterns of GLUT-1 expression and AMPK and ACC phosphorylation were detected in the different types of xenograft TC tumors in vivo. Therefore, such data indicated that NBR2 acted as a tumor suppressor of thyroid cancers associated with enhancing the AMPK signaling and NBR2 may be a potential biomarker and therapeutic target for thyroid cancers.
Keywords: AMPK; EMT; LncRNA NBR2; malignancy; thyroid cancer.
Copyright © 2020 Yang, Zheng, Yi, Wang, Zhang, Ming, Tan and Guo.
28 references6 figures
full-text links
full-text provider logo
Proceed to details Cite
Share
14
Front Oncol
. 2020 Jun 12;10:839. doi: 10.3389/fonc.2020.00839. eCollection 2020.
Triple Immunotherapy Overcomes Immune Evasion by Tumor in a Melanoma Mouse Model
Mary-Ann N Jallad 1, Abdo R Jurjus 2, Elias A Rahal 1, Alexander M Abdelnoor 1
Affiliations expand
PMID: 32596146 PMCID: PMC7304320 DOI: 10.3389/fonc.2020.00839
Free PMC article
Abstract
Background: Melanoma is a malignancy with increasing incidence that underlies most skin cancer-related deaths. Advanced melanoma patients still have poor prognosis despite recently developed immunotherapies. This study devises a triple immunotherapy to treat melanoma in a mouse model. The combination includes anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) antibodies, Monophosphoryl-lipid-A (MPLA), and an Indolamine-Dioxygenase-1 (IDO1) inhibitor. The aim of the study is, first, to rule out any major toxic effects related to this therapy and, second, to assess its antitumor effects. Methods: Cancer-free C57BL/6 mice were randomized into control groups and groups receiving single, dual, or triple therapies of the defined treatments. Clinical signs, weight gain, and histological sections from their main organs were assessed. Then, melanoma-bearing mice were segregated into similar groups, monitored for survival, and their tumor size was measured repeatedly. Finally, flow cytometry was used to analyze immune cell populations in the tumor masses including CD4+, CD8+, and regulatory T cells in addition to natural killer cells. Results: No adverse effects were detected in any of the treated groups. Survival analysis indicated that the groups receiving dual or triple therapies had prolonged survival compared to the controls. However, the group receiving triple therapy was the only group to show statistically significant increase in survival compared to the controls. Tumor size progression paralleled the survival outcome. The group receiving the triple therapy showed statistically significant smaller tumor sizes compared to all the other groups throughout the whole monitoring period. Flow cytometry used to analyze immune cell populations in the tumor mass indicated that the triple immune therapy was capable of significantly enhancing the natural killer cell counts as well as the CD3+CD4+/Treg and CD3+CD8+/Treg ratios possibly enhancing the anti-tumorigenic environment. Conclusions: Generated data rule out any major adverse events pertaining to the triple immunotherapy and reveal its enhanced effectiveness in thwarting melanoma progression over all other tested treatments.
Keywords: 1-MT; IDO; MPLA; anti-CTLA-4 antibodies; immunotherapy; melanoma.
Copyright © 2020 Jallad, Jurjus, Rahal and Abdelnoor.
38 references6 figures
full-text links
full-text provider logo
Proceed to details Cite
Share
15
Front Oncol
. 2020 Jun 11;10:910. doi: 10.3389/fonc.2020.00910. eCollection 2020.
External Validation of a Predictive Model of Urethral Strictures for Prostate Patients Treated With HDR Brachytherapy Boost
Vanessa Panettieri 1 2, Tiziana Rancati 3, Eva Onjukka 4, Martin A Ebert 5 6 7, David J Joseph 7 8 9, James W Denham 10, Allison Steigler 10, Jeremy L Millar 1 11
Affiliations expand
PMID: 32596153 PMCID: PMC7300245 DOI: 10.3389/fonc.2020.00910
Free PMC article
Abstract
Purpose: For prostate cancer treatment, comparable or superior biochemical control was reported when using External-Beam-Radiotherapy (EBRT) with High-Dose-Rate-Brachytherapy (HDRB)-boost, compared to dose-escalation with EBRT alone. The conformal doses produced by HDRB could allow further beneficial prostate dose-escalation, but increase in dose is limited by normal tissue toxicity. Previous works showed correlation between urethral dose and incidence of urinary toxicity, but there is a lack of established guidelines on the dose constraints to this organ. This work aimed at fitting a Normal-Tissue-Complication-Probability model to urethral stricture data collected at one institution and validating it with an external cohort, looking at neo-adjuvant androgen deprivation as dose-modifying factor. Materials and Methods: Clinical and dosimetric data of 258 patients, with a toxicity rate of 12.8%, treated at a single institution with a variety of prescription doses, were collected to fit the Lyman-Kutcher-Burman (LKB) model using the maximum likelihood method. Due to the different fractionations, doses were converted into 2 Gy-equivalent doses (α/β = 5 Gy), and urethral stricture was used as an end-point. For validation, an external cohort of 187 patients treated as part of the TROG (Trans Tasman Radiation Oncology Group) 03.04 RADAR trial with a toxicity rate of 8.7%, was used. The goodness of fit was assessed using calibration plots. The effect of neo-adjuvant androgen deprivation (AD) was analyzed separating patients who had received it prior to treatment from those who did not receive it. Results: The obtained LKB parameters were TD50 = 116.7 Gy and m = 0.23; n was fixed to 0.3, based on numerical optimization of the likelihood. The calibration plot showed a good agreement between the observed toxicity and the probability predicted by the model, confirmed by bootstrapping. For the external validation, the calibration plot showed that the observed toxicity obtained with the RADAR patients was well-represented by the fitted LKB model parameters. When patients were stratified by the use of AD TD50 decreased when AD was not present. Conclusions: Lyman-Kutcher-Burman model parameters were fitted to the risk of urethral stricture and externally validated with an independent cohort, to provide guidance on urethral tolerance doses for patients treated with a HDRB boost. For patients that did not receive AD, model fitting provided a lower TD50 suggesting a protective effect on urethra toxicity.
Keywords: HDR brachytherapy; NTCP; predictive modeling; prostate cancer; urethra.
Copyright © 2020 Panettieri, Rancati, Onjukka, Ebert, Joseph, Denham, Steigler and Millar.
45 references5 figures
full-text links
full-text provider logo
Proceed to details Cite
Share
16
Review Front Oncol
. 2020 Jun 11;10:941. doi: 10.3389/fonc.2020.00941. eCollection 2020.
The Role of Long Non-Coding RNAs in Thyroid Cancer
Xuejiao Peng 1, Kun Zhang 2, Li Ma 1, Junfeng Xu 1, Weiqin Chang 1
Affiliations expand
PMID: 32596158 PMCID: PMC7300266 DOI: 10.3389/fonc.2020.00941
Free PMC article
Abstract
Thyroid cancer, the most common endocrine malignancy, has become the most commonly diagnosed malignant solid tumor. Moreover, some cases have poor prognosis, and the survival period is only 3-5 months. Long noncoding RNAs (lncRNAs) are a group of functional RNA molecules more than 200 nucleotides in length that lack the ability to encode protein but participate in all aspects of gene regulation. Functionally, many lncRNAs play essential roles in epigenetic regulation at transcriptional and post-transcriptional levels via various molecular mechanisms. Recent studies have discovered important roles for lncRNAs during the complex process of carcinogenesis in thyroid cancer. In this review, we focus on lncRNAs dysregulated in thyroid cancer and summarize recently reported associations between lncRNAs and thyroid cancer in order to demonstrate the significant value of lncRNAs in diagnosis and treatment.
Keywords: biomarker; long non-coding RNAs; molecular mechanism; thyroid cancer; tumorigenesis.
Copyright © 2020 Peng, Zhang, Ma, Xu and Chang.
127 references
supplementary info
Publication typesexpand
full-text links
full-text provider logo
Proceed to details Cite
Share
17
Review Front Oncol
. 2020 Jun 12;10:782. doi: 10.3389/fonc.2020.00782. eCollection 2020.
PARP Inhibitors in First-Line Therapy of Ovarian Cancer: Are There Any Doubts?
Elisena Franzese 1, Anna Diana 1, Sara Centonze 1, Sandro Pignata 2, Ferdinando De Vita 1, Fortunato Ciardiello 1, Michele Orditura 1
Affiliations expand
PMID: 32596142 PMCID: PMC7303974 DOI: 10.3389/fonc.2020.00782
Free PMC article
Abstract
The standard of care for newly diagnosed advanced ovarian cancer (NADOC) is represented by surgical debulking followed by systemic platinum-taxanes combination chemotherapy. At the last European Society for Medical Oncology (ESMO) Congress, results from three trials testing three different poly-adenosine-diphosphate-ribose-polymerase (PARP) inhibitors (olaparib, niraparib, veliparib) in first-line therapy of OC have been presented. For the first time, these studies evaluated the efficacy of PARP inhibitors in this setting and the relative predictive biomarkers for patients' selection. The use of a PARP inhibitor is related with prolonged progression free survival (PFS) in the whole population of NADOC, although the magnitude of benefit varies widely among subgroups, highlighting the need to identify specific biological subtypes into clinical practice. In this minireview, we discuss the updated data available from clinical studies in this scenario.
Keywords: BRCA 1/2 mutation carriers; PARP inhibitor (PARPi); first line; homologous recombination; ovarian cancer.
Copyright © 2020 Franzese, Diana, Centonze, Pignata, De Vita, Ciardiello and Orditura.
14 references
supplementary info
Publication typesexpand
full-text links
full-text provider logo
Proceed to details Cite
Share
18
Editorial Front Oncol
. 2020 Jun 12;10:939. doi: 10.3389/fonc.2020.00939. eCollection 2020.
Editorial: Emerging Therapies for Malignant Mesothelioma
Nico van Zandwijk 1, Glen Reid 2, Paul Baas 3
Affiliations expand
PMID: 32596157 PMCID: PMC7304317 DOI: 10.3389/fonc.2020.00939
Free PMC article
Abstract
No abstract available
Keywords: angiogenesis inhibitors; chemotherapy; immune environment; immunotherapy; malignant mesothelioma; microRNA; preclinical models; tumor biology.
Comment on
Editorial on the Research Topic Emerging Therapies for Malignant Mesothelioma
14 references
supplementary info
Publication typesexpand
full-text links
full-text provider logo
Proceed to details Cite
Share
19
Front Oncol
. 2020 Jun 12;10:949. doi: 10.3389/fonc.2020.00949. eCollection 2020.
Broad Spectrum Deubiquitinase Inhibition Induces Both Apoptosis and Ferroptosis in Cancer Cells
Li Yang 1 2, Xin Chen 2, Qianqian Yang 2, Jinghong Chen 2 3, Qingtian Huang 2, Leyi Yao 2, Ding Yan 2, Jiawen Wu 2, Peiquan Zhang 2, Daolin Tang 4, Nanshan Zhong 2, Jinbao Liu 2
Affiliations expand
PMID: 32596160 PMCID: PMC7304060 DOI: 10.3389/fonc.2020.00949
Free PMC article
Abstract
Proteasomal deubiquitinase (DUB) inhibition has been found to be effective in experimental cancer therapy by inducing proteasome inhibition and apoptosis. Ferroptosis is a form of regulated cell death characterized by an iron-dependent lipid peroxidation. Antioxidant enzyme glutathione peroxidase 4 (GPX4) plays a key role in blocking ferroptosis through directly reducing phospholipid hydroperoxides production. Since cytoplasmic DUB inhibition can promote protein degradation in the cell, we hypothesize that DUB inhibition induces GPX4 degradation. Here we used palladium pyrithione complex (PdPT), a broad spectrum deubiquitinase inhibitor, to explore its cell death induction and anti-cancer effect in vitro, ex vivo, and in vivo. Mechanically, caspase activation and GPX4 protein degradation are required for PdPT-induced apoptosis and ferroptosis, respectively. Notably, PdPT-induced multiple deubiquitinase inhibition is essential for proteasomal degradation of GPX4. These findings not only identify a novel mechanism of post-translational modification of GPX4 in ferroptosis, but also suggest a potential anti-caner therapeutic strategy using Pan-DUB inhibition.
Keywords: GPX4; apoptosis; cancer; deubiquitinase; ferroptosis.
Copyright © 2020 Yang, Chen, Yang, Chen, Huang, Yao, Yan, Wu, Zhang, Tang, Zhong and Liu.
53 references7 figures
full-text links
full-text provider logo
Proceed to details Cite
Share
20
Front Oncol
. 2020 Jun 11;10:896. doi: 10.3389/fonc.2020.00896. eCollection 2020.
Activation of STING by cGAMP Regulates MDSCs to Suppress Tumor Metastasis via Reversing Epithelial-Mesenchymal Transition
Hao Cheng 1 2, Qiming Xu 1 2, Xing Lu 1 2, Hong Yuan 1 2, Tiejun Li 3, Yuefan Zhang 4, Xiangshi Tan 1 2
Affiliations expand
PMID: 32596152 PMCID: PMC7300176 DOI: 10.3389/fonc.2020.00896
Free PMC article
Abstract
The role of cGAMP stimulating cGAS-cGAMP-STING-IRF3 pathway to inhibit tumor growth was well-established. Herein, the efficiency and pharmacological mechanism of cGAMP on regulating tumor metastasis was investigated. The effects of cGAMP regulating CD8+ T cells and myeloid-derived suppressor cells (MDSCs) in tumor microenvironment was explored. In this study, we found that cGAMP boosted STING signaling pathway to activate the production of IFN-γ from CD8+ T cells, and decreased the population of MDSCs in vivo. The metastasis in CT26 tumor bearing mice was inhibited by cGAMP via regulating EMT process. cGAMP played an important role in suppressing the production of reactive oxygen species (ROS) and nitric oxide (NO) from MDSCs, abolished the suppressive function of MDSCs to the T cells. All in all, the results indicated that the STING agonist cGAMP activated the production of IFN-γ from CD8+ T cells to suppress MDSCs in vivo.
Keywords: STING; cGAMP; epithelial-mesenchymal transition; metastasis; myeloid-derived suppressor cells.
Copyright © 2020 Cheng, Xu, Lu, Yuan, Li, Zhang and Tan.
45 references7 figures
full-text links
full-text provider logo
Proceed to details Cite
Share
21
Front Oncol
. 2020 Jun 12;10:824. doi: 10.3389/fonc.2020.00824. eCollection 2020.
GATA6 Exerts Potent Lung Cancer Suppressive Function by Inducing Cell Senescence
Wensheng Chen 1, Zhipeng Chen 1, Miaomiao Zhang 1, Yahui Tian 1, Lu Liu 1, Ruirui Lan 2, Guandi Zeng 1, Xiaolong Fu 3, Guoqing Ru 4, Wanting Liu 1, Liang Chen 1, Zhenzhen Fan 1
Affiliations expand
PMID: 32596145 PMCID: PMC7304445 DOI: 10.3389/fonc.2020.00824
Free PMC article
Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide. Tumor suppressor genes (TSGs) play a critical role in restricting tumorigenesis and impact the therapeutic effect of various treatments. However, TSGs remain to be systemically determined in lung cancer. Here, we identified GATA6 as a potent lung cancer TSG. GATA6 inhibited lung cancer cell growth in vitro and tumorigenesis in vivo. Mechanistically, GATA6 upregulated p53 and p21 mRNA while it inhibited AKT activation to stabilize p21 protein, thus inducing lung cancer cell senescence. Furthermore, we showed that ectopic expression of GATA6 led to dramatic slowdown of growth rate of established lung tumor xenograft in vivo.
Keywords: AKT; GATA6; lung cancer; p21; tumor suppressor genes.
Copyright © 2020 Chen, Chen, Zhang, Tian, Liu, Lan, Zeng, Fu, Ru, Liu, Chen and Fan.
43 references4 figures
full-text links
full-text provider logo
Proceed to details Cite
Share
Δεν υπάρχουν σχόλια:
Δημοσίευση σχολίου