Microbiota in cancer chemoradiotherapy resistance.
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ABSTRACT:
SUBMITTER: He Y
PROVIDER: S-EPMC7774460 | biostudies-literature | 2021 Jan
REPOSITORIES: biostudies-literature
Publications
Microbiota in cancer chemoradiotherapy resistance.
He Yan Y Liu Qin Wen QW Liao Hua Xin HX Xu Wen Wen WW
Clinical and translational medicine 20210101 1
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Project description:Colorectal cancer (CRC) is among the main tumor-related causes of death worldwide. The fact that the majority of the patients develop resistance to chemoradiotherapy (CRT) is a major obstacle for the treatment of CRC. In order to develop more effective treatment strategies, it is crucial to elucidate the mechanisms underlying the development of resistance to CRT. Several studies have recently indicated the regulatory effects of microRNAs (miRNAs) in response to antitumor agents. For example, miR-34a attenuates the chemoresistance of colon cancer to 5-FU by inhibiting E2F3 and SIRT1. The miR-34a mimic MRX34 is the first synthetic miRNA to have been entered into clinical trials. miR-21 prevents tumor cell stemness, invasion and drug resistance, which are required for the development of CRC. These findings suggest that miRNAs represent a focus in the research of novel cancer treatments aimed at sensitizing cancer cells to chemotherapeutic drugs. The aim of the present study was to review the functions of miRNAs and investigate the roles of miRNAs in CRC radioresistance or chemoresistance. Furthermore, the potential of including miRNAs in therapeutic strategies and using them as molecular biomarkers for predicting radiosensitivity and chemosensitivity was discussed.
| S-EPMC5844042 | biostudies-literature
Project description:Activation of Wnt/β-catenin signaling plays a central role in the development and progression of colorectal cancer (CRC). Previously, we demonstrated that the Wnt transcription factor, TCF7L2, was overexpressed in primary rectal cancers that were resistant to chemoradiotherapy (CRT), and that TCF7L2 functionally mediates resistance of CRC cells to CRT. However, it remained unclear whether the resistance was mediated by a TCF7L2 inherent mechanism or Wnt/β-catenin signaling in general. We now show that silencing of β-catenin resulted in sensitization of the CRC cell lines LS1034, SW480, and SW837 to CRT, demonstrating a relationship between Wnt/β-catenin signaling and CRT resistance. To investigate the potential role of Wnt/β-catenin signaling in controlling therapeutic responsiveness, non-tumorigenic RPE-1 cells were stimulated with Wnt-3a, a physiological ligand at the Frizzled receptor, which significantly increased resistance to CRT. This effect could be recapitulated by overexpression of mutated, undegradable β-catenin (S33Y). Again, this resulted in a significantly boosted resistance of RPE-1 cells to CRT, which was abrogated by siRNA-mediated silencing of β-catenin. Consistent with these findings, we observed higher expression levels of active (unphosphorylated) β-catenin as well as increased TCF/LEF reporter activity in SW1463 cells that evolved radiation-resistance due to repeated radiation-treatment. Global gene expression profiling identified several altered pathways associated with treatment response as a consequence of Wnt/β-catenin pathway activation, sheading new light on PPARD signaling as a possible mechanism of Wnt mediated resistance. Hence, synergistic pathway inhibition of either Wnt and/or one of the downstream-pathways may represent a promising strategy to increase therapeutic responsiveness to CRT.
2017-05-01 | GSE97543 | GEO
Project description:Objectives:Patients with head and neck squamous cell carcinoma undergoing concomitant chemoradiotherapy (CCRT) frequently experience weight loss, especially loss of lean body mass (LBM), and reduced functional performance. This study investigated whether a 12-week hospital-based progressive resistance training (PRT) program during CCRT is feasible in the clinical setting before planning initiation of a larger randomized study which is the long-term goal. Study design:Prospective pilot study. Methods:Twelve patients receiving CCRT were planned to attend a 12-week PRT program. Primary endpoint was feasibility measured as attendance to training sessions. Secondary endpoints included changes in functional performance, muscle strength, and body composition measured by Dual-energy X-ray Absorptiometry (DXA) scans. Furthermore, sarcomeric protein content, pentose phosphate pathway (PPP) activity, and glycolysis were determined in muscle biopsies. Results:Twelve patients with p16 positive oropharyngeal cancer were enrolled. The primary endpoint was met with 9 of the 12 patients completing at least 25 of 36 planned training sessions. The mean attendance rate was 77%. Functional performance was maintained during the treatment period and increased during follow-up (p < 0.01). Strength was regained after an initial dip during treatment, paralleling responses in LBM and sarcomeric protein content. LBM began to increase immediately after treatment. The PPP was upregulated after the treatment period, whilst glycolysis remained unchanged. No adverse events were related to PRT and in questionnaires, patients emphasized the social and psychological benefits of attendance. Conclusion:Progressive resistance training is feasible and safe during CCRT for head and neck cancer, and is associated with high patient satisfaction. Level of Evidence:2C.
| S-EPMC5654939 | biostudies-literature
Project description:PurposePreoperative concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced rectal cancer patients. However, the poor therapeutic efficacy of CCRT was found in rectal cancer patients with hyperglycemia. This study investigated how hyperglycemia affects radiochemotherapy resistance in rectal cancer.Methods and materialsWe analyzed the correlation between prognosis indexes with hypoxia-inducible factor-1 alpha (HIF-1α) in rectal cancer patients with preoperative CCRT. In vitro, we investigated the effect of different concentrated glucose of environments on the radiation tolerance of rectal cancers. Further, we analyzed the combined HIF-1α inhibitor with radiation therapy in hyperglycemic rectal cancers.ResultsThe prognosis indexes of euglycemic or hyperglycemic rectal cancer patients after receiving CCRT treatment were investigated. The hyperglycemic rectal cancer patients (n = 13, glycosylated hemoglobin, HbA1c > 6.5%) had poorer prognosis indexes. In addition, a positive correlation was observed between HIF-1α expression and HbA1c levels (p = 0.046). Therefore, it is very important to clarify the relationship between HIF-1α and poor response in patients with hyperglycemia receiving pre-operative CCRT. Under a high glucose environment, rectal cancer cells express higher levels of glucose transport 1 (GLUT1), O-GlcNAc transferase (OGT), and HIF-1α, suggesting that the high glucose environment might stimulate HIF-1α expression through the GLUT1-OGT-HIF-1α pathway promoting tolerance to Fluorouracil (5-FU) and radiation. In the hyperglycemic rectal cancer animal model, rectal cancer cells confirmed that radiation exposure reduces apoptosis by overexpressing HIF-1α. Combining HIF-1α inhibitors was able to reverse radioresistance in a high glucose environment. Lower HIF-1α levels increased DNA damage in tumors leading to apoptosis.ConclusionsThe findings here show that hyperglycemia induces the expression of GLUT1, OGT, and HIF-1α to cause CCRT tolerance in rectal cancer and suggest that combining HIF-1α inhibitors could reverse radioresistance in a high glucose environment. HIF-1α inhibitors may be useful for development as CCRT sensitizers in patients with hyperglycemic rectal cancer.
| S-EPMC9406860 | biostudies-literature
Project description:Activation of Wnt/β-catenin signaling plays a central role in the development and progression of colorectal cancer. The Wnt-transcription factor, TCF7L2, is overexpressed in primary rectal cancers that are resistant to chemoradiotherapy and TCF7L2 mediates resistance to chemoradiotherapy. However, it is unclear whether the resistance is mediated by a TCF7L2 inherent mechanism or Wnt/β-catenin signaling in general. Here, inhibition of β-catenin by siRNAs or a small-molecule inhibitor (XAV-939) resulted in sensitization of colorectal cancer cells to chemoradiotherapy. To investigate the potential role of Wnt/β-catenin signaling in controlling therapeutic responsiveness, nontumorigenic RPE-1 cells were stimulated with Wnt-3a, a physiologic ligand of Frizzled receptors, which increased resistance to chemoradiotherapy. This effect could be recapitulated by overexpression of a degradation-resistant mutant of β-catenin (S33Y), also boosting resistance of RPE-1 cells to chemoradiotherapy, which was, conversely, abrogated by siRNA-mediated silencing of β-catenin. Consistent with these findings, higher expression levels of active β-catenin were observed as well as increased TCF/LEF reporter activity in SW1463 cells that evolved radiation resistance due to repeated radiation treatment. Global gene expression profiling identified several altered pathways, including PPAR signaling and other metabolic pathways, associated with cellular response to radiation. In summary, aberrant activation of Wnt/β-catenin signaling not only regulates the development and progression of colorectal cancer, but also mediates resistance of rectal cancers to chemoradiotherapy.Implications: Targeting Wnt/β-catenin signaling or one of the downstream pathways represents a promising strategy to increase response to chemoradiotherapy. Mol Cancer Res; 15(11); 1481-90. ©2017 AACR.
| S-EPMC5772978 | biostudies-literature
Project description:We isolated quiescent CSCs using chemoradiotherapy resistance assays on tumors of MMTV-PyMT transgenic (specific breast cancer model) mice. We found that quiescent CSCs specifically expressed SETD4 without exception, and beyond activation exhibited high capacity of tumor-initiation in vivo and tumorsphere formation in vitro. Quiescent CSCs expressed high levels of ALDH1 and CD44 and low levels of CD24, that corresponds with their use as breast CSCs markers. Quiescent CSCs were showed to be resistant and able to survive under chemoradiotherapy treatment in either in vivo or in vitro models. Similarly, SETD4 overexpression caused cells extracted from tumors to exhibit clear chemoradiotherapy resistance. Transcriptomic analysis revealed that the molecular processes associated with cellular quiescence included those of DNA damage response and the Wnt/β-catenin signaling pathway. Together with our previous results, these findings showed that SETD4 marks quiescent CSCs and suggest that SETD4-marked quiescent CSCs could be used as key targets in clinical treatment for multiple cancers.
2021-01-24 | GSE165380 | GEO
Project description:RNA-Seq data of human colorectal cancer cell line SW837 transfected with siRNA against STAT3 (siSTAT3) or control RNA (siCtrl), untreated or treated with Hyper-IL-6 (Hy-IL-6)
2021-01-25 | GSE139455 | GEO
Project description: Not available
| S-EPMC1774863 | biostudies-literature
Project description:Approximately 30% of locally advanced rectal cancer patients might not benefit from chemoradiotherapy; however, the response to neoadjuvant chemoradiotherapy in these cases is difficult to predict. Pim-3 is a member of the provirus integration site for a moloney murine leukemia virus family of proteins that contributes to cell proliferation, survival, and chemotherapy resistance. Therefore, the relationship between Pim-3 expression and response to neoadjuvant chemoradiotherapy in rectal cancer patients is important to evaluate. 175 rectal cancer patients who underwent neoadjuvant treatment enrolled in this study. The relationship between Pim-3 expression on immunohistochemical analysis of rectal cancer tissue, which was obtained before treatment, the response to chemoradiotherapy and survival was investigated. The patients with no Pim-3 expression were more likely to achieve a pathologic complete response to chemoradiotherapy than patients with Pim-3 expression (P = 0.001). Cox multivariate analysis showed that the significant prognostic factors were Pim-3 expression (P = 0.003) and the number of neoadjuvant chemotherapy cycles (P = 0.005) for overall survival. Neoadjuvant chemotherapy cycles (P = 0.007), adjuvant chemotherapy cycles (P = 0.004) and pathology types (P = 0.049) were significant prognostic factors for disease-free survival. Pim-3 is a potential predictive biomarker for the response of rectal cancer to chemoradiotherapy.
| S-EPMC5700084 | biostudies-literature
Project description:The excision repair cross-complementing group 1 (ERCC1) gene performs a critical incision step in DNA repair and is reported to be correlated with carcinogenesis and resistance to drug or ionizing radiation therapy. We reviewed the correlation between ERCC1 and bladder cancer. In carcinogenesis, several reports discussed the relation between ERCC1 single nucleotide polymorphisms and carcinogenesis in bladder cancer only in case-control studies. Regarding the relation between ERCC1 and resistance to chemoradiotherapy, in vitro and clinical studies indicate that ERCC1 might be related to resistance to radiation therapy rather than cisplatin therapy. It is controversial whether ERCC1 predicts prognosis of bladder cancer treated with cisplatin-based chemotherapy. Tyrosine kinase receptors or endothelial-mesenchymal transition are reported to regulate the expression of ERCC1, and further study is needed to clarify the mechanism of ERCC1 expression and resistance to chemoradiotherapy in vitro and to discover novel therapies for advanced and metastatic bladder cancer.
| S-EPMC3205704 | biostudies-literature