scholarly journals IL-6 regulates autophagy and chemotherapy resistance by promoting BECN1 phosphorylation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Fuqing Hu ◽  
Da Song ◽  
Yumeng Yan ◽  
Changsheng Huang ◽  
Chentao Shen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Cancer Therapy ◽  
Complex Formation ◽  
Combination Treatment ◽  
Molecular Mechanisms ◽  
Chemotherapy Resistance ◽  
Predictive Marker ◽  
Pharmacological Agents ◽  
Potential Strategy

AbstractExtracellular cytokines are enriched in the tumor microenvironment and regulate various important properties of cancers, including autophagy. However, the precise molecular mechanisms underlying the link between autophagy and extracellular cytokines remain to be elucidated. In the present study, we demonstrate that IL-6 activates autophagy through the IL-6/JAK2/BECN1 pathway and promotes chemotherapy resistance in colorectal cancer (CRC). Mechanistically, IL-6 triggers the interaction between JAK2 and BECN1, where JAK2 phosphorylates BECN1 at Y333. We demonstrate that BECN1 Y333 phosphorylation is crucial for BECN1 activation and IL-6-induced autophagy by regulating PI3KC3 complex formation. Furthermore, we investigate BECN1 Y333 phosphorylation as a predictive marker for poor CRC prognosis and chemotherapy resistance. Combination treatment with autophagy inhibitors or pharmacological agents targeting the IL-6/JAK2/BECN1 signaling pathway may represent a potential strategy for CRC cancer therapy.

scholarly journals A tumor microenvironment-specific gene expression signature predicts chemotherapy resistance in colorectal cancer patients

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Xiaoqiang Zhu ◽  
Xianglong Tian ◽  
Linhua Ji ◽  
Xinyu Zhang ◽  
Yingying Cao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Drug Sensitivity ◽  
Chemotherapy Resistance ◽  
Gene Expression Signature ◽  
Prediction Algorithm ◽  
Specific Gene ◽  
Chemotherapy Response ◽  
Rna Seq ◽  
Mesenchymal Transition

AbstractStudies have shown that tumor microenvironment (TME) might affect drug sensitivity and the classification of colorectal cancer (CRC). Using TME-specific gene signature to identify CRC subtypes with distinctive clinical relevance has not yet been tested. A total of 18 “bulk” RNA-seq datasets (total n = 2269) and four single-cell RNA-seq datasets were included in this study. We constructed a “Signature associated with FOLFIRI resistant and Microenvironment” (SFM) that could discriminate both TME and drug sensitivity. Further, SFM subtypes were identified using K-means clustering and verified in three independent cohorts. Nearest template prediction algorithm was used to predict drug response. TME estimation was performed by CIBERSORT and microenvironment cell populations-counter (MCP-counter) methods. We identified six SFM subtypes based on SFM signature that discriminated both TME and drug sensitivity. The SFM subtypes were associated with distinct clinicopathological, molecular and phenotypic characteristics, specific enrichments of gene signatures, signaling pathways, prognosis, gut microbiome patterns, and tumor lymphocytes infiltration. Among them, SFM-C and -F were immune suppressive. SFM-F had higher stromal fraction with epithelial-to-mesenchymal transition phenotype, while SFM-C was characterized as microsatellite instability phenotype which was responsive to immunotherapy. SFM-D, -E, and -F were sensitive to FOLFIRI and FOLFOX, while SFM-A, -B, and -C were responsive to EGFR inhibitors. Finally, SFM subtypes had strong prognostic value in which SFM-E and -F had worse survival than other subtypes. SFM subtypes enable the stratification of CRC with potential chemotherapy response thereby providing more precise therapeutic options for these patients.

scholarly journals The Mechanism of Warburg Effect-Induced Chemoresistance in Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Chang Liu ◽  
Ying Jin ◽  
Zhimin Fan
Keyword(s):  
Overall Survival ◽  
Tumor Microenvironment ◽  
Cancer Therapy ◽  
Cancer Patients ◽  
Warburg Effect ◽  
Molecular Mechanisms ◽  
Molecular Targets ◽  
Glycolysis Process ◽  
New Molecular Targets ◽  
The Warburg Effect

Although chemotherapy can improve the overall survival and prognosis of cancer patients, chemoresistance remains an obstacle due to the diversity, heterogeneity, and adaptability to environmental alters in clinic. To determine more possibilities for cancer therapy, recent studies have begun to explore changes in the metabolism, especially glycolysis. The Warburg effect is a hallmark of cancer that refers to the preference of cancer cells to metabolize glucose anaerobically rather than aerobically, even under normoxia, which contributes to chemoresistance. However, the association between glycolysis and chemoresistance and molecular mechanisms of glycolysis-induced chemoresistance remains unclear. This review describes the mechanism of glycolysis-induced chemoresistance from the aspects of glycolysis process, signaling pathways, tumor microenvironment, and their interactions. The understanding of how glycolysis induces chemoresistance may provide new molecular targets and concepts for cancer therapy.

Tumor microenvironment acid-sensitive liposomes enhanced colorectal cancer therapy by acting on both tumor cells and cancer-associated fibroblasts

Nanoscale ◽  
2021 ◽  
Author(s):  
chenglei li ◽  
Zhaohuan Li ◽  
Xue Gong ◽  
Jianhao Liu ◽  
Tingyue Zheng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Cancer Therapy ◽  
Tumor Cells ◽  
Crucial Role ◽  
Tumor Invasion ◽  
Cancer Associated Fibroblasts ◽  
Invasion And Metastasis ◽  
Promising Strategy

Cancer-associated fibroblasts (CAFs) play a crucial role in facilitating tumor invasion and metastasis, which act as the “soils” in tumor microenvironment (TME). Accordingly, it would be a promising strategy to...

scholarly journals Angioregulatory microRNAs in Colorectal Cancer

Cancers ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 71 ◽  
Author(s):  
Mohammad Hasan Soheilifar ◽  
Michael Grusch ◽  
Hoda Keshmiri Neghab ◽  
Razieh Amini ◽  
Hamid Maadi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Molecular Mechanisms ◽  
The Other ◽  
Angiogenic Response ◽  
Rate Determining Step ◽  
Antiangiogenic Factors ◽  
The One ◽  
Tumor Suppressor Mirnas

Colorectal cancer (CRC) is one of the leading causes of cancer mortality. Angiogenesis is a rate-determining step in CRC development and metastasis. The balance of angiogenic and antiangiogenic factors is crucial in this process. Angiogenesis-related genes can be regulated post-transcriptionally by microRNAs (miRNAs) and some miRNAs have been shown to shuttle between tumor cells and the tumor microenvironment (TME). MiRNAs have context-dependent actions and can promote or suppress angiogenesis dependent on the type of cancer. On the one hand, miRNAs downregulate anti-angiogenic targets and lead to angiogenesis induction. Tumor suppressor miRNAs, on the other hand, enhance anti-angiogenic response by targeting pro-angiogenic factors. Understanding the interaction between these miRNAs and their target mRNAs will help to unravel molecular mechanisms involved in CRC progression. The aim of this article is to review the current literature on angioregulatory miRNAs in CRC.

scholarly journals Cyclodextrin-based host-guest complexes loaded with regorafenib for colorectal cancer treatment

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hongzhen Bai ◽  
Jianwei Wang ◽  
Chi Uyen Phan ◽  
Qi Chen ◽  
Xiurong Hu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Tumor Microenvironment ◽  
Tumor Cell ◽  
Tumor Cell Proliferation ◽  
Therapeutic Targeting ◽  
Potential Strategy ◽  
Colorectal Cancer Treatment ◽  
Channel Type

AbstractThe malignancy of colorectal cancer (CRC) is connected with inflammation and tumor-associated macrophages (TAMs), but effective therapeutics for CRC are limited. To integrate therapeutic targeting with tumor microenvironment (TME) reprogramming, here we develop biocompatible, non-covalent channel-type nanoparticles (CNPs) that are fabricated through host-guest complexation and self-assemble of mannose-modified γ-cyclodextrin (M-γ-CD) with Regorafenib (RG), RG@M-γ-CD CNPs. In addition to its carrier role, M-γ-CD serves as a targeting device and participates in TME regulation. RG@M-γ-CD CNPs attenuate inflammation and inhibit TAM activation by targeting macrophages. They also improve RG’s anti-tumor effect by potentiating kinase suppression. In vivo application shows that the channel-type formulation optimizes the pharmacokinetics and bio-distribution of RG. In colitis-associated cancer and CT26 mouse models, RG@M-γ-CD is proven to be a targeted, safe and effective anti-tumor nanomedicine that suppresses tumor cell proliferation, lesions neovascularization, and remodels TME. These findings indicate RG@M-γ-CD CNPs as a potential strategy for CRC treatment.

scholarly journals Cancer-Associated Fibroblasts Promote the Upregulation of PD-L1 Expression Through Akt Phosphorylation in Colorectal Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Yang Gao ◽  
Zhao Sun ◽  
Junjie Gu ◽  
Zhe Li ◽  
Xiuxiu Xu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Molecular Mechanisms ◽  
Immune Escape ◽  
Disease Free Survival ◽  
Epithelial Tissue ◽  
Cancer Associated Fibroblasts ◽  
Tumor Immune Escape ◽  
Akt Phosphorylation

Upregulation of immune checkpoint proteins is one of the main mechanisms for tumor immune escape. The expression of programmed death ligand-1 (PD-L1) in colorectal cancer (CRC) is higher than in normal colorectal epithelial tissue, and patients with higher PD-L1 expression have a poorer prognosis. Additionally, PD-L1 expression in CRC is affected by the tumor microenvironment (TME). As a major component of the TME, cancer-associated fibroblasts (CAFs) can act as immune regulators and generate an immunosuppressive tumor microenvironment. Therefore, we speculated that CAFs may be related to the upregulation of PD-L1 in CRC, which leads to tumor immune escape. We found that CAFs upregulate PD-L1 expression in CRC cells through AKT phosphorylation, thereby reducing the killing of CRC cells by peripheral blood mononuclear cells. The ratio of CAFs to CRC cells was positively correlated with AKT phosphorylation and the expression of PD-L1 in CRC in vitro. Consistent with the in vitro results, high CAF content and high expression of PD-L1 were negatively correlated with disease-free survival (DFS) of CRC patients. These results indicate that the upregulation of PD-L1 expression in CRC by CAFs through the activation of Akt is one of the molecular mechanisms of tumor immune escape. Thus, targeted anti-CAF therapy may help improve the efficacy of immunotherapy.

scholarly journals Colorectal cancer treatment using bacteria: focus on molecular mechanisms

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Sara Ebrahimzadeh ◽  
Hossein Ahangari ◽  
Alireza Soleimanian ◽  
Kamran Hosseini ◽  
Vida Ebrahimi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Therapy ◽  
Cancer Treatment ◽  
Pathogenic Bacteria ◽  
Molecular Mechanisms ◽  
Treatment Strategies ◽  
Cancer Etiology ◽  
Beneficial Effects ◽  
Life Threatening ◽  
Colorectal Cancer Patients

Abstract Background Colorectal cancer which is related to genetic and environmental risk factors, is among the most prevalent life-threatening cancers. Although several pathogenic bacteria are associated with colorectal cancer etiology, some others are considered as highly selective therapeutic agents in colorectal cancer. Nowadays, researchers are concentrating on bacteriotherapy as a novel effective therapeutic method with fewer or no side effects to pay the way of cancer therapy. The introduction of advanced and successful strategies in bacterial colorectal cancer therapy could be useful to identify new promising treatment strategies for colorectal cancer patients. Main text In this article, we scrutinized the beneficial effects of bacterial therapy in colorectal cancer amelioration focusing on different strategies to use a complete bacterial cell or bacterial-related biotherapeutics including toxins, bacteriocins, and other bacterial peptides and proteins. In addition, the utilization of bacteria as carriers for gene delivery or other known active ingredients in colorectal cancer therapy are reviewed and ultimately, the molecular mechanisms targeted by the bacterial treatment in the colorectal cancer tumors are detailed. Conclusions Application of the bacterial instrument in cancer treatment is on its way through becoming a promising method of colorectal cancer targeted therapy with numerous successful studies and may someday be a practical strategy for cancer treatment, particularly colorectal cancer.

Regorafenib in metastatic colorectal cancer: An exploratory biomarker trial.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. TPS773-TPS773 ◽  
Author(s):  
Mohamed E. Salem ◽  
Emanuel Petricoin ◽  
Anton Wellstein ◽  
Mariaelena Pierobon ◽  
Hongkun Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Dna Analysis ◽  
Biomarker Discovery ◽  
Immune Cell ◽  
Predictive Marker ◽  
Primary Objective ◽  
Protein Signaling ◽  
Blood Samples

TPS773 Background: Treatment with Regorafenib (REGO) has shown significant clinical benefits in metastatic colorectal cancer (mCRC) patients (pts) as demonstrated in the CORRECT and CONCUR trials. Results from both studies suggest that subgroups have differential responses. Further research to identify these subgroups through the identification of molecular biomarkers is needed. Methods: Forty pts with refractory mCRC are being enrolled in this study. The primary objective is to prospectively identify tissue and serum-based biomarkers that can predict response to REGO. Secondary objectives are to determine molecular mechanisms by which REGO controls refractory mCRC, as well as molecular pathways involved in the acquisition of resistance. Tumor and blood samples are obtained prior to and 2 weeks after starting REGO. Blood samples are collected on day 1 of each cycle thereafter. Pts will receive 160 mg REGO daily for 3 weeks of each 4-week cycle until disease progression or unacceptable toxicity. Multi-omic based biomarker discovery approaches will be used to uncover predictive marker candidates with special attention to the tumor microenvironment. Laser capture microdissection will be used on tumor tissue to procure highly enriched populations of pt-matched epithelial and stromal/immune cell infiltrates. Each of these entities will be analyzed for RNA expression changes and protein signaling/drug target activation mapping. Protein signaling analysis will be performed by reverse phase protein array of key REGO-related proteins and phosphoproteins (e.g. phosphoVEGFR, Tie2, phosphoRET), as well as broad-scale mapping of mitogenic, survival, autophagy, inflammatory, motility, and signaling networks. Tumor profiling will include next-generation sequencing for 592 genes with 53 selected gene fusions, and IHC and FISH/CISH for selected biomarkers, including PDL1, HER2, MSI, TS, ERCC1, and TOPO1. Blood samples will undergo protein, miRNA, and mutated DNA analysis, as well as exosomal signature study via a proprietary synthetic polyligand multiplexed aptamer-based assay. Exploratory analysis of biomarkers will be used to determine correlations between the presence of, or change in, biomarker levels and clinical response. Clinical trial information: NCT01949194.

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