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 Gene Expression Signature-Based Approach Identifies Antifungal Drug Ciclopirox As a Novel Inhibitor of HMGA2 in Colorectal Cancer

Biomolecules ◽  
2019 ◽  
Vol 9 (11) ◽  
pp. 688 ◽  
Author(s):  
Yu-Min Huang ◽  
Chia-Hsiung Cheng ◽  
Shiow-Lin Pan ◽  
Pei-Ming Yang ◽  
Ding-Yen Lin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Cell Cycle ◽  
Therapeutic Potential ◽  
Specific Inhibitor ◽  
Gene Expression Signature ◽  
Hsp90 Inhibitor ◽  
Response To Therapy ◽  
Mesenchymal Transition ◽  
Potential Inhibitor

Human high-mobility group A2 (HMGA2) encodes for a non-histone chromatin protein which influences a variety of biological processes, including the cell cycle process, apoptosis, the DNA damage repair process, and epithelial–mesenchymal transition. The accumulated evidence suggests that high expression of HMGA2 is related to tumor progression, poor prognosis, and a poor response to therapy. Thus, HMGA2 is an important molecular target for many types of malignancies. Our recent studies revealed the positive connections between heat shock protein 90 (Hsp90) and HMGA2 and that the Hsp90 inhibitor has therapeutic potential to inhibit HMGA2-triggered tumorigenesis. However, 43% of patients suffered visual disturbances in a phase I trial of the second-generation Hsp90 inhibitor, NVP-AUY922. To identify a specific inhibitor to target HMGA2, the Gene Expression Omnibus (GEO) database and the Library of Integrated Network-based Cellular Signatures (LINCS) L1000platform were both analyzed. We identified the approved small-molecule antifungal agent ciclopirox (CPX) as a novel potential inhibitor of HMGA2. In addition, CPX induces cytotoxicity of colorectal cancer (CRC) cells by induction of cell cycle arrest and apoptosis in vitro and in vivo through direct interaction with the AT-hook motif (a small DNA-binding protein motif) of HMGA2. In conclusion, this study is the first to report that CPX is a novel potential inhibitor of HMGA2 using a drug-repurposing approach, which can provide a potential therapeutic intervention in CRC patients.

scholarly journals Cross-platform Data Analysis Reveals a Generic Gene Expression Signature for Microsatellite Instability in Colorectal Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Anna Pačínková ◽  
Vlad Popovici
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Colon Cancer ◽  
Microsatellite Instability ◽  
Gene Expression Signature ◽  
Data Sets ◽  
Rna Seq ◽  
Cancer Data ◽  
Expression Signature ◽  
Endometrial Cancers

The dysfunction of the DNA mismatch repair system results in microsatellite instability (MSI). MSI plays a central role in the development of multiple human cancers. In colon cancer, despite being associated with resistance to 5-fluorouracil treatment, MSI is a favourable prognostic marker. In gastric and endometrial cancers, its prognostic value is not so well established. Nevertheless, recognising the MSI tumours may be important for predicting the therapeutic effect of immune checkpoint inhibitors. Several gene expression signatures were trained on microarray data sets to understand the regulatory mechanisms underlying microsatellite instability in colorectal cancer. A wealth of expression data already exists in the form of microarray data sets. However, the RNA-seq has become a routine for transcriptome analysis. A new MSI gene expression signature presented here is the first to be valid across two different platforms, microarrays and RNA-seq. In the case of colon cancer, its estimated performance was (i) AUC = 0.94, 95% CI = (0.90 – 0.97) on RNA-seq and (ii) AUC = 0.95, 95% CI = (0.92 – 0.97) on microarray. The 25-gene expression signature was also validated in two independent microarray colon cancer data sets. Despite being derived from colorectal cancer, the signature maintained good performance on RNA-seq and microarray gastric cancer data sets (AUC = 0.90, 95% CI = (0.85 – 0.94) and AUC = 0.83, 95% CI = (0.69 – 0.97), respectively). Furthermore, this classifier retained high concordance even when classifying RNA-seq endometrial cancers (AUC = 0.71, 95% CI = (0.62 – 0.81). These results indicate that the new signature was able to remove the platform-specific differences while preserving the underlying biological differences between MSI/MSS phenotypes in colon cancer samples.

Combined analysis of tumor budding and tumor microenvironment in patients with stage III colorectal cancer.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 652-652
Author(s):  
Hiromichi Nakajima ◽  
Naoko Inoshita ◽  
Chihiro Kondoh ◽  
Yukinori Ozaki ◽  
Kenji Tomizawa ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Prognostic Factor ◽  
Tumor Microenvironment ◽  
Epithelial Mesenchymal Transition ◽  
Cox Proportional Hazards ◽  
Stage Iii ◽  
Tumor Budding ◽  
Poor Prognostic Factor ◽  
Combined Analysis ◽  
Mesenchymal Transition

652 Background: Tumor budding (TB) represents the epithelial-mesenchymal transition (EMT) and is a novel marker that predicts metastasis and poor survival in patients with colorectal cancer. Although recent preclinical studies have elucidated the interaction between the EMT process and tumor microenvironment (TME), the clinicopathological correlation between TB and TME remains unclear. Methods: Formalin-fixed paraffin-embedded blocks of specimens were obtained from patients with stage III colorectal cancer who underwent surgical resection and adjuvant chemotherapy at our institution between January 2009 and July 2012. TB, tumor stroma percentage (TSP), and inflammatory reaction (IR) graded using the Klintrup-Mäkinen method were evaluated on hematoxylin and eosin sections. The densities of CD8+ T-cells at the tumor centers and invasive margins were analyzed using immunohistochemistry and digital image analysis. Cox proportional hazards models were used to assess the effect of clinicopathological variables on relapse-free survival (RFS). Results: One hundred and ninety-five patients were included in this analysis. The median age was 62 years (range 32–84 years). The median follow-up duration of this study was 5.8 years. High TB ( > 5 buds/0.785 mm2) was observed in 106 patients (54.4%) and was associated with high TSP (P < 0.01), but not with IR and CD8 expression. Multivariate analysis, including clinicopathological factors such as histology, TB, TSP, and IR revealed that high TB was an independent poor prognostic factor (hazard ratio, 1.89; 95% confidence interval, 1.04–3.45; P = 0.04). Patients with high TB and low IR (21.0%) exhibited a shorter survival than others; the 5-year RFS rates were 82.7%, 81.1%, 78.4%, and 40.8% in patients with low TB and high IR, low TB and IR, high TB and high IR, and high TB and low IR, respectively. Conclusions: Our study demonstrated that high TB was an adverse prognostic factor, regardless of TME status. The combined analysis of TB plus IR could improve prognostic value in patients with stage III colorectal cancer. Patients with high TB and low IR may need novel therapeutic approaches.

Association of PARP inhibitors and docetaxel resistance through suppressing a tumor microenvironment-associated secretory program.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e22212-e22212
Author(s):  
Song Zhao ◽  
Ilsa Coleman ◽  
Roger Coleman ◽  
Peter Nelson
Keyword(s):  
Growth Factors ◽  
Tumor Microenvironment ◽  
Metastatic Cancer ◽  
Chemotherapy Resistance ◽  
Genotoxic Stress ◽  
Parp Inhibitors ◽  
Cytotoxic Agents ◽  
Parp Inhibition ◽  
Mesenchymal Transition ◽  
Docetaxel Resistance

e22212 Background: Acquired resistance to therapeutics accounts for the majority of treatment failures in metastatic cancer. In response to genotoxic stress induced by therapeutics such as radiation and chemotherapy, tumor microenvironment (TME) undergoes marked molecular alterations manifested by increased secretion of cytokines and growth factors, which in turn promote tumor growth, facilitate epithelial-mesenchymal transition, and ultimately result in resistance to chemotherapy. Fibroblasts are a major component of TME and a primary source of cytokines and growth factor secretion following damage. Preliminary results from our lab indicated PARP1 may be involved in regulating this secretory program. We hypothesized that PARP inhibition would suppress the TME-associated secretory program and thereby overcome chemotherapy resistance. Methods: Transcript profiles of cytokines and growth factors were analyzed with quantitative real-time PCR and cDNA microarrays in prostate fibroblasts after treatment with radiation or docetaxel, in combination with one of three PARP inhibitors (PARPi). We evaluated the effects of the docetaxel-induced fibroblast secretory program, in the absence or presence of PARPi, on the proliferation and drug sensitivity of prostate cancer cell lines. Results: Similar to radiation, docetaxel induced the secretion of cytokines and growth factors in prostate fibroblasts. PARP1 was activated by docetaxel treatment. Exposure to PARPi suppressed the docetaxel-induced secretory program. Further analysis suggested that PARPi abrogates activation of p38MAPK pathway. While conditioned medium from docetaxel-treated prostate fibroblasts stimulated growth and chemotherapy resistance, the addition of PARPi attenuated these effects. Conclusions: Docetaxel induces extracellular secretion of pro-tumorigenic cytokines and growth factors by components of the TME. PARP inhibitors attenuated docetaxel resistance through suppression of this secretory program, supporting a new mechanism of action for this class of drugs. Combinatorial use of cytotoxic agents and microenvironment-directed therapies may reduce treatment resistance.

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 The Consumption of Cholesterol-Enriched Diets Conditions the Development of a Subtype of HCC with High Aggressiveness and Poor Prognosis

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1721
Author(s):  
Arturo Simoni-Nieves ◽  
Soraya Salas-Silva ◽  
Lisette Chávez-Rodríguez ◽  
Alejandro Escobedo-Calvario ◽  
Matthis Desoteux ◽  
...  
Keyword(s):  
Poor Prognosis ◽  
Gene Expression Signature ◽  
Cholesterol Content ◽  
Specific Gene ◽  
Chow Diet ◽  
Detailed Knowledge ◽  
Rna Seq ◽  
Alcoholic Fatty Liver ◽  
Aggressive Phenotype ◽  
Molecular Alterations

Non-alcoholic fatty liver disease (NAFLD) and progression to non-alcoholic steatohepatitis (NASH) result as a consequence of diverse conditions, mainly unbalanced diets. Particularly, high-fat and cholesterol content, as well as carbohydrates, such as those commonly ingested in Western countries, frequently drive adverse metabolic alterations in the liver and promote NAFLD development. Lipid liver overload is also one of the main risk factors for initiation and progression of hepatocellular carcinoma (HCC), but detailed knowledge on the relevance of high nutritional cholesterol remains elusive. We were aimed to characterize HCC development in mice fed with a Western diet (high in lipids and cholesterol) and to identify molecular alterations that define a subtype of liver cancer induced by lipid overload. Mice under western or high cholesterol diets more frequently developed tumors with a more aggressive phenotype than animals fed with a chow diet. Associated changes involved macrophage infiltration, angiogenesis, and stemness features. RNA-seq revealed a specific gene expression signature (Slc41a; Fabp5; Igdcc4 and Mthfd1l) resembling the adverse phenotypic features and poor clinical outcomes seen in patients with HCC. In conclusion; consumption of lipid enriched diets; particularly cholesterol; could accelerate HCC development with an aggressive phenotype and poor prognosis

scholarly journals Correlation between Lgr5 Expression and 5-FU based Chemotherapy Response in Stage IV Colorectal Cancer Patients

2021 ◽  
Vol 5 (10) ◽  
pp. 931-939
Author(s):  
Kgs. M. Rosyidi ◽  
Mediarty Syahrir ◽  
Suly Auline Rusminan ◽  
Legiran
Keyword(s):  
Colorectal Cancer ◽  
Wnt Signaling ◽  
Cancer Patients ◽  
Chemotherapy Resistance ◽  
Stage Iv ◽  
Chemotherapy Response ◽  
Stage Iv Colorectal Cancer ◽  
Contingency Coefficient ◽  
Lgr5 Expression ◽  
Colorectal Cancer Patients

Background. Colorectal cancer is the third commonest malignancy and the second leading cause of cancer death in the world. 5-Fluorouracyl-based chemotherapy is the primary treatment modality for colorectal cancer. Cancer stem cells are known to be responsible for chemotherapy resistance. Lgr5 is a colorectal cancer stem cell marker that is the target gene for Wnt signaling. Lgr5 potentiates the Wnt signaling pathway through inhibition of a regulator that inhibits Wnt signaling. Lgr5 overexpression is associated with a worse prognosis and chemotherapy resistance. This study was aimed to investigate the correlation between Lgr5 expression and 5-FU-based chemotherapy response in stage IV colorectal cancer patients at Dr. Mohammad Hoesin Hospital Palembang.Methods. This study used a correlative analysis study with a retrospective design using secondary data from medical records and paraffin blocks of stage IV colorectal cancer patients who received 5-FU-based chemotherapy from September 2018 to September 2020. The number of samples was 30 subjects consisting of 22 cases of negative responses and eight positive responses. All samples were stained with Lgr5 immunohistochemistry. Data analysis used the contingency coefficient correlation test.Results. Of the 30 research subjects, 20 subjects (66.7%) had high Lgr5 expression and ten subjects (33.3%) with low Lgr5 expression. Correlation analysis using the contingency coefficient test showed a weak correlation between Lgr5 expression and 5-FU based chemotherapy response with a positive direction, which means the higher the Lgr5 expression, the less response to chemotherapy.Conclusion. There is a weak correlation between Lgr5 expression and 5-FU based chemotherapy response in stage IV colorectal cancer patients at dr.Mohammad Hoesin Hospital Palembang.

scholarly journals Resveratrol Chemosensitizes TNF-β-Induced Survival of 5-FU-Treated Colorectal Cancer Cells

Nutrients ◽  
2018 ◽  
Vol 10 (7) ◽  
pp. 888 ◽  
Author(s):  
Constanze Buhrmann ◽  
Mina Yazdi ◽  
Bastian Popper ◽  
Parviz Shayan ◽  
Ajay Goel ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Epithelial To Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Tnf Α ◽  
Colorectal Cancer Cells ◽  
Carcinogenic Effects ◽  
Underlying Mechanisms ◽  
Lymphotoxin Α ◽  
First Time

Objective: Resveratrol, a safe and multitargeted natural agent, has been linked with inhibition of survival and invasion of tumor cells. Tumor Necrosis Factor-β (TNF-β) (Lymphotoxin α) is known as an inflammatory cytokine, however, the underlying mechanisms for its pro-carcinogenic effects and whether resveratrol can suppress these effects in the tumor microenvironment are poorly understood. Methods: We investigated whether resveratrol modulates the effects of 5-Fluorouracil (5-FU) and TNF-β on the malignant potential of human colorectal cancer (CRC) cells (HCT116) and their corresponding isogenic 5-FU-chemoresistant derived clones (HCT116R) in 3D-alginate tumor microenvironment. Results: CRC cells cultured in alginate were able to migrate from alginate and the numbers of migrated cells were significantly increased in the presence of TNF-β, similar to TNF-α, and dramatically decreased by resveratrol. We found that TNF-β promoted chemoresistance in CRC cells to 5-FU compared to control cultures and resveratrol chemosensitizes TNF-β-induced increased capacity for survival and invasion of HCT116 and HCT116R cells to 5-FU. Furthermore, TNF-β induced a more pronounced cancer stem cell-like (CSC) phenotype (CD133, CD44, ALDH1) and resveratrol suppressed formation of CSC cells in two different CRC cells and this was accompanied with a significant increase in apoptosis (caspase-3). It is noteworthy that resveratrol strongly suppressed TNF-β-induced activation of tumor-promoting factors (NF-κB, MMP-9, CXCR4) and epithelial-to-mesenchymal-transition-factors (increased vimentin and slug, decreased E-cadherin) in CRC cells. Conclusion: Our results clearly demonstrate for the first time that resveratrol modulates the TNF-β signaling pathway, induces apoptosis, suppresses NF-κB activation, epithelial-to-mesenchymal-transition (EMT), CSCs formation and chemosensitizes CRC cells to 5-FU in a tumor microenvironment.

6-phosphofructo-2-kinase as therapeutic targets in cancer based on an integrated pan-cancer study6-phosphofructo-2-kinase as therapeutic targets in cancer based on an integrated pan-cancer study

2020 ◽  
Author(s):  
Haimei Qin ◽  
Junli Wang ◽  
Biyun Liao ◽  
Zhonglin Liu ◽  
Feng Shi ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Drug Sensitivity ◽  
Clinical Phenotype ◽  
Therapeutic Targets ◽  
Tumour Microenvironment ◽  
Rna Seq ◽  
Cancer Subtypes ◽  
R Language ◽  
Cancer Data ◽  
Pan Cancer

Abstract Background: Warburg effect confirm that tumor cells prefer to use glycolysis to perform metabolism glucose metabolism. PFKFB enzymes involve the activity of 6-phosphofructo-1-kinase in the metabolism of glycolysis. But their roles in immunity and the regulation of tumor microenvironment has not been fully understood. Methods: We performed a comprehensive analysis of PFKFB in with immune subtypes, tumour microenvironment, and drug sensitivity from data of pan-cancer. Data of 33 cancer subtypes including RNA-Seq, clinical phenotype, stemness scores of mRNA (RNAss) and DNA-methylation (DNAss), and immune subtypes was downloaded from TCGA. NCI-60 data and RNA-seq data were acquired from the CellMiner. Perl language and R language with packages were used to deal with data. Results: Expression of PFKFB family emerges different heterogeneity in different cancer. PFKFB1, PFKFB3 and PFKFB4 predicted poor prognosis of patients with multiple cancers. All members are associated with immune response. PFKFB3 and PFKFB4 involved tumor microenvironment of pan-cancer. Importantly, our study found that PFKFB genes, especially PFKFB2 and PFKFB4 may contribute to drug resistance in cancer cells. Conclusions: PFKFB family member possess special characters in each cancer based on gene expression and their correlation with immune infiltrates, tumor microenvironment. PFKFB2 and PFKFB4 may act as therapeutic targets in cancer.

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