Chemoresistance mechanisms in colon cancer: focus on conventional chemotherapy

2021 ◽  
Vol 08 ◽  
Author(s):  
Klara Mladenić ◽  
Mirela Sedić
Keyword(s):  
Colon Cancer ◽  
Ribosome Biogenesis ◽  
Signalling Pathway ◽  
Screening Tests ◽  
Pathway Enrichment Analysis ◽  
Stem Cell Markers ◽  
Conventional Chemotherapy ◽  
Comprehensive Overview ◽  
Chemotherapy Drugs ◽  
Molecular Features

Background: Colorectal cancer (CRC) is a widespread tumour type amongst men and women. Despite the available screening tests, advanced stage CRC is the most frequent diagnosis. It is treated with cytotoxic chemotherapeutics 5-fluorouracil (5-FU), oxaliplatin (Ox) and irinotecan (CPT-11) that eventually lose their effectiveness as chemoresistance develops. Methods: In this review, the compilation and analysis of PUBMED-retrieved literature data was comprehensively presented and some novel and/or previously poorly described molecular features of CRC unresponsiveness to conventional chemotherapy drugs identified using bioinformatics approach. Complex interactions between previously reported biomarkers of resistance to 5-FU, Ox and CPT-11 were analysed by STRING and cytoHubba accompanied by KEGG pathway enrichment analysis using DAVID functional annotation tool. Results: The bioinformatics analysis has revealed that 5-FU affects ribosome biogenesis and functioning (translational activity) leading to colon cancer cells resistance to 5-FU. Unresponsiveness of CRC to Ox was associated with Rap1 signalling pathway, which opens the possibility of using RAP1A inhibitors as an adjuvant to oxaliplatin in CRC. Furthermore, stem cell markers c-Myc and CD44 as well as Akt kinase emerged as novel resistance biomarkers whose pharmacological targeting could elevate the therapeutic efficacy of irinotecan. Lastly, several pathways common to the resistance to all three drugs were revealed including miRNAs in cancer, proteoglycans in cancer, cellular senescence and the sphingolipid signalling pathway. Conclusion: This paper gives a comprehensive overview of resistance mechanisms to 5-FU, Ox and irinotecan in colon cancer and reveals several novel molecular players and associated mechanisms that could account for development of chemoresistance and whose targeting might enable design of novel combination strategies to overcome resistance to conventional treatment in CRC.

scholarly journals Sphingosine 1-Phosphate Signaling and Metabolism in Chemoprevention and Chemoresistance in Colon Cancer

Molecules ◽  
2020 ◽  
Vol 25 (10) ◽  
pp. 2436 ◽  
Author(s):  
Petra Grbčić ◽  
Mirela Sedić
Keyword(s):  
Colon Cancer ◽  
Cancer Cell ◽  
Anticancer Agents ◽  
Molecular Mechanisms ◽  
Treatment Modalities ◽  
Rational Approach ◽  
Cancer Drug ◽  
Comprehensive Overview ◽  
Chemotherapy Drugs ◽  
Sphingosine 1 Phosphate

Colorectal carcinoma (CRC) is the leading cause of cancer-related deaths worldwide. Despite advances in prevention and treatment modalities for CRC, rapidly developing resistance to chemotherapy limits its effectiveness. For that reason, it is important to better understand the mechanisms that undergird the process of chemoresistance to enable design of novel anticancer agents specifically targeting malignant properties of cancer cells. Over recent decades, bioactive sphingolipid species have come under the spotlight for their recognized role in cancer development and progression, and the evidence has surfaced to support their role as regulators of anti-cancer drug resistance. Colon cancer is characterized by a shift in sphingolipid balance that favors the production and accumulation of oncogenic species such as sphingosine 1-phosphate (S1P). S1P is known to govern the processes that facilitate cancer cell growth and progression including proliferation, survival, migration, invasion and inflammation. In this review paper, we will give a comprehensive overview of current literature findings on the molecular mechanisms by which S1P turnover, transport and signaling via receptor-dependent and independent pathways shape colon cancer cell behavior and influence treatment outcome in colon cancer. Combining available modulators of S1P metabolism and signaling with standard chemotherapy drugs could provide a rational approach to achieve enhanced therapeutic response, diminish chemoresistance development and improve the survival outcome in CRC patients.

scholarly journals Contribution of Immunoscore and Molecular Features to Survival Prediction in Stage III Colon Cancer

2020 ◽  
Vol 4 (3) ◽  
Author(s):  
Frank A Sinicrope ◽  
Qian Shi ◽  
Fabienne Hermitte ◽  
Tyler J Zemla ◽  
Bernhard Mlecnik ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Statistical Tests ◽  
Disease Free Survival ◽  
Braf V600e ◽  
Stage Iii ◽  
Survival Prediction ◽  
Cox Models ◽  
Stage Iii Colon Cancer ◽  
T Stage ◽  
Molecular Features

Abstract Background The American Joint Committee on Cancer staging and other prognostic tools fail to account for stage-independent variability in outcome. We developed a prognostic classifier adding Immunoscore to clinicopathological and molecular features in patients with stage III colon cancer. Methods Patient (n = 559) data from the FOLFOX arm of adjuvant trial NCCTG N0147 were used to construct Cox models for predicting disease-free survival (DFS). Variables included age, sex, T stage, positive lymph nodes (+LNs), N stage, performance status, histologic grade, sidedness, KRAS/BRAF, mismatch repair, and Immunoscore (CD3+, CD8+ T-cell densities). After determining optimal functional form (continuous or categorical) and within Cox models, backward selection was performed to analyze all variables as candidate predictors. All statistical tests were two-sided. Results Poorer DFS was found for tumors that were T4 vs T3 (hazard ratio [HR] = 1.76, 95% confidence interval [CI] = 1.19 to 2.60; P = .004), right- vs left-sided (HR = 1.52, 95% CI = 1.14 to 2.04; P = .005), BRAF V600E (HR = 1.74, 95% CI = 1.26 to 2.40; P < .001), mutant KRAS (HR = 1.66, 95% CI = 1.08 to 2.55; P = .02), and low vs high Immunoscore (HR = 1.69, 95% CI = 1.22 to 2.33; P = .001) (all P < .02). Increasing numbers of +LNs and lower continuous Immunoscore were associated with poorer DFS that achieved significance (both Ps< .0001). After number of +LNs, T stage, and BRAF/KRAS, Immunoscore was the most informative predictor of DFS shown multivariately. Among T1–3 N1 tumors, Immunoscore was the only variable associated with DFS that achieved statistical significance. A nomogram was generated to determine the likelihood of being recurrence-free at 3 years. Conclusions The Immunoscore can enhance the accuracy of survival prediction among patients with stage III colon cancer.

scholarly journals Adjuvant Therapy for Colon Cancer in the New Millenium

2003 ◽  
Vol 92 (1) ◽  
pp. 57-64 ◽  
Author(s):  
S. Rao ◽  
D. Cunningham
Keyword(s):  
Colon Cancer ◽  
Adjuvant Therapy ◽  
Advanced Colorectal Cancer ◽  
Significant Proportion ◽  
Adjuvant Setting ◽  
Conventional Chemotherapy ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Stage Iii Colon Cancer

A significant proportion of patients with colon cancer who undergo curative surgical resection develop metastatic disease. Over the last 20 years large prospective randomised studies have demonstrated a clear survival benefit for patients with stage III colon cancer who are treated with adjuvant 5FU based chemotherapy. At the present time 6 months of 5FU and leucovorin is generally considered the standard adjuvant therapy. For stage II disease the routine use of adjuvant treatment remains controversial. Newer drugs such as oxaliplatin, irinotecan, and the oral fluoropyrimidines have proven active in advanced colorectal cancer and are currently being evaluated in the adjuvant setting. Molecular markers for this disease are being identified and may help define those patients who would benefit from therapy. The integration of adjuvant immunotherapy with conventional chemotherapy offers the potential to improve the long-term outcome for surgically resected colon cancer.

scholarly journals Protein–Protein Interaction Network Analysis Reveals Several Diseases Highly Associated with Polycystic Ovarian Syndrome

2019 ◽  
Vol 20 (12) ◽  
pp. 2959 ◽  
Author(s):  
Balqis Ramly ◽  
Nor Afiqah-Aleng ◽  
Zeti-Azura Mohamed-Hussein
Keyword(s):  
Network Analysis ◽  
Protein Interaction ◽  
Ribosome Biogenesis ◽  
Antigen Processing ◽  
Polycystic Ovarian Syndrome ◽  
Interaction Network ◽  
Pathway Enrichment Analysis ◽  
Ppi Network ◽  
Protein Protein Interaction ◽  
Ovarian Syndrome

Based on clinical observations, women with polycystic ovarian syndrome (PCOS) are prone to developing several other diseases, such as metabolic and cardiovascular diseases. However, the molecular association between PCOS and these diseases remains poorly understood. Recent studies showed that the information from protein–protein interaction (PPI) network analysis are useful in understanding the disease association in detail. This study utilized this approach to deepen the knowledge on the association between PCOS and other diseases. A PPI network for PCOS was constructed using PCOS-related proteins (PCOSrp) obtained from PCOSBase. MCODE was used to identify highly connected regions in the PCOS network, known as subnetworks. These subnetworks represent protein families, where their molecular information is used to explain the association between PCOS and other diseases. Fisher’s exact test and comorbidity data were used to identify PCOS–disease subnetworks. Pathway enrichment analysis was performed on the PCOS–disease subnetworks to identify significant pathways that are highly involved in the PCOS–disease associations. Migraine, schizophrenia, depressive disorder, obesity, and hypertension, along with twelve other diseases, were identified to be highly associated with PCOS. The identification of significant pathways, such as ribosome biogenesis, antigen processing and presentation, and mitophagy, suggest their involvement in the association between PCOS and migraine, schizophrenia, and hypertension.

scholarly journals The Target of Rapamycin Signalling Pathway in Ageing and Lifespan Regulation

Genes ◽  
2020 ◽  
Vol 11 (9) ◽  
pp. 1043
Author(s):  
Ivana Bjedov ◽  
Charalampos Rallis
Keyword(s):  
Ribosome Biogenesis ◽  
Complex Trait ◽  
Signalling Pathway ◽  
Target Of Rapamycin ◽  
Cellular Functions ◽  
Pharmacological Interventions ◽  
Age Related ◽  
Energy Sensing ◽  
Mtor Signalling ◽  
Mtor Signalling Pathway

Ageing is a complex trait controlled by genes and the environment. The highly conserved mechanistic target of rapamycin signalling pathway (mTOR) is a major regulator of lifespan in all eukaryotes and is thought to be mediating some of the effects of dietary restriction. mTOR is a rheostat of energy sensing diverse inputs such as amino acids, oxygen, hormones, and stress and regulates lifespan by tuning cellular functions such as gene expression, ribosome biogenesis, proteostasis, and mitochondrial metabolism. Deregulation of the mTOR signalling pathway is implicated in multiple age-related diseases such as cancer, neurodegeneration, and auto-immunity. In this review, we briefly summarise some of the workings of mTOR in lifespan and ageing through the processes of transcription, translation, autophagy, and metabolism. A good understanding of the pathway’s outputs and connectivity is paramount towards our ability for genetic and pharmacological interventions for healthy ageing and amelioration of age-related disease.

Clinical Factors Affecting Bevacizumab Efficacy With and Without Conventional Chemotherapy in Metastatic Colon Cancer

2018 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Rezwan Islam ◽  
Rafiullah Khan ◽  
Asad Ali ◽  
Vidya Kollu ◽  
TramAnh Phan ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Metastatic Colon Cancer ◽  
Clinical Factors ◽  
Conventional Chemotherapy ◽  
Factors Affecting

Overexpressing microRNA-34a overcomes ABCG2-mediated drug resistance to 5-FU in side population cells from colon cancer via suppressing DLL1

2020 ◽  
Vol 167 (6) ◽  
pp. 557-564
Author(s):  
Zheng-Yuan Xie ◽  
Fen-Fen Wang ◽  
Zhi-Hua Xiao ◽  
Si-Fu Liu ◽  
Sheng-Lan Tang ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Drug Resistance ◽  
Side Population ◽  
Critical Role ◽  
Notch Pathway ◽  
Notch Signalling ◽  
Signalling Pathway ◽  
Luciferase Reporter ◽  
Small Subset ◽  
Notch Signalling Pathway

Abstract Colon cancer side population (SP) cells are a small subset of cancer cells that have cancer stemness capacity and enhanced drug resistance. ABCG2 is a multidrug resistance-related protein in SP cells and has been demonstrated to be regulated by Notch signalling pathway. Recently, microRNAs are reported to play a critical role in SP cell fate. However, their role in ABCG2-mediated drug resistance in colon cancer SP cells remains unclear. In the current study, the different expressions of miR-552, miR-611, miR-34a and miR-5000-3p were compared within SP and non-SP cells, which were separated from human colon cancer cell lines (SW480 and LoVo). We found that miR-34a was significantly down-regulated in SP cells and that overexpressing miR-34a overcame drug resistance to 5-fluorouracil (5-FU). The luciferase reporter assay indicated that miR-34a negatively regulated DLL1, a ligand of Notch signalling pathway, via binding with 3′-untranslated region of its messenger RNA. In addition, overexpressing miR-34a overcame ABCG2-mediated resistance to 5-FU via DLL1/Notch pathway in vitro, and suppressed tumour growth under 5-FU treatment in vivo. In conclusion, our findings suggest that miR-34a acts as a tumour suppressor via enhancing chemosensitivity to 5-FU in SP cells, which provides a novel therapeutic target in chemotherapy-resistant colon cancer.

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