Obesity and inflammation: colorectal cancer engines

2021 ◽  
Vol 14 ◽  
Author(s):  
Lara J. Bou Malhab ◽  
Wael M. Abdel-Rahman
Keyword(s):  
Colorectal Cancer ◽  
Immune Cell ◽  
Obese Patients ◽  
Epigenetic Alterations ◽  
Molecular Alterations ◽  
Stat3 Signaling ◽  
Therapeutic Choice ◽  
Prevalence Of Obesity ◽  
Inhibitory Molecules

: The prevalence of obesity continues to increase to the extent that it became a worldwide pandemic. An accumulating body of evidence has associated obesity with the development of different types of cancer, including colorectal cancer, which is a notorious disease with a high mortality rate. At the molecular level, colorectal cancer is a heterogenous disease characterized by a myriad of genetic and epigenetic alterations associated with various forms of genomic instability (detailed in Supplementary Materials). Recently, the microenvironment has emerged as a major factor in carcinogenesis. Our aim is to define the different molecular alterations leading to the development of colorectal cancer in obese patients with a focus on the role of the microenvironment in carcinogenesis. We also highlight all existent molecules in clinical trials that target the activated pathways in obesity-associated colorectal cancer, whether used as single treatments or in combination. Obesity predisposes to colorectal cancer via creating a state of chronic inflammation with dysregulated adipokines, inflammatory mediators, and other factors such as immune cell infiltration. A unifying theme in obesity-mediated colorectal cancer is the activation of the PI3K/AKT, mTOR/MAPK, and STAT3 signaling pathways. Different inhibitory molecules towards these pathways exist, increasing the therapeutic choice of obesity-associated colon cancer. However, obese patients are more likely to suffer from chemotherapy overdosing. Preventing obesity through maintaining a healthy and active lifestyle remains to be the best remedy.

KMT2C as a positive predictor for treatment of immune checkpoint inhibitor and correlation with immune infiltrates in colorectal cancer (CRC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3538-3538
Author(s):  
Ling Zhang ◽  
Jianping Song ◽  
Yiting Wang ◽  
Yaoxu Chen
Keyword(s):  
Colorectal Cancer ◽  
Survival Data ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Immune Cell ◽  
Checkpoint Inhibitor ◽  
Colon Adenocarcinoma ◽  
Treg Cells ◽  
Prognostic Effect

3538 Background: Lysine Methyltransferase 2C (KMT2C), a member of the myeloid/lymphoid or mixed-lineage leukemia (MLL) family, possesses histone methylation activity and is involved in transcriptional co-activation. Present study has shown that KMT2C is positive correlated with better efficacy of Immune checkpoint inhibitor (ICI) in NSCLC. However, the role of KMT2C in treatment of ICI on colorectal cancer (CRC) is still unknown. Methods: NGS (Next Generation Sequencing) was performed on 1628 CRC patients. TMB of these patients were analyzed. A public accessible cohort (Samstein2018) with data from 130 CRC patients were used to investigate the correlation between KMT2C mutation and efficacy of ICI. WES and survival data of TCGA database (1099 CRC) was used to analyze prognostic effect of KMT2C mutation. Furthermore, CIBERSORT was used to analyze the tumor-infiltrating immune cells present in COAD（colon adenocarcinoma, 404 patients）from TCGA database. Results: Among 1628 CRC patient, 230(14.1%) had KMT2C mutation. TMB was positive correlated with KMT2C mutation (Mut vs. WT, 30.75 vs. 7.26 mut/Mb, p < 0.0001). The Samstein2018 cohort showed that KMT2C mutations (15.4%, 20/130) were significantly associated with better OS (Mut vs. WT, 11.5 vs. 7.5 month, HR = 0.29; 95% CI, 0.1-0.81; P = 0.012), and a higher TMB was also observed in KMT2C-Mut group (p = 1.98e-08). In TCGA, no association between KMT2C mutation and OS was observed (P = 0.23), suggesting that was not prognostic factor. Moreover, we analyzed the relationship between KMT2C mutation and immune cell infiltration through CRC TCGA database. The results showed, in COAD, KMT2C mutation was positively correlated with the abundance of CD8+ T cells (P = 0.0014), B cells (P = 0.014), M1 macrophages (P = 0.015), neutrophil (P = 0.0019) and NK cells (P = 0.043), and negatively correlated with Treg cells (p = 0.0063). Conclusions: KMT2C has an impact on the immune microenvironment and may be used as a potential positive predictor for treatment of ICI on CRC patients. The role of KMT2C in immunotherapy warrant further studies.

MYC as a candidate upstream controller involved in TYMS gene expression and 5-FU/folate treatment efficacy in colorectal cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15512-e15512
Author(s):  
David A. Drubin ◽  
Anne-Katrin Hess ◽  
Natalie L. Catlett ◽  
Alessandro Di Cara ◽  
Yvonne Wettergren ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Immune Cell ◽  
Stage Iv ◽  
Gene Signature ◽  
Immune Cell Population ◽  
Potential Biomarker ◽  
Cancer Genome Atlas ◽  
Classical Monocytes

e15512 Background: One of the target enzymes of 5-fluorouracil (5-FU)-based therapies is thymidylate synthase (TS) encoded by the TYMS gene. To enhance the effect of 5-FU, a folate analogue is often provided as part of the treatment. In this context, it has previously been shown in the ISO-CC-005 clinical study that TYMS gene expression can be predictive of response to 5-FU + folate analogue Arfolitixorin. Methods: To better understand the role of TYMS expression as a predictor of response to 5-FU + folate-based therapies and identify potential mechanisms and biomarkers of sensitivity/resistance, we leveraged data from the publicly available cancer genome atlas database (TCGA). We combined this information with a knowledgebase of causal biological relationships extracted from peer reviewed publications, to identify other relevant genes and candidate upstream controllers directly or indirectly related to TYMS expression and 5-FU + folate efficacy. Results: In TCGA subjects suffering from colorectal cancer (CRC) (stage IV tumors, treated with FOLFOX/FOLFIRI (n = 38)), lower TYMS expression was associated with a better overall survival (OS). This is consistent with what has been observed in the ISO-CC-005 study. Applying our causal biology knowledgebase to both genes identified as correlated to TYMS expression in TCGA CRC tumors and other published sets of genes associated with FOLFOX or FOLFIRI efficacy, we identified overlap with a MYCN signature. Notably MYC has been shown to directly activate TYMS expression. Thus, the MYC family is a compelling candidate upstream controller of these genes. We scored TCGA CRC tumors for inferred MYC activity, using this MYCN gene signature, and evaluated the inferred activity with respect to OS. In stage IV tumors, higher inferred MYC activity appears to be associated with worse OS. To further characterize this inferred MYC activity, we employed a transcriptomics-based cell deconvolution estimation of immune cell population proportions in the TCGA CRC cohort. We found inferred MYC activity inversely correlated with immune cell proportions overall, specifically strongest with those of pDCs and classical monocytes. Conclusions: MYC activation, a known transcriptional regulator of TYMS, has been identified as a potentially relevant common upstream controller of a group of genes involved in 5-FU + folate analogue efficacy. Here we have also observed a similar relationship to OS between TYMS and inferred MYC activity in Stage IV CRC. MYC family activity (and activated protein forms), genes of the MYCN signature, or the identified immune cell proportions are all potential biomarker candidates to explore as factors in 5-FU + folate analogue efficacy.

Treatment of Advanced Colorectal Cancer (CRC) in Daily Practice: Results of a Survey in two Italian Regions, Piemonte and Valle D'aosta

1998 ◽  
Vol 84 (5) ◽  
pp. 562-566 ◽  
Author(s):  
Alessandro Comandone ◽  
Roberto Berardo ◽  
Roberto Faggiuolo ◽  
Antonella Boglione ◽  
Paola Bergnolo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Performance Status ◽  
Daily Practice ◽  
New Drugs ◽  
Therapeutic Choice ◽  
Italian Regions ◽  
Important Health ◽  
Definition Of ◽  
No Gold Standard

Aims and background Colorectal cancer (CRC) is one of the most important health problems in Western countries: it is the fourth cancer in terms of incidence and the second cause of cancer death. Surgery is the main therapeutic choice and there is broad consensus on the role of adjuvant chemotherapy (CT) after resection. Unfortunately, 50% of the patients will relapse and die of the disease. Palliative CT based on 5-fluorouracil (5FU) may induce a 9-48% response rate with a median survival of 11.5 months. At present there is no gold standard for CT in advanced CRC and the situation has become more complicated since the advent of new drugs (Raltitrexed, Irinotecan, Oxaliplatin). The aim of this study was the identification of the different approaches to treatment of advanced CRC among the clinicians (oncologists, radiologists, internal medicine specialists, surgeons) who practice CT. Methods and study design Forty-six clinicians from two Italian Regions (Piemonte and Valle d'Aosta) were interviewed by telephone. Results 5FU modulated with Lederfolin according to the classic Machover scheme is the main option in daily practice. More sophisticated therapies are reserved to patients with a good performance status (PS) and are prescribed only in the larger centers. The planned therapies usually consist of six courses. Restaging may be performed after three or six courses. A marked difference has been recorded in the evaluation of a situation of no change (NC): 25.5% of the clinicians evaluate stable disease as a positive result. In the event of disease progression or relapse, 35% of the clinicians do not prescribe second-line CT. In case of further treatment, the options are totally subjective. Conclusions A national survey on this issue is necessary under the auspices of AIOM (Associazione Italiana Oncologia Medica) and involving oncologists, epidemiologists and statisticians, in order to define the reasons for variations in therapy in advanced CRC and determine the differences between clinicians of different age, specialization and location. This survey could lead to a definition of guidelines for the treatment of advanced CRC.

scholarly journals Host–MicroRNA–Microbiota Interactions in Colorectal Cancer

Genes ◽  
2019 ◽  
Vol 10 (4) ◽  
pp. 270 ◽  
Author(s):  
Ce Yuan ◽  
Clifford J. Steer ◽  
Subbaya Subramanian
Keyword(s):  
Colorectal Cancer ◽  
Gut Microbiota ◽  
Tumor Cells ◽  
Immune Cell ◽  
Review Article ◽  
Microbiota Composition ◽  
Cell Fractions ◽  
High Level ◽  
Gut Microbiota Composition

Changes in gut microbiota composition have consistently been observed in patients with colorectal cancer (CRC). Yet, it is not entirely clear how the gut microbiota interacts with tumor cells. We know that tumor cells undergo a drastic change in energy metabolism, mediated by microRNAs (miRNAs), and that tumor-derived miRNAs affect the stromal and immune cell fractions of the tumor microenvironment. Recent studies suggest that host intestinal miRNAs can also affect the growth and composition of the gut microbiota. Our previous CRC studies showed a high-level of interconnectedness between host miRNAs and their microbiota. Considering all the evidence to date, we postulate that the altered nutrient composition and miRNA expression in the CRC microenvironment selectively exerts pressure on the surrounding microbiota, leading to alterations in its composition. In this review article, we present our current understanding of the role of miRNAs in mediating host–microbiota interactions in CRC.

scholarly journals The possible role of SRMS in colorectal cancer by bioinformatics analysis

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Jie Zhang ◽  
Weidong Liu ◽  
Sisi Feng ◽  
Baiyun Zhong
Keyword(s):  
Colorectal Cancer ◽  
Immune Cell ◽  
Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Receptor Interaction ◽  
Marker Genes ◽  
Cell Marker ◽  
Translational Initiation ◽  
Expression Levels

Abstract Background Src-related kinase lacking C-terminal regulatory tyrosine and N-terminal myristoylation sites (SRMS) is a non-receptor tyrosine kinase that has been found to be overexpressed in various tumors. However, the role of SRMS in colorectal cancer (CRC) has not been well established. Methods We evaluated the expression levels of SRMS in CRC using GEPIA, Oncomine, and HPA datasets. Survival information and gene expression data of CRC were obtained from The Cancer Genome Atlas (TCGA). Then, the association between SRMS and clinicopathological features was analyzed using UALCAN dataset. LinkedOmics was used to determine co-expression and functional networks associated with SRMS. Besides, we used TISIDB to assess the correlation between SRMS and immune signatures, including tumor-infiltrating immune cells and immunomodulators. Lastly, protein-protein interaction network (PPI) was established and the function enrichment analysis of the SRMS-associated immunomodulators and immune cell marker genes were performed using the STRING portal. Results Compared to normal colorectal tissues, SRMS was found to be overexpressed in CRC tissues, which was correlated with a poor prognosis. In colon adenocarcinoma (COAD), the expression levels of SRMS are significantly correlated with pathological stages and nodal metastasis status. Functional network analysis suggested that SRMS regulates intermediate filament-based processes, protein autophosphorylation, translational initiation, and elongation signaling through pathways involving ribosomes, proteasomes, oxidative phosphorylation, and DNA replication. In addition, SRMS expression was correlated with infiltrating levels of CD4+ T cells, CD56dim, MEM B, Neutrophils, Th2, Th17, and Act DC. The gene ontology (GO) analysis of SRMS-associated immunomodulators and immune cell marker genes showed that they were mainly enriched in the immune microenvironment molecule-related signals. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of these genes indicated that they are involved in multiple cancer-related pathways. Conclusions SRMS is a promising prognostic biomarker and potential therapeutic target for CRC patients. In particular, SRMS regulates CRC progression by modulating cytokine-cytokine receptor interaction, chemokines, IL-17, and intestinal immune networks for IgA production signaling pathways among others. However, more studies are needed to validate these findings.

scholarly journals Derivation and Clinical Validation of a Redox-Driven Prognostic Signature for Colorectal Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Qin Dang ◽  
Zaoqu Liu ◽  
Shengyun Hu ◽  
Zhuang Chen ◽  
Lingfang Meng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Signaling Pathways ◽  
Risk Score ◽  
Immune Cell ◽  
Risk Model ◽  
Prognostic Signature ◽  
Related Factors ◽  
Recurrence Prediction ◽  
Intimate Association

Colorectal cancer (CRC), a seriously threat that endangers public health, has a striking tendency to relapse and metastasize. Redox-related signaling pathways have recently been extensively studied in cancers. However, the study and potential role of redox in CRC remain unelucidated. We developed and validated a risk model for prognosis and recurrence prediction in CRC patients via identifying gene signatures driven by redox-related signaling pathways. The redox-driven prognostic signature (RDPS) was demonstrated to be an independent risk factor for patient survival (including OS and RFS) in four public cohorts and one clinical in-house cohort. Additionally, there was an intimate association between the risk score and tumor immune infiltration, with higher risk score accompanied with less immune cell infiltration. In this study, we used redox-related factors as an entry point, which may provide a broader perspective for prognosis prediction in CRC and have the potential to provide more promising evidence for immunotherapy.

scholarly journals Stem Cell Impairment at the Host-Microbiota Interface in Colorectal Cancer

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 996
Author(s):  
Marinella Marzano ◽  
Bruno Fosso ◽  
Elisabetta Piancone ◽  
Giuseppe Defazio ◽  
Graziano Pesole ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Stem Cells ◽  
Gut Microbiota ◽  
The Body ◽  
Intestinal Stem Cells ◽  
Epigenetic Alterations ◽  
Tumor Initiating Cells ◽  
Diverse Community ◽  
The Relationship

Colorectal cancer (CRC) initiation is believed to result from the conversion of normal intestinal stem cells (ISCs) into cancer stem cells (CSCs), also known as tumor-initiating cells (TICs). Hence, CRC evolves through the multiple acquisition of well-established genetic and epigenetic alterations with an adenoma-carcinoma sequence progression. Unlike other stem cells elsewhere in the body, ISCs cohabit with the intestinal microbiota, which consists of a diverse community of microorganisms, including bacteria, fungi, and viruses. The gut microbiota communicates closely with ISCs and mounting evidence suggests that there is significant crosstalk between host and microbiota at the ISC niche level. Metagenomic analyses have demonstrated that the host-microbiota mutually beneficial symbiosis existing under physiologic conditions is lost during a state of pathological microbial imbalance due to the alteration of microbiota composition (dysbiosis) and/or the genetic susceptibility of the host. The complex interaction between CRC and microbiota is at the forefront of the current CRC research, and there is growing attention on a possible role of the gut microbiome in the pathogenesis of CRC through ISC niche impairment. Here we primarily review the most recent findings on the molecular mechanism underlying the complex interplay between gut microbiota and ISCs, revealing a possible key role of microbiota in the aberrant reprogramming of CSCs in the initiation of CRC. We also discuss recent advances in OMICS approaches and single-cell analyses to explore the relationship between gut microbiota and ISC/CSC niche biology leading to a desirable implementation of the current precision medicine approaches.

scholarly journals MicroRNA Promoter Methylation in Colorectal Cancer

2021 ◽  
Author(s):  
Masoud Asefi ◽  
Nayebali Rezvani ◽  
Mohammad Hasan Soheilifar ◽  
Massoud Saidijam ◽  
Ali Mahdavinezhad
Keyword(s):  
Colorectal Cancer ◽  
Promoter Methylation ◽  
Cpg Island ◽  
Gene Promoter ◽  
Epigenetic Alterations ◽  
Genetic Changes ◽  
Microrna Gene ◽  
Cancer Types ◽  
Cpg Island Methylation

Colorectal cancer (CRC) is one of the most common cancers worldwide. The beginning and progression of the disease are thought to be determined by combinations of epigenetic and genetic changes that trigger multistep programs of carcinogenesis. In colorectal cancer, epigenetic alterations, in particular promoter CpG island methylation, occur more commonly than genetic mutations. Hyper-methylation contributes to carcinogenesis via inducing transcriptional silencing or down-regulation of tumor suppressor genes. DNA methylation alteration has a high potential for minimally invasive biomarker identification. Genome analysis has confirmed that microRNA expression is deregulated in most cancer types through several mechanisms, including failings in the microRNA biogenesis machinery. Moreover, microRNAs can be dysregulated by abnormal CpG methylation in cancer. Since it is believed that epigenetic changes occur in the early stages of the disease, these changes can be used for the early detection of cancer. In this review, we intend to study the role of microRNA gene promoter methylation in colorectal cancer.

scholarly journals Aberrant SLC6A14 Expression Promotes Proliferation and Metastasis of Colorectal Cancer Via Enhancing the JAK2/STAT3 Pathway

2020 ◽  
Author(s):  
Hongli Mao ◽  
Jinxiu Sheng ◽  
Jinlin Jia ◽  
Chang Wang ◽  
Shanfeng Zhang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Lines ◽  
Mammalian Cells ◽  
Metabolic Reprogramming ◽  
Cell Counting ◽  
Migration And Invasion ◽  
Advanced Tumor Stage ◽  
Stat3 Signaling

Abstract Background: Solute carrier family 6 member 14 (SLC6A14) is a high-capacity amino acid transporter in mammalian cells. It has gained increasing attention for its potential involvement in the progression and metabolic reprogramming of various malignant tumors. However, the role of SLC6A14 in colorectal cancer (CRC) remains unclear. Methods: Real-time polymerase chain reaction (qRT-PCR), immunoblotting and immunohistochemistry were carried out to detect the expression level of SLC6A14 in human CRC tissues and CRC-derived cell lines. HCT-116 and Caco-2 cell lines were selected to conduct the in vitro functional studies. Cell Counting Kit-8 (CCK-8), colony formation, flow cytometry, cell migration and invasion assays were performed to investigate the role of SLC6A14 in CRC cells. Besides, Azoxymethane/Dextran Sulfate Sodium Salt (AOM/DSS)-induced CRC and tumor xenograft models were constructed to explore the effects of SLC6A14 blockade or overexpression on tumor progression in vivo. Results: SLC6A14 was substantially increased in human CRC samples and higher levels of SLC6A14 was correlated with advanced tumor stage, lymph node metastasis and dismal survival of CRC patients. SLC6A14 markedly promoted cell growth, inhibited cell apoptosis, exacerbated migration and invasion of CRC cells in vitro. Mechanistically, SLC6A14 aggravated these malignant phenotypes through activating JAK2/STAT3 signaling pathway, and inhibiting JAK2/STAT3 signaling with specific inhibitors could reverse SLC6A14-mediated tumorigenic effects. Besides, two different animal studies verified the tumor-promoting effect of SLC6A14 in CRC. Conclusion: Our data illustrated the crucial function that SLC6A14 played in the promotion of CRC, suggesting SLC6A14/JAK2/STAT3 axis may serve as novel therapeutic targets for patients with CRC.

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