Exploring the Inflammatory Pathogenesis of Colorectal Cancer

Colorectal cancer is one of the most commonly diagnosed cancers worldwide. Traditionally, mechanisms of colorectal cancer formation have focused on genetic alterations including chromosomal damage and microsatellite instability. In recent years, there has been a growing body of evidence supporting the role of inflammation in colorectal cancer formation. Multiple cytokines, immune cells such T cells and macrophages, and other immune mediators have been identified in pathways leading to the initiation, growth, and metastasis of colorectal cancer. Outside the previously explored mechanisms and pathways leading to colorectal cancer, initiatives have been shifted to further study the role of inflammation in pathogenesis. Inflammatory pathways have also been linked to some traditional risk factors of colorectal cancer such as obesity, smoking and diabetes, as well as more novel associations such as the gut microbiome, the gut mycobiome and exosomes. In this review, we will explore the roles of obesity and diet, smoking, diabetes, the microbiome, the mycobiome and exosomes in colorectal cancer, with a specific focus on the underlying inflammatory and metabolic pathways involved. We will also investigate how the study of colon cancer from an inflammatory background not only creates a more holistic and inclusive understanding of this disease, but also creates unique opportunities for prevention, early diagnosis and therapy.

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Tumor-Associated Macrophages (TAMs) in Colorectal Cancer (CRC): From Mechanism to Therapy and Prognosis

International Journal of Molecular Sciences ◽

10.3390/ijms22168470 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8470

Author(s):

Hui Wang ◽

Tian Tian ◽

Jinhua Zhang

Keyword(s):

Colorectal Cancer ◽

Clinical Care ◽

Inflammatory Cells ◽

Genetic Alterations ◽

Tumor Associated Macrophages ◽

Invasion And Migration ◽

Complex Process ◽

Incidence And Mortality ◽

And Migration

Colorectal cancer (CRC) is a malignant tumor in the digestive system whose incidence and mortality is high-ranking among tumors worldwide. The initiation and progression of CRC is a complex process involving genetic alterations in cancer cells and multiple factors from the surrounding tumor cell microenvironment. As accumulating evidence has shown, tumor-associated macrophages (TAMs)—as abundant and active infiltrated inflammatory cells in the tumor microenvironment (TME)—play a crucial role in CRC. This review focuses on the different mechanisms of TAM in CRC, including switching of phenotypical subtypes; promoting tumor proliferation, invasion, and migration; facilitating angiogenesis; mediating immunosuppression; regulating metabolism; and interacting with the microbiota. Although controversy remains in clinical evidence regarding the role of TAMs in CRC, clarifying their significance in therapy and the prognosis of CRC may shed new light on the optimization of TAM-centered approaches in clinical care.

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High Expression of Pd-1 in Circulating Cells of Patients With Advanced Colorectal Cancer Receiving Adjuvant Therapy

Technology in Cancer Research & Treatment ◽

10.1177/1533033820969446 ◽

2020 ◽

Vol 19 ◽

pp. 153303382096944

Author(s):

Muhammed A. Bakhrebah ◽

Mohammad Nasrullah ◽

Wesam H. Abdulaal ◽

Mohammed A. Hassan ◽

Halima Siddiqui ◽

...

Keyword(s):

Colorectal Cancer ◽

Immune Response ◽

Adjuvant Therapy ◽

Tumor Cells ◽

Immune Cells ◽

Human Leukocyte ◽

Genetic Alterations ◽

Programmed Death ◽

Programmed Death 1 ◽

Cancer Types

Among all cancer types, colorectal cancer is the third most common in men and the second most common in women globally. Generally, the risk of colorectal cancer increases with age, and colorectal cancer is modulated by various genetic alterations. Alterations in the immune response serve a significant role in the development of colorectal cancer. In primary cancer types, immune cells express a variety of inhibitory molecules that dampen the immune response against tumor cells. Additionally, few reports have demonstrated that classical chemotherapy promotes the immunosuppressive microenvironment in both tissues and immune cells. This study assessed the expression levels of genes using RT-qPCR associated with the immune system, including interferon-γ, programmed death-1, β2-microglobulin, human leukocyte antigen-A, CD3e, CD28 and intracellular adhesion molecule 1, in patients with colorectal cancer, as these genes are known to serve important roles in immune regulation during cancer incidence. Gene expression analysis was performed with the whole blood cells of patients with colorectal cancer and healthy volunteers. Compared with the normal controls, programmed death-1was highly expressed in patients with advanced-stage colorectal cancer. Furthermore, the expression of programmed death-1 was higher in patients receiving adjuvant therapy, which suggests the therapy dampened the immune response against tumor cells. The results of the present study indicate that classical adjuvant therapies, which are currently used for patients with colorectal cancer, should be modulated, and a combination of classical therapy with anti-programmed death-1 antibody should be conducted for improved management of patients with colorectal cancer.

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Antioxidant Agents and Colorectal Carcinogenesis: Role of β-Carotene, Vitamin E and Vitamin C

Tumori Journal ◽

10.1177/030089169608200102 ◽

1996 ◽

Vol 82 (1) ◽

pp. 6-11 ◽

Cited By ~ 7

Author(s):

Giuseppe Pappalardo ◽

Antonio Guadalaxara ◽

Giuseppe Maiani ◽

Giovanni Illomei ◽

Mauro Trifero ◽

...

Keyword(s):

Colorectal Cancer ◽

Vitamin E ◽

Vitamin C ◽

Colonic Mucosa ◽

Genetic Alterations ◽

Colorectal Carcinogenesis ◽

Normal Colonic Mucosa ◽

Antioxidant Agents ◽

Β Carotene

In consideration of findings reported in the literature and of our study, we examined the correlation between antioxidants (β-carotene, vitamin C, vitamin E) and colorectal carcinogenesis. Although diagnostic progress has been made in the last decades, no significant improvements in death rates have been achieved in the western world. Exogenous factors might be responsible for a complex alteration process of normal colonic mucosa into adenoma and carcinoma. Free radicals and reactive oxygen metabolites, due to increased production or to reduced inactivation, following a decrease in the antioxidant burden in the mucosa, might cause damage to DNA, thereby resulting in genetic alterations. This might represent the cause of the transformation process: normal mucosa→ adenoma→ carcinoma. In a prospective study, we observed a reduction of β-carotene levels in normal colonic mucosa in patients with polyps and colorectal cancer. We also showed that β-carotene supplementation raises levels of this micronutrient in the colonic mucosa of these patients. Findings from the literature and our trials show a significant decrease in the antioxidant capacity of colorectal mucosa in patients affected by colorectal cancer, although there is a significant interindividual variability. Such results suggest a possible chemopreventive role of antioxidant agents in colorectal cancer.

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Inflammatory Bowel Disease and Risk of Colorectal Cancer: An Overview From Pathophysiology to Pharmacological Prevention

Frontiers in Pharmacology ◽

10.3389/fphar.2021.772101 ◽

2021 ◽

Vol 12 ◽

Author(s):

Marianna Lucafò ◽

Debora Curci ◽

Martina Franzin ◽

Giuliana Decorti ◽

Gabriele Stocco

Keyword(s):

Colorectal Cancer ◽

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Inflammatory Process ◽

Current Knowledge ◽

Genetic Alterations ◽

Pharmacological Prevention ◽

Increased Risk ◽

Inflammatory Bowel

Increased risk of colorectal cancer (CRC) in inflammatory bowel disease (IBD) patients has been attributed to long-standing chronic inflammation, with the contribution of genetic alterations and environmental factors such as the microbiota. Moreover, accumulating data indicate that IBD-associated CRC (IBD-CRC) may initiate and develop through a pathway of tumorigenesis distinct from that of sporadic CRC. This mini-review summarizes the current knowledge of IBD-CRC, focusing on the main mechanisms underlying its pathogenesis, and on the important role of immunomodulators and biologics used to treat IBD patients in interfering with the inflammatory process involved in carcinogenesis.

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SHMT2 is Associated with Tumor Purity, CD8+ T Immune Cells Infiltration, and a Novel Therapeutic Target in Four Different Human Cancers

Current Molecular Medicine ◽

10.2174/1566524022666220112142409 ◽

2022 ◽

Vol 22 ◽

Author(s):

Muhammad Usman ◽

Yasir Hameed ◽

Mukhtiar Ahmad ◽

Muhammad Junaid Iqbal ◽

Aghna Maryam ◽

...

Keyword(s):

Immune Cells ◽

Promoter Methylation ◽

In Silico ◽

Human Cancer ◽

Enrichment Analysis ◽

Genetic Alterations ◽

Pathway Enrichment Analysis ◽

Human Cancers ◽

Tumor Purity

Aims: This study was launched to identify the SHMT2 associated Human Cancer subtypes. Background: Cancer is the 2nd leading cause of death worldwide. Previous reports revealed the limited involvement of SHMT2 in human cancer. In the current study, we comprehensively analyzed the role of SHMT2 in 24 major subtypes of human cancers using in silico approach and identified a few subtypes that are mainly associated with SHMT2. Objective:: We aim to comprehensively analyze the role of SHMT2 in 24 major subtypes of human cancers using in silico approach and identified a few subtypes that are mainly associated with SHMT2. Earlier, limited knowledge exists in the medical literature regarding the involvement of Serine Hydroxymethyltransferase 2 (SHMT2) in human cancer. Methods: In the current study, we comprehensively analyzed the role of SHMT2 in 24 major subtypes of human cancers using in silico approach and identified a few subtypes that are mainly associated with SHMT2. Pan-cancer transcriptional expression profiling of SHMT2 was done using UALCAN while further validation was performed using GENT2. For translational profiling of SHMT2, we utilized Human Protein Atlas (HPA) platform. Promoter methylation, genetic alteration, and copy number variations (CNVs) profiles were analyzed through MEXPRESS and cBioPortal. Survival analysis was carried out through Kaplan–Meier (KM) plotter platform. Pathway enrichment analysis of SHMT2 was performed using DAVID, while the gene-drug network was drawn through CTD and Cytoscape. Furthermore, in the tumor microenvironment, a correlation between tumor purity, CD8+ T immune cells infiltration, and SHMT2 expression was accessed using TIMER. Results: SHMT2 was found overexpressed in 24 different subtypes of human cancers and its overexpression was significantly associated with the reduced Overall survival (OS) and Relapse-free survival durations of Breast cancer (BRCA), Kidney renal papillary cell carcinoma (KIRP), Liver hepatocellular carcinoma (LIHC), and Lung adenocarcinoma (LUAD) patients. This implies that SHMT2 plays a significant role in the development and progression of these cancers. We further noticed that SHMT2 was also up-regulated in BRCA, KIRP, LIHC, and LUAD patients of different clinicopathological features. Pathways enrichment analysis revealed the involvement of SHMT2 enriched genes in five diverse pathways. Furthermore, we also explored some interesting correlations between SHMT2 expression and promoter methylation, genetic alterations, CNVs, tumor purity, and CD8+ T immune cell infiltrates. Conclusion: Our results suggested that overexpressed SHMT2 is correlated with the reduced OS and RFS of the BRCA, KIRP, LIHC, and LUAD patients and can be a potential diagnostic and prognostic biomarker for these cancers.

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Ironing out Macrophage Immunometabolism

Pharmaceuticals ◽

10.3390/ph12020094 ◽

2019 ◽

Vol 12 (2) ◽

pp. 94 ◽

Cited By ~ 7

Author(s):

Stefania Recalcati ◽

Elena Gammella ◽

Gaetano Cairo

Keyword(s):

Iron Metabolism ◽

Immune Cells ◽

Metabolic Pathways ◽

Macrophage Activation ◽

Metabolic Reprogramming ◽

Iron Availability ◽

Effector Functions ◽

Expression Of Genes ◽

Macrophage Plasticity

Over the last decade, increasing evidence has reinforced the key role of metabolic reprogramming in macrophage activation. In addition to supporting the specific immune response of different subsets of macrophages, intracellular metabolic pathways also directly control the specialized effector functions of immune cells. In this context, iron metabolism has been recognized as an important component of macrophage plasticity. Since macrophages control the availability of this essential metal, changes in the expression of genes coding for the major proteins of iron metabolism may result in different iron availability for the macrophage itself and for other cells in the microenvironment. In this review, we discuss how macrophage iron can also play a role in immunometabolism.

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Role of different immune cells and metabolic pathways in modulating the immune response in pancreatic cancer (Review)

Molecular Medicine Reports ◽

10.3892/mmr.2020.11622 ◽

2020 ◽

Vol 22 (6) ◽

pp. 4981-4991

Author(s):

Nnenna Elebo ◽

Pascaline Fru ◽

Jones Omoshoro‑Jones ◽

Geoffrey Patrick Candy ◽

Ekene Nweke

Keyword(s):

Pancreatic Cancer ◽

Immune Response ◽

Immune Cells ◽

Metabolic Pathways ◽

Cancer Review

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The Role of the Immune System in IBD-Associated Colorectal Cancer: From Pro to Anti-Tumorigenic Mechanisms

International Journal of Molecular Sciences ◽

10.3390/ijms222312739 ◽

2021 ◽

Vol 22 (23) ◽

pp. 12739

Author(s):

Sofía Frigerio ◽

Dalia A. Lartey ◽

Geert R. D’Haens ◽

Joep Grootjans

Keyword(s):

Colorectal Cancer ◽

Immune System ◽

Chronic Inflammation ◽

Immune Cells ◽

Checkpoint Inhibitors ◽

Inflammatory Diseases ◽

Cancer Development ◽

Anti Inflammatory ◽

Immunosuppressive Microenvironment

Patients with inflammatory bowel disease (IBD) have increased incidence of colorectal cancer (CRC). IBD-associated cancer follows a well-characterized sequence of intestinal epithelial changes, in which genetic mutations and molecular aberrations play a key role. IBD-associated cancer develops against a background of chronic inflammation and pro-inflammatory immune cells, and their products contribute to cancer development and progression. In recent years, the effect of the immunosuppressive microenvironment in cancer development and progression has gained more attention, mainly because of the unprecedented anti-tumor effects of immune checkpoint inhibitors in selected groups of patients. Even though IBD-associated cancer develops in the background of chronic inflammation which is associated with activation of endogenous anti-inflammatory or suppressive mechanisms, the potential role of an immunosuppressive microenvironment in these cancers is largely unknown. In this review, we outline the role of the immune system in promoting cancer development in chronic inflammatory diseases such as IBD, with a specific focus on the anti-inflammatory mechanisms and suppressive immune cells that may play a role in IBD-associated tumorigenesis.

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Associations with metabolites in Chinese suggest new metabolic roles in Alzheimer’s and Parkinson’s diseases

Human Molecular Genetics ◽

10.1093/hmg/ddz246 ◽

2019 ◽

Cited By ~ 1

Author(s):

Jin-Fang Chai ◽

Suryaprakash Raichur ◽

Ing Wei Khor ◽

Federico Torta ◽

Wee Siong Chew ◽

...

Keyword(s):

Genetic Variants ◽

Metabolic Pathways ◽

Genetic Associations ◽

Complex Disorders ◽

Genome Wide ◽

Parkinson’S Diseases ◽

Metabolite Concentrations ◽

Sphingosine 1 Phosphate ◽

Novel Associations

Abstract Metabolites are small intermediate products of cellular metabolism perturbed in a variety of complex disorders. Identifying genetic markers associated with metabolite concentrations could delineate disease-related metabolic pathways in humans. We tested genetic variants for associations with 136 metabolites in 1,954 Chinese from Singapore. At a conservative genome-wide threshold (3.7 x 10-10), we detected 1,899 variant-metabolite associations at 16 genetic loci. Three loci (ABCA7, A4GALT, GSTM2) represented novel associations with metabolites, with the strongest association observed between ABCA7 and d18:1/24:1 dihexosylceramide. Among 13 replicated loci, we identified six new variants independent of previously reported metabolite or lipid signals. We observed variant-metabolite associations at two loci (ABCA7, CHCHD2) that have been linked to neurodegenerative diseases. At SGPP1 and SPTLC3 loci, genetic variants showed preferential selectivity for sphingolipids with d16 (rather than d18) sphingosine backbone, including sphingosine-1-phosphate (S1P). Our results provide new genetic associations for metabolites and highlight the role of metabolites as intermediate modulators in disease metabolic pathways.

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