Immune System, Microbiota, and Microbial Metabolites: The Unresolved Triad in Colorectal Cancer Microenvironment

Abstract

Colorectal cancer (CRC) is one of the most common cancers worldwide. As with other cancers, CRC is a multifactorial disease due to the combined effect of genetic and environmental factors. Most cases are sporadic, but a small proportion is hereditary, estimated at around 5-10%. In both, the tumor interacts with heterogeneous cell populations, such as endothelial, stromal, and immune cells, secreting different signals (cytokines, chemokines or growth factors) to generate a favorable tumor microenvironment for cancer cell invasion and metastasis. There is ample evidence that inflammatory processes have a role in carcinogenesis and tumor progression in CCR. Different profiles of cell activation of the tumor microenvironment can promote pro or anti-tumor pathways; hence they are studied as a key target for the control of cancer progression. Additionally, the intestinal mucosa is in close contact with a microorganism community, including bacteria, bacteriophages, viruses, archaea, and fungi composing the gut microbiota. Aberrant composition of this microbiota, together with alteration in the diet‐derived microbial metabolites content (such as butyrate and polyamines) and environmental compounds has been related to CRC. Some bacteria, such as pks+ Escherichia coli or Fusobacterium nucleatum, are involved in colorectal carcinogenesis through different pathomechanisms including the induction of genetic mutations in epithelial cells and modulation of tumor microenvironment. Epithelial and immune cells from intestinal mucosa have Pattern-recognition receptors and G-protein coupled receptors (receptor of butyrate), suggesting that their activation can be regulated by intestinal microbiota and metabolites. In this review, we discuss how dynamics in the gut microbiota, their metabolites, and tumor microenvironment interplays in sporadic and hereditary CRC, modulating tumor progression.

Metabolic Reprogramming of Colorectal Cancer Cells and the Microenvironment: Implication for Therapy

“…Intestinal inflammation and malignancy influence microbiota metabolites and host-microbiota interactions [228,229]. Impairment in microbiota affects the epithelial barrier of the intestine and facilitates the transduction of tumorigenic signaling [230,231]. Intestinal cancer cells together with the components of the TME communicate with microbiota.…”

“…On the other hand, low levels of some bacteria such as Holdemanella biformis have been detected in CRC [231,237]. These bacteria showed anti-tumor activity through increasing the generation of SCFAs and inhibiting HDAC in adenomas [231,237]. Intestinal flora misbalance is associated with an impaired level of SCFAs and polyamines.…”

“…Intestinal flora misbalance is associated with an impaired level of SCFAs and polyamines. SCFAs, including butyrate, acetate and propionate, are known as microbiota metabolites and play a role in maintaining intestinal homeostasis [231,238]. SCFAs, particularly butyrate, enhance the cytotoxic function of CD8 Teff [222,[239][240][241].…”

The Role of Gut Microbiota in Tumor Immunotherapy

“…The intestinal microbiota is closely related to the occurrence and development of tumors, and its main mechanism may include releasing toxins to destroy the DNA of normal cells, causing gene mutations and directly leading to cell cancer [ 15 , 16 ]. For example, the E. coli PKS genome encodes the colibactin protein, and the toxin produced by the fragile enterotoxin is related to acute inflammatory bowel disease and colorectal tumors.…”

Gut Microbiota for Esophageal Cancer: Role in Carcinogenesis and Clinical Implications

“…In addition to specific infectious microorganisms, several researchers have started to focus on the symbiotic microbial community, which may lead to tumorigenesis. In the case of the esophagus, these microorganisms are important to esophageal physiology such as metabolism ( 15 ) and immune maturation ( 16 ), and changes in their relative abundance can disrupt their balanced interaction with the esophagus, leading to esophageal diseases, such as EC ( 17 ). In this review, we summarize the relationships between gut microbiota and EC and evaluate their potential for clinical applications.…”