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.

Keywords: colorectal cancer; diet-derived metabolites; immune system; intestinal microbiota; tumor micronvironment (TME).

Figure 1

Pro-tumorigenic effects of pks⁺ E. coli. Strains having the pathogenicity island pks can synthesize colibactin toxin having oncogenic potential. Colibactin damages colonocyte DNA by inducing double-stranded DNA breaks and single-base substitution, deletion, and insertion mutations, favoring accumulation of damage and increasing the risk of malignant cell transformation.

Figure 2

Roles of F. nucleatum in CRC tumoral development and metastasis. F. nucleatum virulence factors are FadA and Fap2: (A) FadA is an adhesin that binds to E-cadherin and allows bacterial invasion, which also induces the colonocyte proliferation through ß-catenin signaling and NFkB2-associated pro-inflammatory response. (B) Fap2 interacts with the TIGIT inhibitory receptor of NK cells resulting in cytotoxic inhibition, leading to immune evasion. (C) This bacterium associates with post-chemotherapy recurrence, suggested through LPS-TLR4 interaction activating autophagy, and altering chemotherapy response. Furthermore, Fap2 recognizes and binds to Gal-GalNac expressed in colorectal tumor cells; high F. nucleatum content found in distal metastases. The above-mentioned effects indicate that this bacterium participates in both carcinogenic and metastatic processes and may be a potential therapeutic target.

Figure 3

Dual role of butyrate in colorectal cancer. Butyrate exerts dual effects on normal and tumor colonocytes. In normal colonocytes, it functions as an energy source, being metabolized to acetyl-CoA in the Krebs cycle, allowing cell proliferation. Alternatively, in tumor colonocytes due to the Warburg effect, anaerobic glycolysis is the main energetic source, therefore, butyrate does not enter the Krebs cycle and available to the nucleus, modulating gene expression through the HDAC inhibition, leading to p21 and p27 downregulation and inhibiting cell proliferation, thus explaining the beneficial effect associated in cancer.

Figure 4

Effects of polyamines in the tumor microenvironment. Red arrows indicate inhibition and black arrows enhancement. Polyamines in TME: a) inhibit cytotoxic CD8+ LTs function and decrease quantity, inhibit: b) tumor cell apoptosis, c) macrophage polarization toward M1 pro-inflammatory phenotype, d) antitumor responses and e) pro-inflammatory cytokine production. Alternatively, polyamines enhance: f) tumor angiogenesis, g) tumor cell proliferation, h) macrophage polarization toward M2 immunosuppressive phenotype and i) tumor cell metastasis. Together, their effects produce an immunosuppressed environment facilitating tumor progression and metastasis.