Chapter 4 : Microbial Interactions and Interventions in Colorectal Cancer

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Colorectal cancer (CRC), the most common form of gastrointestinal (GI) tract cancer, is globally the third leading cause of cancer and is associated with significant mortality ( ). Approximately 90% of CRC cases are sporadic, caused by somatic mutations leading to the progression of invasive carcinomas ( ). There are numerous risk factors associated with the development of CRC, and the disease is more common in industrialized countries than it is in the developing world ( ). Poor diet (in particular, a diet that is low in fiber and high in fat) appears to be a major influencing factor for disease development and progression, and recently it has been recognized that gut microbes may act as the interface between dietary factors and tumor development (reviewed in reference ). This chapter will review the pathways that lead to CRC, what is currently known about microbial involvement in these processes, and how these may be manipulated therapeutically.

Citation: van Raay T, Allen-Vercoe E. 2018. Microbial Interactions and Interventions in Colorectal Cancer, p 101-130. In Britton R, Cani P (ed), Bugs as Drugs. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.BAD-0004-2016
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Figure 1a

(A) Schematic of the anatomy of the human colon, indicating right/proximal and left/distal regions and their designations.

Citation: van Raay T, Allen-Vercoe E. 2018. Microbial Interactions and Interventions in Colorectal Cancer, p 101-130. In Britton R, Cani P (ed), Bugs as Drugs. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.BAD-0004-2016
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Figure 1b

(B) Depiction of the overlap between development, innervation, vascularization, and tumorigenesis of the human colon. Abbreviations: superscript c, chick; superscript m, mouse; superscript z, zebrafish; PMF, parasympathetic motor fibers; SMF, sympathetic motor fibers; SF, sensory fibers.

Citation: van Raay T, Allen-Vercoe E. 2018. Microbial Interactions and Interventions in Colorectal Cancer, p 101-130. In Britton R, Cani P (ed), Bugs as Drugs. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.BAD-0004-2016
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Figure 2

Colonic crypt and aberrant Wnt signaling. (A) Model of Wnt signaling. In the absence of Wnt-ligand stimulation, the central signaling molecule β-catenin is degraded and Wnt target genes remain silent (left). In the presence of Wnt ligand-mediated signaling, β-catenin becomes stabilized, resulting in cytoplasmic and nuclear accumulation and active transcription of Wnt target genes (center). APC mutations disrupt the destruction complex resulting in constitutively active Wnt signaling (right). Under normal circumstances, β-catenin-E-cadherin-mediated cell adhesion is not thought to have a role in Wnt signaling. (B) The left side of the crypt depicts normal development. Black nuclei represent β-catenin-positive stem cells, with varying gray scale levels representing decreasing Wnt signaling, which is shut down (white nuclei) as the precursor cells differentiate. Colors represent the four major lineages of the colonic epithelium, with lighter colors representing less differentiated forms in the colonic crypt. On the right side, a mutation in APC renders the Wnt signaling pathway constitutively active, resulting in the proliferation of stem cells that become hyperplastic, eventually forming polyps on the luminal surface. Wnt signaling inhibits mucin-2 synthesis, possibly generating the nonmucinous phenotype characteristic of distal cancers. It is expected that cells in the polyp would consist of a heterogenous mixture of cells, some more differentiated (with less nuclear β-catenin) than others. The selection of APC alleles to generate the just-right amount of Wnt signaling results in the elimination of cells with too much or too little β-catenin signaling. The loss of E-cadherin (E-CAD) could have a role in generating this “just-right” amount of signaling.

Citation: van Raay T, Allen-Vercoe E. 2018. Microbial Interactions and Interventions in Colorectal Cancer, p 101-130. In Britton R, Cani P (ed), Bugs as Drugs. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.BAD-0004-2016
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Figure 3

Schematic detailing microbiome changes that can lead to the development of CRC. In the normal, healthy state (normal tissue), the gut microbiota is diverse and in balance within the host. The mucosal layer of the gut is intact, and microbes are not found directly in the vicinity of the colonic cells. In the alpha-bug model, certain pathobionts within the microbiome obtain entry to host tissues, e.g., by interfering with mucus secretion or by penetrating the mucus layer, and directly secrete metabolites and/or virulence determinants such as toxins to modulate host cells. Colonization by alpha-bugs in this way can also directly modulate the composition of the local microbiota. The driver-passenger model suggests that the major CRC-promoting factors come from colonization by passenger microbes that can settle within a niche prepared for them by the driver species. The biofilm model indicates that certain colonizing microbes, particularly in the proximal colon, can form aggregates, perhaps with cooperating species, that are able to persist in the niche and to secrete factors (including, in particular, polyamines) that potentiate CRC development. In the intestinal microbiota adaptations model, exogenous factors, such as diet, as well as endogenous factors, such as immune system function, behave as forces that shape the overall balance of cancer-promoting versus cancer-protective microbiota compositions. Finally, the bystander-effect model proposes that certain superoxides produced by the metabolism of certain microbial species can stimulate stromal macrophages to produce clastogens, which in turn have a directly carcinogenic effect on host cells.

Citation: van Raay T, Allen-Vercoe E. 2018. Microbial Interactions and Interventions in Colorectal Cancer, p 101-130. In Britton R, Cani P (ed), Bugs as Drugs. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.BAD-0004-2016
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