How the microbiome is shaping our understanding of cancer biology and its treatment
Introduction
Human tissues are complex, incorporating both human cells and coexisting microorganisms. Commensal bacteria inhabit all epithelial lined surfaces in the body. The ratio of bacterial to human cells is estimated to be 1:1, with microbial genes outnumbering human genes 100:1.1, 2 The human body can therefore be reconceived as a metaorganism, made up of both the individual and that individual’s microbiome.3 We have only recently begun to appreciate the complexity of the bidirectional signaling between these components, which can regulate both the metaorganism’s daily physiologic function and ultimately its malignant pathology.4 Thus, understanding the development of malignancy within a metaorganism is in part, a study of the microbial influence on cellular transformation, genetic instability, somatic mutations, and microenvironmental shifts.5 With the development of advanced sampling and analysis of both nucleic acids (RNA sequencing) and protein products (transcriptomics), researchers have been able to characterize the microbial communities which inhabit specific anatomic locations during various disease processes. These emerging data provide new information that relates bacterial communities and tumorigenesis.
Recent research has demonstrated that infectious agents can directly promote malignant transformation. In 2008, two million cancer cases globally were directly attributed to infectious agents, with Helicobacter pylori as the first bacterium considered by the International Agency for Research on Cancer as a human carcinogen for gastric cancer.6, 7 H. pylori production of the cytotoxin-associated gene A (CagA) results in host DNA damage, promotion of inflammation, and release of growth factors.8 Thus, CagA functions as an oncoprotein and acts to damage DNA through host overproduction of reactive oxygen species, leading to a six-fold increase risk in cancer.9 Helicobacter’s pro-neoplastic effect has also been documented in the development of breast cancer.10 Further, bacteria are implicated in tumorigenesis outside of the GI tract. Chlamydia pneumoniae promotes lung carcinoma and Neisseria gonorrhea facilitates the induction of prostate cancer.11, 12 Given the abundance of bacteria in the lower gastrointestinal tract, it is not surprising that the link between bacteria and colorectal cancer (CRC) has emerged as a particularly intriguing area of inquiry. Extensive studies and preclinical models have demonstrated a role for microbial dysbiosis in the development of colorectal cancer.13 Thus, understanding the contribution of the microbiome to colorectal carcinogenesis may be particularly valuable as we seek to uncover novel modalities for prevention and treatment of this common neoplasm.
Section snippets
Microbiome and colorectal cancer
Colorectal cancer remains the third most common malignancy in the world. While advances in treatment strategies have improved overall survival rates, nearly 20% of patients present with metastatic disease at the time of diagnosis.14 Despite advancements in therapy, patients with metastatic disease remain with a poor 5-year survival of <10%.15 Of interest, colorectal cancer has been termed a “Westernized disease,” and is thought to arise in a stepwise fashion. Alterations in microbial
Microbes and inflammation
The immune system functions to maintain a symbiotic relationship with bacteria. Anatomical barriers, either physical or chemical, prevent the translocation of bacteria or bacterial products into systemic circulation. Through a break in tight junction or a loss of mucus production, the immune cells′ pattern recognition receptors (i.e., Toll-like receptors) are activated by bacterial LPS, peptidoglycan, or DNA/RNA. Once activated, macrophages, myofibroblasts, and epithelial cells release
Pathobiome
The first step in understanding the gut microbiota’s role in tumorigenesis through dysbiosis is the establishment of a bacterial profile during homeostasis, i.e., “normal intestinal microbiota”. The gut is first colonized at birth, and stabilizes through adaptation into four dominate phyla early in life: Firmicutes, Bacteriodetes, Proteobacteria, and Actinobacteria. The presence and dominance of an individual species is highly dynamic, continually influenced by the environment, genetics, the
Diet
One of the most popular and heavily debated risk factors for the development of CRC is a diet rich in red meats/fat, and low in dietary fiber. Recent meta-analyses found that individuals with a diet lacking in high fiber foods had a higher incidence of colorectal adenomas, whereas individuals who consumed whole grains demonstrated lower rates of CRC.38, 39 Studies have shown that the gut microbial community is extremely sensitive to changes in diet, with alterations noted in fecal samples
Modulating the immune system
As introduced earlier in this review, several pathobionts are able to modulate the immune system and initiate the development of CRC. Enterotoxic Bacteriodes fragilis activates STAT3 and T helper cell 17 leading to inflammation. In ApcMin/+ mice colonized with B. fragilis, inhibition of IL-17 or depletion of T-helper cells prevented the formation of tumors, suggestive of an enterotoxigenic-triggered neoplasia through an oncogenic immune response.48, 49 Another bacterium found in high proportion
Epithelial to mesenchymal transition
Recent studies demonstrate that, in addition to stimulating the immune system, the B. fragilis toxin can clear E-cadherin, a transmembrane adhesion protein, leading to colonic epithelial proliferation. Genes for this toxin are prevalent in mucosal samples of patients with CRC.58, 59 E-cadherin plays a role in epithelial to mesenchymal transition (EMT), a set of key steps in malignant transformation. EMT involves the phenotypic and genetic shift from mature, stationary epithelial cells anchored
Therapeutics and the future
The potential for targeted interventions addressing the specific mechanisms outlined above remain an area of great interest. For instance, probiotics have long been promoted as having health benefits, a promotion which is currently poorly supported by clinical evidence.74 The development of capsule delivery of probiotics produced increased microbial diversity and decreased Fusobacterium in CRC patients, but the clinical significance of this restoration has not been established.75 The proposed
Conclusions
The malignant potential of human tissues has been shown to be influenced by the microbial composition of the environment. Of particular interest is the role of the microbiome in colorectal cancer, given the functional importance, density, and variety of bacterial species located within the colon. Further, the products of microbial metabolism and toxins may directly influence not only the initiation of malignant transformation, but the metastatic potential of transformed colonic cells. The
References (77)
- et al.
Are we really vastly outnumbered? Revisiting the ratio of bacterial to host cells in humans
Cell
(2016) - et al.
Metaorganisms as the new frontier
Zoology
(2011) - et al.
Intestinal microbiota is a plastic factor responding to environmental changes
Trends Microbiol
(2012) - et al.
Global burden of cancers attributed to infections in 2008: a review and synthetic analysis
Lancet Oncol
(2012) - et al.
Helicobacter pylori infection causes characteristic DNA damage patterns in human cells
Cell Rep
(2015) - et al.
Sexually transmitted infections and prostate cancer risk: a systematic review and meta-analysis
Cancer Epidemiol
(2014) - et al.
Colorectal cancer
The Lancet
(2014) - et al.
Liocalin 2 protects from inflammation and tumorigenesis associated with gut microbiota alterations
Cell Host Microbe
(2016) - et al.
Crosstalk between the microbiome and cancer cells by quorum sensing peptides
Peptides
(2015) - et al.
Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment
Cell Host Microbe
(2013)
Decreased dietary fiber intake structural alteration of gut microbiota in patients with advanced colorectal adenoma
Am J Clin Nutr
The Warburg effect dictates the mechanism of butyrate-mediated histone acetylation and cell proliferation
Mol Cell
Gut microbial metabolism drives transformation of MSH2-deficient colon epithelia cells
Cell
N-nitroso compounds and cancer incidence: the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk Study
Am J Clin Nutr
Microbiome-driven carcinogenesis in colorectal cancer: models and mechanisms
Free Radical Med
Human colorectal cancer-associated biofilms promote tumorigenesis in susceptible mice
Gastroenterology
Epithelial-mesenchymal transition in colorectal cancer metastasis: a system review
Pathol Res Practice
Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties
Cell
Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/B-catenin signaling via its FadA adhesion
Cell Host Microbe
Gut microbiota and probiotics in colon tumorigenesis
Cancer Lett
Consort: structure, function and diversity of the healthy human microbiome
Nature
Collateral damage: insights into bacterial mechanisms that predispose host cells to cancer
Nat Rev Microbiol
Helicobacter pylori and gastrointestinal tract adenocarcinomas
Nat Rev Cancer
Helicobacter pylori and gastric cancer: factors that modulate disease risk
Clin Microbiol Rev
Gut bacteria require neutrophils to promote mammary tumorigenesis
Oncotarget
Chlamydia pneumonia infection and risk for lung cancer
Cancer Epidemiol Biomarkers Prev
Carcinogenesis and therapeutics: the microbiota perceptive
Nat Microbiol
Diagnostic accuracy of computed tomography for colon cancer staging: a systemic review
Scand J Gastroenterol
A bacterial driver-passenger model for colorectal cancer: beyond the usual suspects
Nat Rev Microbiol
Intestinal neoplasia in the ApcMin mouse: independent from the microbial and natural killer (beige locus) status
Cancer Res
Toll-like repector-4 promotes the development of colitis-associated colorectal tumors
Gastroenterology
Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract
Science
Dismicrobism in inflammatory bowel disease and colorectal cancer: changes in response of colonocytes
World J. Gastroenterol
The microbiome and cancer
Nat Rev Cancer
Human microbiome and their roles in dysbiosis, common diseases, and novel therapeutic approaches
Front Microbiol
Inflammation-induced cancer: crosstalk between tumors, immune cells and microorganisms
Nat Rev Cancer
The dynamics of gut-associated microbial communities during inflammation
EMBO Rep
Cancer and the microbiome
Science
Cited by (9)
Significance of human microbiome in breast cancer: Tale of an invisible and an invincible
2021, Seminars in Cancer BiologyCitation Excerpt :A fundamental mechanistic association between the occurrence of therapeutic resistance in the cancer cells and the evolution of the bacterial communities within those malignant tissues have been an enigma to the scientific societies for a long time. A number of microbes, including Bacteroides fragilis, Fusobacterium nucleatum, and Enterococcus faecalis have been demonstrated to cause aberrations to host cell adhesions and promote epithelial-to-mesenchymal transitions, which is intimately connected to metastasis [166]. Bacterially induced inflammatory response, production, and secretion of bacterial toxins, enzymes, and oncogenic peptides have been deemed as important contributors to oncogenesis.
The Prevention of Inflammation and the Maintenance of Iron and Hepcidin Homeostasis in the Gut, Liver, and Brain Pathologies
2023, Journal of Alzheimer's DiseaseDiet, Microbes, and Cancer Across the Tree of Life: a Systematic Review
2022, Current Nutrition ReportsThe dysbiosis signature of Fusobacterium nucleatum in colorectal cancer-cause or consequences? A systematic review
2021, Cancer Cell InternationalDiet, microbes, and cancer across the tree of life: A systematic review
2021, Research SquareMicrobiome
2021, Indian Journal of Medical and Paediatric Oncology
Supported in part by Ruth L. Kirschstein National Research Service Award – T32 Institutional Training Grant, awarded to Sara Gaines MD, from the Digestive Disease Research Core Center, University of Chicago Medical Center.