How the microbiome is shaping our understanding of cancer biology and its treatment

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Abstract

The human body is a metaorganism: it is composed of the individual and the individual’s microbiome. Therefore, the study of malignancy within a metaorganism must include an understanding of the microbial contribution to tumorigenesis, response to treatment, and ultimately recurrence. The colon and rectum harbor more microbes than any other anatomic system, and the interplay of microbes with colorectal cancer has emerged as an exciting area of research. This article highlights the leading theories on the microbial contribution to colorectal tumorigenesis and proposes novel, therapeutic strategies for the future treatment of this disease.

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

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    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.

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