Bacterial Biofilms in Colorectal Cancer Initiation and Progression

doi:10.1016/j.molmed.2016.11.004

Trends in Molecular Medicine

Volume 23, Issue 1, January 2017, Pages 18-30

https://doi.org/10.1016/j.molmed.2016.11.004 Get rights and content

Trends

The organization of bacterial communities into biofilms (higher-order spatial structures of bacterial species) may be necessary for bacteria-induced CRC initiation.

The interaction of the intestinal epithelium with the microbiota is highly dependent on the nature of the spatial organization of bacterial communities.

Bacterial biofilms might act as direct triggering factors contributing to colorectal cancer.

The biofilm confers highly-invasive properties to opportunistic bacteria, and a putative tumor-promoting potential.

In experimental models, biofilm microbial populations can significantly impair the intestinal epithelial barrier function, alter polyamine metabolism affecting cellular proliferation, enhance proinflammatory/pro-oncogenic responses, and exacerbate intestinal dysbiosis.

The invasive and co-aggregation capacity of microbiota may be essential for biofilm-promoted colon tumorigenesis.

Intestinal microbiota have emerged as an important factor in colorectal cancer (CRC) initiation and progression. The currently prominent view on bacterial tumorigenesis is that CRC initiation is triggered by local mucosal colonization with specific pathogens (drivers), and that subsequent changes in the peritumoral environment allow colonization by opportunistic (passenger) microbes, further facilitating disease progression. Screening for CRC ‘driver-passenger’ microorganisms might thus allow early CRC diagnosis or preventive intervention. Such efforts are now being revolutionized by the notion that CRC initiation and progression require organization of bacterial communities into higher-order structures termed biofilms. We explore here the concept that a polymicrobial biofilm promotes pro-carcinogenic activities that may partially underlie progression along the adenoma–CRC axis.

Section snippets

The Intestinal Microbiome: A New Window to Studying Colon Carcinogenesis

Nowhere in the human body are interactions between the microbiome (see Glossary) and host physiology as pronounced as in the gastrointestinal (GI) tract. It hosts an estimated 40 trillion microbes composed of at least 1000 species of which the vast majority reside in the colon [1]. It is thus to be expected that, if the microbiome and human pathophysiology are interlinked, this should be especially pronounced in the colon. A principal role for the microbiome in the pathophysiology of acute and

From Single Pathogenic Microorganism to Polymicrobial Infections and Cancer

As shown in the quintessential example of H. pylori in gastric cancer, specific microorganisms per se are capable of driving carcinogenic and other cancerous processes in the human GI tract 23, 24, 25, 26. In addition, other types of human cancer can also be provoked by infection with a specific pathogen, examples being liver cancer (chronic hepatitis B or C virus), cervical cancer (human papilloma virus), Burkitt's lymphoma (Epstein–Barr virus), and bladder cancer (induced by Schistosoma

Biofilm Organization May Be Necessary for Bacteria-Induced CRC Initiation

Ecological constraints in the human intestine favor a higher-order level of spatial organization of multi-organism structures in mucosal microbial communities, of which biofilm formation is the best-known 11, 13, 39. Such biofilms are associated with chronic bacterial infection that is not always easy to eradicate. Biofilms appear to be an important etiological factor in human infectious disease, especially endocarditis and cystic fibrosis lung disease 40, 41. With respect to the former, the

Biofilms Require Invasion and Coaggregation Properties to Stimulate CRC

Bacterial biofilms are not carcinogenic per se but only in the context of specific invasive bacteria, especially Fusobacteria [11]. Accordingly, biofilms have been observed in the rat, baboon, and human non-tumorous gut by electron microscopy [43]. One study also showed that biofilms could be detected in the colon of normal mice, and biofilms have been sampled from healthy individuals using colonoscopy [38]. Moreover, colonoscopy biopsy specimens from healthy individuals have revealed that thin

Biofilms Enhance Host–Microbe Interactions in CRC

Bacterial biofilms can contribute to increases in intestinal permeability and enhanced bacterium-induced barrier function loss which, in turn, is one of the most important early pathophysiologic alterations in colorectal carcinogenesis [56]. There are two lines of evidence supporting the biofilm-promoted barrier-loss concept. First, bacterial invasion is present in all biofilm-positive human colorectal tumors, including CRCs and adenomas, but invasive characteristics are absent from

Biofilm Formation and Enhanced Bacteria-Mediated Genotoxicity in CRC

Of the possible mechanisms by which bacterial biofilms can promote oncological disease, genotoxic stress resulting from bacterial toxins appears to bear the most evident link to transformation per se. For instance, different bacteria produce various toxins, of which BFT and CDT contribute to genotoxicity and human CRC initiation 58, 59, 60, 61, 62, 63. Indeed, BFT (generated from ETBF) is a genotoxin that indirectly causes DNA damage 34, 60, 64. For example, the BFT, in HT29/C1 and T84 colonic

The Biofilm Influences Host Metabolism in CRC

Microbe–host metabolic interactions may directly or indirectly provoke bacteria-induced CRC progression. Accumulating evidence has linked the intestinal microbiota to the regulation of multiple metabolic pathways of endogenous and exogenous substrates, such as secondary bile acid biosynthesis, polyamine catabolism, and activation of carcinogens, which in turn are associated with increased risk for various human cancers such as CRC, esophageal cancer, and liver cancer 13, 60, 69, 70, 71, 72, 73,

Polymicrobial Biofilm As a Trigger of Pro-Carcinogenic Inflammatory Responses

The contribution of bacterium-induced inflammation to tumor growth is well-accepted 34, 86, 87. Specifically, the IL-23/IL-17 signaling axis appears to be important in bacterium-induced inflammation 36, 88. This pathway has been shown to promote granulocyte accumulation with antibacterial activity, but it can also lead to DNA damage in humans and mice 22, 36, 87. Moreover, granulocytes are especially prone to releasing proinflammatory cytokines such as IL-1, IL-6, and IL-21 22, 36. A

Concluding Remarks

Intestinal bacterial biofilms and their composition appear to play an important role in triggering and sustaining CRC progression. The molecular mechanisms underlying the crosstalk between bacteria-produced carcinogenic factors, bacterial biofilms, and host responses in CRC initiation and progression are only now emerging and, evidently, further research will be necessary to provide mechanistic insight into their precise involvement in the cancer process. The relative importance of these events

Acknowledgments

S.L. is supported by a PhD fellowship from the China Scholarship Council (CSC, 201408060053).

Glossary

Absent in melanoma 2 (Aim2): an innate immune sensor encoded by the AIM2 gene that is frequently mutated in patients with CRC. The mouse homolog is Aim2.
Adenoma: a benign tumor originating in epithelial tissue within glandular structures; it may affect various organs such as stomach, colon, and lung.
Adenoma–carcinoma sequence model: an experimental model described as a stepwise progression from normal colorectal epithelium to adenoma, and eventually to invasive carcinoma as a result of the

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Citation Excerpt :
The wealth of data on planktonic lifestyles dwarfs the available knowledge on biofilms [1]. This recently started to change, as biofilms were recognized to be a significant contributor to many bacterial diseases: almost 80% of all bacterial infections in humans are a direct consequence of biofilms [5], including cystic fibrosis, urinary tract infections, and even cancer development [6,7]. Biofilms can cause chronic wound infection, leading to limb amputations in diabetic patients [8].
Biofilms are communities of bacteria forming high-density sessile colonies. Such a lifestyle comes associated with costs and benefits: while the growth rate of biofilms is often lower than that of their free-living counterparts, this cost is readily repaid once the colony is subjected to antibiotics. Biofilms can grow in antibiotic concentrations a thousand times higher than planktonic bacteria. While numerous mechanisms have been proposed to explain biofilm recalcitrance towards antibiotics, little is yet known about their effect on the evolution of resistance. We synthesize the current understanding of biofilm recalcitrance from a pharmacodynamic and a population genetics perspective. Using the pharmacodynamic framework, we discuss the effects of various mechanisms and show that biofilms can either promote or impede resistance evolution.

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Trends in Molecular Medicine

OpinionBacterial Biofilms in Colorectal Cancer Initiation and Progression

Trends

Section snippets

The Intestinal Microbiome: A New Window to Studying Colon Carcinogenesis

From Single Pathogenic Microorganism to Polymicrobial Infections and Cancer

Biofilm Organization May Be Necessary for Bacteria-Induced CRC Initiation

Biofilms Require Invasion and Coaggregation Properties to Stimulate CRC

Biofilms Enhance Host–Microbe Interactions in CRC

Biofilm Formation and Enhanced Bacteria-Mediated Genotoxicity in CRC

The Biofilm Influences Host Metabolism in CRC

Polymicrobial Biofilm As a Trigger of Pro-Carcinogenic Inflammatory Responses

Concluding Remarks

Acknowledgments

Glossary

Cell

Cell Host Microbe

Cell. Metab.

Cell

Lancet Oncol.

Cell Host Microbe

Cell

Trends Microbiol.

Gastroenterology

Cancer Cell

Bioorg. Med. Chem.

Cell

Cancer Cell

Gastroenterology

Immunity

Secretory diarrhoea: mechanisms and emerging therapies

Nat. Rev. Gastroenterol. Hepatol.

The intestinal microbiota and chronic disorders of the gut

Nat. Rev. Gastroenterol. Hepatol.

Stomach microbiota composition varies between patients with non-atrophic gastritis and patients with intestinal type of gastric cancer

Sci. Rep.

Differences in gastric mucosal microbiota profiling in patients with chronic gastritis, intestinal metaplasia, and gastric cancer using pyrosequencing methods

Helicobacter

Atrophic gastritis, Helicobacter pylori, and colorectal cancer risk: a case-control study

Helicobacter

Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma

Genome Res.

Microbial genomic analysis reveals the essential role of inflammation in bacteria-induced colorectal cancer

Nat. Commun.

Genomic analysis identifies association of Fusobacterium with colorectal carcinoma

Genome Res.

Microbiota organization is a distinct feature of proximal colorectal cancers

Proc. Natl. Acad. Sci. U. S. A.

Microbiota disbiosis is associated with colorectal cancer

Front. Microbiol.

Colorectal cancer statistics, 2014

CA Cancer J. Clin.

Global cancer statistics, 2012

CA Cancer J. Clin.

The human gut microbiome as a screening tool for colorectal cancer

Cancer Prev. Res.

Microbiota-based model improves the sensitivity of fecal immunochemical test for detecting colonic lesions

Genome Med.

Dysbiosis signature of fecal microbiota in colorectal cancer patients

Microb. Ecol.

The keystone-pathogen hypothesis

Nat. Rev. Microbiol.

Perspective: alpha-bugs, their microbial partners, and the link to colon cancer

J. Infect. Dis.

A bacterial driver-passenger model for colorectal cancer: beyond the usual suspects

Nat. Rev. Microbiol.

Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii

N. Engl. J. Med.

Helicobacter pylori infection and the risk of gastric carcinoma

N. Engl. J. Med.

Gastric adenocarcinoma and Helicobacter pylori infection

J. Natl. Cancer Inst.

Helicobacter pylori infection in intestinal- and diffuse-type gastric adenocarcinomas

J. Natl. Cancer Inst.

Potential of fecal microbiota for early-stage detection of colorectal cancer

Mol. Syst. Biol.

Two FOXP3+CD4+ T cell subpopulations distinctly control the prognosis of colorectal cancers

Nat. Med.

Fusobacterium is associated with colorectal adenomas

PLoS One

Opinion
Bacterial Biofilms in Colorectal Cancer Initiation and Progression

Two FOXP3⁺CD4⁺ T cell subpopulations distinctly control the prognosis of colorectal cancers