PLoS One. 2013 Aug 26;8(8):e73933. doi: 10.1371/journal.pone.0073933.

Pathogenic intestinal bacteria enhance prostate cancer development via systemic activation of immune cells in mice.

Poutahidis T, Cappelle K, Levkovich T, Lee CW, Doulberis M, Ge Z, Fox JG, Horwitz BH, Erdman SE.

Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

 

ABSTRACT:

A role for microbes has been suspected in prostate cancer but difficult to confirm in human patients. We show here that a gastrointestinal (GI) tract bacterial infection is sufficient to enhance prostate intraepithelial neoplasia (PIN) and microinvasive carcinoma in a mouse model. We found that animals with a genetic predilection for dysregulation of wnt signaling, ApcMin/+ mutant mice, were significantly susceptible to prostate cancer in an inflammation-dependent manner following infection with Helicobacter hepaticus. Further, early neoplasia observed in infected ApcMin/+ mice was transmissible to uninfected mice by intraperitoneal injection of mesenteric lymph node (MLN) cells alone from H. hepaticus-infected mutant mice. Transmissibility of neoplasia was preventable by prior neutralization of inflammation using anti-TNF-α antibody in infected MLN donor mice. Taken together, these data confirm that systemic inflammation triggered by GI tract bacteria plays a pivotal role in tumorigenesis of the prostate gland.

PMID: 23991210

 

SUPPLEMENT: Intestinal bacteria modulate prostate cancer development

A role for microbes has been suspected in cancers throughout the body, but is difficult to confirm in human patients. Malignancies induced in mice after exposure to external agents such as bacteria provide valuable model systems to interrogate cancer pathogenesis otherwise not feasible in humans. For example, murine models have greatly facilitated our current understanding of Helicobacter pylori infection-associated gastric cancer in humans. In a series of studies published 2006 – present, we present data using mouse models as an experimental system to probe and better understand associations of intestinal microbes and cancers in extra-intestinal tissues, such as in prostate and mammary glands. Importantly, we show in each model that targeted intestinal tract bacterial infections are sufficient to trigger systemic events that lead to cancers in distant non-intestinal sites.

Gut microbe infections trigger cancers in distant tissues

During investigations of colorectal cancer, we discovered that orogastric infection of susceptible mutant mice with H. hepaticus bacteria rapidly promotes extra-intestinal tumors. In mouse models that have been designed to resemble cancer processes in humans, clinically silent gastrointestinal tract immune networks triggered by gut microbiota create systemic imbalances. Proposed events include: 1) systemic activation of immune cells; 2) enhanced trafficking of bone marrow derived cells; and 3) dissemination of microbes or their antigens from the bowel to distant tissues, together impact the fate of topographically distant epithelia such as those of the prostate or mammary glands; are outlined in our earlier manuscript by Rao et al (2007). We show in Poutahidis et al (2013) that gut microbe-induced prostate cancer is transplantable to naïve mice using isolated mesenteric lymph node tissues alone (Figure 1). This was a key finding to help understand how gut microbes contribute to cancer.

Do gut bacteria stimulate systemic inflammatory responses?

Precisely how gastrointestinal bacteria may trigger carcinogenesis in distant tissues is not entirely clear, but data from other systems support a key role for inflammatory cells in this process. Along these lines, we have shown that within days of gastric gavage with H. hepaticus, mice develop enlarged peripheral lymph nodes that become filled with inflammatory cells. These gut bacteria-induced events feature cells and systemic signaling factors that regulate bone marrow release and tissue trafficking of myeloid precursor cells. In particular, we observe elevations in cytokines eotaxin, Interleukin (IL)-3, and IL-9 that stimulate the growth of hematopoietic cells and recruit mast cells, neutrophils, and myeloid precursor cells bearing ring-shaped nuclei to inflamed prostate and mammary tissues. The important role of IL-9 in autoimmunity and allergy may provide important clues, especially in connecting prostate inflammation with cancer.

Indeed, there is precedent for prolonged immune activation due to pathogenic bacterial infections such as H. pylori in people that clearly contribute to cancer in susceptible individuals. Further, anti-inflammatory drugs inhibit prostate cancer in humans. During our search for ways in which gut bacteria enhance the risk of developing cancer, we have found that blocking inflammatory cytokines, such as Tumor Necrosis Factor (TNF)-alpha, is sufficient to inhibit distant tumor development.

Do gut microbes or their products translocate from bowel to non-intestinal tissues?

Another interesting possibility is that translocation of intestinal bacteria to prostate or mammary tissue via immune cells may explain the rapid onset of cancer in these genetically susceptible mice. Recent scientific data show that breaks in the intestinal epithelial barrier, such as those that occur with pathogenic bacterial infections, making the host animal highly susceptible to dissemination of gut bacteria throughout the body via the bloodstream or lymphatics. Although we did not specifically detect H. hepaticus organisms within the prostate tissue in the present study, the possibility that carcinogenic micro-organisms or their antigens may be contained with lymphatic tissues or the carcinoma itself remains a focus of our current studies.

Gut microbes influence a systemic cancer macroenvironment

The challenge now is to integrate findings from basic science with those from clinical studies, so we can sufficiently understand the systemic cross-talk between microbial and immune homeostatic mechanisms that govern our health in the bowel to achieve optimal protection from cancer in the prostate, breast and other tissue sites. In the present study, systemic lymph node cells were sufficient to transplant the bacterial cancerous effect to naive recipient animals. It is probable that lymph nodes are a conduit for systemic trafficking of inflammatory cells, and perhaps bone marrow-derived stem cells, recently shown to contribute to carcinoma. To the same same extent, we have previously shown using mouse models that supplementation with gut microbe-programmed anti-inflammatory immune cells is sufficient to normalize downstream expression of the c-myc oncogene in tumor tissues, as previously linked with cancers in human subjects. Enormous potential now exists to engineer the microbiome to modulate the whole body cancer macroenvironment. These possibilities remain to be explored in future studies.

Correspondence and requests for materials should be addressed to Susan Erdman, serdman@mit.edu, ph 617-252-1804, fax 617-258-5708 Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139.
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