Pathogenic Intestinal Bacteria Enhance Prostate Cancer Development via Systemic Activation of Immune Cells in Mice

Deyu Fang,Theofilos Poutahidis,Susan E Erdman,Michael Doulberis,James G Fox,Bruce H Horwitz,Zhongming Ge,Chung-Wei Lee,Tatiana Levkovich,Kelsey Cappelle

doi:10.1371/journal.pone.0073933

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, Apc Min/+ mutant mice, were significantly susceptible to prostate cancer in an inflammation-dependent manner following infection with Helicobacter hepaticus. Further, early neoplasia observed in infected Apc Min/+ 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.

Highlights

A small proportion of dysplastic and early neoplastic lesions arising in epithelia throughout the body advance into cancer [1,2,3]
By 12 weeks of age, ApcMin/+ mice infected with H. hepaticus displayed features of prostate carcinoma consistent with those observed in human males (Figure 1A, 1B; Table S1)
Neither H. hepaticusinfected nor uninfected 12-week-old wt mice exhibited significant prostate pathology. Together these results demonstrate that infection of the GI tract with H. hepaticus rapidly enhances prostate carcinogenesis in genetically susceptible mice

Summary

Introduction

A small proportion of dysplastic and early neoplastic lesions arising in epithelia throughout the body advance into cancer [1,2,3]. It is well documented that for many types of cancer a major contributor is cells and factors of the immune system [4,5,6]. Several lines of evidence suggest that chronic inflammation drives the prostate cancer process [5,7,8], but its source remains elusive. Infectious agents, chemical or physical epithelial cell injury, hormonal imbalances and dietary factors have been proposed as the most probable causes of chronic inflammation in the prostate [8,9,10]. Determining whether prostate malignancy may be preventable by targeting underlying inflammation has particular importance since it is a leading cause of cancer-related disability and death among men. In the gastrointestinal (GI) tract, infections with pathogenic microbes, such as with

Methods

Results

Conclusion