title: Obesity does not promote tumorigenesis of localized patient-derived prostate cancer xenografts.
abstract: There are established epidemiological links between obesity and the severity of prostate cancer. We directly tested this relationship by assessing tumorigenicity of patient-derived xenografts (PDXs) of moderate-grade localized prostate cancer in lean and obese severe combined immunodeficiency (SCID) mice. Mice were rendered obese and insulin resistant by high-fat feeding for 6 weeks prior to transplantation, and PDXs were assessed 10 weeks thereafter. Histological analysis of PDX grafts showed no differences in tumor pathology, prostate-specific antigen, androgen receptor and homeobox protein Nkx-3.1 expression, or proliferation index in lean versus obese mice. Whilst systemic obesity per se did not promote prostate tumorigenicity, we next asked whether the peri-prostatic adipose tissue (PPAT), which covers the prostate anteriorly, plays a role in prostate tumorigenesis. In vitro studies in a cellularized co-culture model of stromal and epithelial cells demonstrated that factors secreted from human PPAT are pro-tumorigenic. Accordingly, we recapitulated the prostate-PPAT spatial relationship by co-grafting human PPAT with prostate cancer in PDX grafts. PDX tissues were harvested 10 weeks after grafting, and histological analysis revealed no evidence of enhanced tumorigenesis with PPAT compared to prostate cancer grafts alone. Altogether, these data demonstrate that prostate cancer tumorigenicity is not accelerated in the setting of diet-induced obesity or in the presence of human PPAT, prompting the need for further work to define the at-risk populations of obesity-driven tumorigenesis and the biological factors linking obesity, adipose tissue and prostate cancer pathogenesis.
authors.affiliation: Metabolic Disease and Obesity Program, Monash Biomedicine Discovery Institute, Department of Physiology, Monash University, VIC 3800, Australia.
authors.forename: Jennifer C Y
authors.initials: JC
authors.lastname: Lo
authors.affiliation: Monash Partners Comprehensive Cancer Consortium and Cancer Program, Monash Biomedicine Discovery Institute, Prostate Cancer Research Group, Departments of Physiology and Anatomy and Developmental Biology, Monash University, VIC 3800, Australia.
authors.forename: Ashlee K
authors.initials: AK
authors.lastname: Clark
authors.affiliation: Monash Partners Comprehensive Cancer Consortium and Cancer Program, Monash Biomedicine Discovery Institute, Prostate Cancer Research Group, Departments of Physiology and Anatomy and Developmental Biology, Monash University, VIC 3800, Australia.
authors.forename: Natasha
authors.initials: N
authors.lastname: Ascui
authors.affiliation: Monash Partners Comprehensive Cancer Consortium and Cancer Program, Monash Biomedicine Discovery Institute, Prostate Cancer Research Group, Departments of Physiology and Anatomy and Developmental Biology, Monash University, VIC 3800, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Frydenberg
authors.affiliation: Monash Partners Comprehensive Cancer Consortium and Cancer Program, Monash Biomedicine Discovery Institute, Prostate Cancer Research Group, Departments of Physiology and Anatomy and Developmental Biology, Monash University, VIC 3800, Australia.
authors.forename: Gail P
authors.initials: GP
authors.lastname: Risbridger
authors.affiliation: Monash Partners Comprehensive Cancer Consortium and Cancer Program, Monash Biomedicine Discovery Institute, Prostate Cancer Research Group, Departments of Physiology and Anatomy and Developmental Biology, Monash University, VIC 3800, Australia.
authors.forename: Renea A
authors.initials: RA
authors.lastname: Taylor
authors.affiliation: Metabolic Disease and Obesity Program, Monash Biomedicine Discovery Institute, Department of Physiology, Monash University, VIC 3800, Australia.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Watt
mesh_terms: D000273:Adipose Tissue / Q000473:pathology*; D000818:Animals; D063646:Carcinogenesis; D049109:Cell Proliferation / Q000502:physiology; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009765:Obesity / Q000150:complications* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000209:etiology* / Q000473:pathology
keywords: human; obesity; periprostatic adipose tissue; prostate cancer; xenograft