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.

CCR5 Directs the Mobilization of CD11b+Gr1+Ly6Clow Polymorphonuclear Myeloid Cells from the Bone Marrow to the Blood to Support Tumor Development

“…The relevance of these data for humans has yet to be studied. One possibility is to set up PDX mice engrafted with the human tumor (Lo et al, 2016). The limitation of such study depends on the level of cross-reactivity between mouse and human CCR5 ligands.…”

The combination of prostate imaging reporting and data system version 2 (PI-RADS v2) and periprostatic fat thickness on multi-parametric MRI to predict the presence of prostate cancer

“…We suggest that periprostatic fat, regarded as metabolically active visceral fat, is a distinct parameter instead of a surrogate marker for general obesity. Previous studies showed conflicting results in the link between PPF and tumorigenesis of PCa [ 7 – 9 , 32 ]. Further studies about the role of PPF in prostate carcinogenesis will be required to elucidate their association.…”

High-Fat Diet-Induced Inflammation Accelerates Prostate Cancer Growth via IL6 Signaling

“…Studies have also shown HFD induced tumor progression via adipose-secretory cytokines or chemokines in TRAMP mice and within a xenograft mouse model of the prostate cancer cell line LNCaP (12)(13)(14). However, in a xenograft model of patient-derived prostate tumor tissue using immunodeficient mice, HFD was reported not to induce tumor progression (15). These results suggest that HFD might accelerate tumor progression of prostate cancer via interactions with immune responses including various cytokines.…”