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    Obesity does not promote tumorigenesis of localized patient-derived prostate cancer xenografts

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    Author
    Lo, JCY; Clark, AK; Ascui, N; Frydenberg, M; Risbridger, GP; Taylor, RA; Watt, MJ
    Date
    2016-07-26
    Source Title
    Oncotarget
    Publisher
    IMPACT JOURNALS LLC
    University of Melbourne Author/s
    Risbridger, Gail; Watt, Matthew
    Affiliation
    Sir Peter MacCallum Department of Oncology
    Physiology
    Metadata
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    Document Type
    Journal Article
    Citations
    Lo, J. C. Y., Clark, A. K., Ascui, N., Frydenberg, M., Risbridger, G. P., Taylor, R. A. & Watt, M. J. (2016). Obesity does not promote tumorigenesis of localized patient-derived prostate cancer xenografts. ONCOTARGET, 7 (30), pp.47650-47662. https://doi.org/10.18632/oncotarget.10258.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/258320
    DOI
    10.18632/oncotarget.10258
    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.

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