Human periprostatic adipose tissue promotes prostate cancer aggressiveness in vitro

Abstract

BackgroundObesity is associated with prostate cancer aggressiveness and mortality. The contribution of periprostatic adipose tissue, which is often infiltrated by malignant cells, to cancer progression is largely unknown. Thus, this study aimed to determine if periprostatic adipose tissue is linked with aggressive tumor biology in prostate cancer.MethodsSupernatants of whole adipose tissue (explants) or stromal vascular fraction (SVF) from paired fat samples of periprostatic (PP) and pre-peritoneal visceral (VIS) anatomic origin from different donors were prepared and analyzed for matrix metalloproteinases (MMPs) 2 and 9 activity. The effects of those conditioned media (CM) on growth and migration of hormone-refractory (PC-3) and hormone-sensitive (LNCaP) prostate cancer cells were measured.ResultsWe show here that PP adipose tissue of overweight men has higher MMP9 activity in comparison with normal subjects. The observed increased activities of both MMP2 and MMP9 in PP whole adipose tissue explants, likely reveal the contribution of adipocytes plus stromal-vascular fraction (SVF) as opposed to SVF alone. MMP2 activity was higher for PP when compared to VIS adipose tissue. When PC-3 cells were stimulated with CM from PP adipose tissue explants, increased proliferative and migratory capacities were observed, but not in the presence of SVF. Conversely, when LNCaP cells were stimulated with PP explants CM, we found enhanced motility despite the inhibition of proliferation, whereas CM derived from SVF increased both cell proliferation and motility. Explants culture and using adipose tissue of PP origin are most effective in promoting proliferation and migration of PC-3 cells, as respectively compared with SVF culture and using adipose tissue of VIS origin. In LNCaP cells, while explants CM cause increased migration compared to SVF, the use of PP adipose tissue to generate CM result in the increase of both cellular proliferation and migration.ConclusionsOur findings suggest that the PP depot has the potential to modulate extra-prostatic tumor cells' microenvironment through increased MMPs activity and to promote prostate cancer cell survival and migration. Adipocyte-derived factors likely have a relevant proliferative and motile role.

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“…Our findings are in agreement with previously reported experimental systems testing various features in which adipocytes affect PCa growth: co-culture of PC-3 cells with rat epididymal adipocytes increased intracellular lipid content in cancer cells and stimulated their proliferation [52]. In vitro culture of PCa cells in the presence of adipocyte conditioned media (CM) was enough to promote increased proliferation and motility [53][54][55][56]. The critical factors present in the adipocyte CM were shown to be monocyte chemotactic protein-1 (MCP-1) [54], CC chemokine ligand 7 (CCL7) [56], and matrix metalloproteinases (MMPs) 2 and 9 [53,54].…”

“…In vitro culture of PCa cells in the presence of adipocyte conditioned media (CM) was enough to promote increased proliferation and motility [53][54][55][56]. The critical factors present in the adipocyte CM were shown to be monocyte chemotactic protein-1 (MCP-1) [54], CC chemokine ligand 7 (CCL7) [56], and matrix metalloproteinases (MMPs) 2 and 9 [53,54]. Of note, conditioned media from PC-3 cells stimulated the expression of a range of adipokines and cytokines such as leptin, IL-6, and TNFα in adipose tissue explants [57].…”

Androgen control of lipid metabolism in prostate cancer: novel insights and future applications

“…These lipids can be derived from dietary lipoproteins in the circulation, which are hydrolyzed by lipoprotein lipase to free fatty acids, or be released by lipolysis from stores in local adipose tissue depots that comprises a major component of the tumor microenvironment (Ribeiro et al 2012). Androgens are generally viewed to stimulate lipolysis of fatty acids from adipocytes (O'Reilly et al 2014), and have been reported to induce the expression of cell surface proteins that regulate the uptake of lipids from the extracellular microenvironment, including phosphatidic acid phosphatase type 2 (Ulrix et al 1998) and plasma membrane fatty acid binding protein (Pinthus et al 2007).…”

Dissémination locale du cancer de la prostate

“…Ces études, bien que préliminaires, renforcent l'idée d'un rôle paracrine du TAPP dans la progression du cancer de la prostate, rôle qui pourrait être amplifié dans un contexte d'obé-sité. Les sécrétions du TAPP semblent avoir un effet sur le comportement des cellules prostatiques en stimulant leur prolifération ainsi que leurs capacités migratoires et invasives et cet effet est régulé par l'obésité [6]. De façon très intéressante, cette influence est moins prononcée pour les sécrétions du TAV que pour celles du TAPP suggérant, pour ce dernier, un profil de sécrétion spécifique.…”

“…De façon très intéressante, cette influence est moins prononcée pour les sécrétions du TAV que pour celles du TAPP suggérant, pour ce dernier, un profil de sécrétion spécifique. Parmi les acteurs impliqués dans cet effet, on retrouve principalement l'IL6 et les métallopro-téases 1 2 et 9 [6]. Les sécrétions du TAPP pourraient donc influencer les propriétés invasives des cellules tumorales bien que ce concept n'ait pas été validé in vivo.…”