Periprostatic Adipose Tissue Favors Prostate Cancer Cell Invasion in an Obesity-Dependent Manner: Role of Oxidative Stress.

Victor Laurent,Mathieu Cinato,Laurence Nieto,Aurélie Toulet,Anne-Catherine Prats,Falek Zaidi,Edith Renaud-Gabardos,Camille Lehuédé,Stéphanie Dauvillier,Bernard Malavaud,Adrien Guérard,Camille Attané,Philippe Valet,Emily Clement,Catherine Muller,Sophie Le Gonidec,Delphine Milhas,David Garandeau

doi:10.1158/1541-7786.mcr-18-0748

Abstract

Prostate gland is surrounded by periprostatic adipose tissue (PPAT), which is increasingly believed to play a paracrine role in prostate cancer progression. Our previous work demonstrates that adipocytes promote homing of prostate cancer cells to PPAT and that this effect is upregulated by obesity. Here, we show that once tumor cells have invaded PPAT (mimicked by an in vitro model of coculture), they establish a bidirectional crosstalk with adipocytes, which promotes tumor cell invasion. Indeed, tumor cells induce adipocyte lipolysis and the free fatty acids (FFA) released are taken up and stored by tumor cells. Incubation with exogenous lipids also stimulates tumor cell invasion, underlining the importance of lipid transfer in prostate cancer aggressiveness. Transferred FFAs (after coculture or exogenous lipid treatment) stimulate the expression of one isoform of the pro-oxidant enzyme NADPH oxidase, NOX5. NOX5 increases intracellular reactive oxygen species (ROS) that, in turn, activate a HIF1/MMP14 pathway, which is responsible for the increased tumor cell invasion. In obesity, tumor-surrounding adipocytes are more prone to activate the depicted signaling pathway and to induce tumor invasion. Finally, the expression of NOX5 and MMP14 is upregulated at the invasive front of human tumors where cancer cells are in close proximity to adipocytes and this process is amplified in obese patients, underlining the clinical relevance of our results. IMPLICATIONS: Our work emphasizes the key role of adjacent PPAT in prostate cancer dissemination and proposes new molecular targets for the treatment of obese patients exhibiting aggressive diseases.

Highlights

Malignant evolution of solid cancers relies on complex cell-tocell interactions sustained by a broad network of physical and chemical mediators that constitute the tumor microenvironment [1]
The crosstalk between prostate cancer cell lines and mature adipocytes was first investigated in vitro using a coculture system originally described by our group in breast cancer [3]
This proinvasive effect was not observed when tumor cells were cocultivated with preadipocytes (Supplementary Fig. S1A)

Summary

Introduction

Malignant evolution of solid cancers relies on complex cell-tocell interactions sustained by a broad network of physical and chemical mediators that constitute the tumor microenvironment [1]. An activated state demonstrated predominantly by the overexpression of proinflammatory cytokines and ECM (extracellular matrix)-related molecules [3] The positive association between obesity and aggressive prostate cancer, defined by an increase in local and distant dissemination, is in favor of a role for adipose tissue in tumor progression [10]. The mechanisms that govern increased prostate cancer cell aggressiveness in the presence of adipocytes are poorly described and have been mainly attributed to soluble factors Lipid transfer between tumorsurrounding adipocytes and cancer cells promotes tumor aggressiveness by inducing oxidative stress in a NADPH oxidase– dependent manner, activating a proinvasive signaling pathway. This study highlights the importance of lipid transfer in the tumor-promoting effect of adipocytes and underlines that the consequence of this process is not univocal among all tumor types

Materials and Methods

Results and Discussion

E Lipolysis

Disclosure of Potential Conflicts of Interest