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

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.

Adipocyte extracellular vesicles carry enzymes and fatty acids that stimulate mitochondrial metabolism and remodeling in tumor cells

“…Until now, studies showed that metabolic exchanges between adipocytes and tumor cells require a close proximity between the two cell types in order for tumors to provoke adipocyte lipolysis. For most types of cancer, this process can only occur at the later stages of cancer progression, when tumors become invasive and penetrate local AT or metastasize to adipocyte-rich environments (Nieman et al, 2011;Wang et al, 2017;Zhang et al, 2018;Laurent et al, 2019). However, whether adipocytes could also influence tumors at distance, for example, during the early stages of disease progression before cancer cells infiltrate surrounding adipose tissue, remains unknown.…”

The Adipose Stem Cell as a Novel Metabolic Actor in Adrenocortical Carcinoma Progression: Evidence from an In Vitro Tumor Microenvironment Crosstalk Model

“…In many solid tumors occurring in organs with particularly abundant fat, the surrounding adipose tissue is often invaded by cancer cells, thus enabling close contact with adipocytes at the tumor invasive front [9][10][11][12]. Invading cells are indeed able to actively interact with the surrounding adipocytes and deeply modify both their phenotype and metabolism.…”

Adipocyte vesicles: ‘all-in-one’ packages that stimulate tumor mitochondrial metabolism and dynamics

“…Until now, studies showed that metabolic exchanges between adipocytes and tumor cells requires a close proximity between the two cells types in order for tumors to provoke adipocyte lipolysis. For most types of cancer, this process can only occur at the later stages of cancer progression, when tumors become invasive and penetrate local AT or metastasize to adipocyte-rich environments (Laurent et al, 2019;Nieman et al, 2011;Wang et al, 2017;Zhang et al, 2018).…”