Periprostatic adipose tissue PPAT abundance correlates with prostate cancer progression, but the mechanism remains unexplained. Here, we used a statistical approach to define abundant PPAT by normalizing PPAT volume to prostate volume in a cohort of patients with a linear regression model. Applying this definition, we find tumors specifically from patients with abundant PPAT exhibit several hallmarks of aggressiveness, suggesting that PPAT abundance might be used to improve risk stratification.
We show that abundant PPAT expands by adipocyte hypertrophy but this does not result in inflammation. Extensive extracellular matrix remodeling, notably of the collagen network, and decreased expression of mechano-sensing proteins in adipocytes explains this inflammation-free expansion by decreasing the mechanical constraints on the adipocytes. Moreover, collagen VI degradation in abundant PPAT is associated with production of endotrophin, a matrikine that promotes cancer progression.
We find high levels of endotrophin specifically in the urine of patients with abundant PPAT, indicating the clinical relevance of our findings. Summary The abundance of periprostatic adipose tissue favors prostate cancer aggressiveness. The increase in extracellular matrix remodeling that occurs in expanded periprostatic fat allows adipocyte hypertrophy without tissue inflammation and generates a matrikine, endotrophin, which favors tumor progression.
Prostate cancer PCa is the second most common form of solid tumor in men worldwide and the fifth leading cause of death from cancer Pernar et al. It is a highly heterogeneous disease, ranging from slow-growing indolent tumors to fatal metastatic carcinomas Pernar et al. Risk stratification is, therefore, the cornerstone for selecting the most appropriate treatment for these men.
Progression from indolent to aggressive PCa depends on endocrine signaling mainly through the androgen receptor and genetic alterations leading to cancer cell-autonomous progression Pernar et al.
