Extra-cellular matrix remodeling as a unique mechanism of expansion of periprostatic adipose tissue: a potential driver of prostate cancer aggressiveness

One of the most striking features of the adipose depot surrounding the prostate (periprostatic adipose tissue, PPAT) is that its accumulation is independent of body mass index. Its volume varies considerably between individual with some patients exhibiting abundant PPATs that have been correlated to occurrence of aggressive prostate cancer (PCa). However, abundant PPAT are not defined at biological levels. We used a new statistical approach to define abundant PPAT by normalizing PPAT volume to prostate volume in a cohort of 351 patients with a linear regression model. Applying this definition, we confirmed the link between abundant PPAT and PCa aggressiveness, therefore validating our approach. At biological levels, we showed that abundant PPAT exhibited extensive extracellular matrix remodeling, notably of the collagen network, decreasing the mechanical constraints in hypertrophic adipocytes leading to an inflammation free-expansion. Degradation of the most abundant collagen in AT, collagen VI was associated with increased production of endotrophin, a signaling peptide derived from AT, that was also elevated in the urine of patients with abundant PPAT confirming the clinical relevance of our results. These results highlight a unique mechanism of expansion of an adipose depot and open new mechanistic avenues to explain its role in prostate-related disorders.