Exploring TGF-β signaling in benign prostatic hyperplasia: from cellular senescence to fibrosis and therapeutic implications

As men get older, they often develop benign prostatic hyperplasia (BPH), an enlarged prostate that is not cancerous or dangerous. Although the etiology of BPH is unknown, increasing evidence indicates that the TGF-beta signaling pathway might be a key player in its pathogenesis. TGF-beta is a pleiotropic cytokine involved in proliferation, differentiation, and extracellular matrix re-modeling, which are all dysregulated in BPH. Cellular senescence is primarily initiated by TGF-beta--induced, irreversible growth arrest and usually limits the prostate gland's hyperplastic growth. Moreover, senescent cells generate a Senescence-Associated Secretory Phenotype (SASP), which consists of numerous proinflammatory and profibrotic factors that can worsen disease ontogeny. In addition, TGF-beta is among the most fibrogenic factors. At the same time, fibrosis involves a massive accumulation of extracellular matrix proteins, which can increase tissue stiffness and a loss of normal organ functions. TGF-beta-mediated fibrosis in BPH changes the mechanical properties of the prostate and surrounding tissues to contribute to lower urinary tract symptoms. This review discusses the complicated molecular signaling of TGF-beta underlying changes in cellular senescence and fibrosis during BPH concerning its therapeutic potential.