Androgen receptors expressed by prostatic stromal cells obtained from younger versus older males exhibit opposite roles in prostate cancer progression

Abstract

Aging is a major risk factor for prostate cancer (PCa), and prostatic stromal cells may also promote PCa progression. Accordingly, stromal cells do not equally promote PCa in older males and younger males. Therefore, it is also possible that the expression of androgen receptors (ARs) by prostatic stromal cells in older versus younger males plays different roles in PCa progression. Using a gene knockdown technique and coculture system, we found that the knockdown of the AR in prostatic stromal cells obtained from younger males could promote the invasiveness and metastasis of cocultured PC3/LNCaP cells in vitro. By contrast, the invasiveness and metastasis of LNCaP cells was inhibited when cocultured with prostatic stromal cells from older males that when AR expression was knocked down. Moreover, after targeting AR expression with small hairpin RNA (shRNA), matrix metalloproteinase (MMP) expression in stromal cells was observed to increase in the younger group, but decreased or remained unchanged in the older group. One exception, however, was observed with MMP9. In vivo, after knocking down AR expression in prostatic stromal cells, the incidence of metastatic lymph nodes was observed to increase in the younger age group, but decreased in the older age group. Together, these data suggest that the AR in prostatic stromal cells played opposite roles in PCa metastasis for older versus younger males. Therefore, collectively, the function of the AR in prostatic stromal cells appears to change with age, and this may account for the increased incidence of PCa in older males.

Androgen Receptor Gene Copy Number and Protein Expression in Treatment-Naïve Prostate Cancer

“…Peritumoral stroma is associated with several tumor-promoting mechanisms, including neoangiogenesis, neurogenesis, remodeling of the extracellular matrix, and induction of epithelial-to-mesenchymal transition [19] . Tissue recombinant experiments have shown that stromal AR expression is necessary for PCa carcinogenesis and tumor growth but that a decreased function of the AR pathway in surrounding stroma promotes tumor aggressiveness [20][21][22] . We also found a lower AR expression in peritumoral stroma in patients with lymph-node or distant metastases compared to those without metastases.…”