Prostate cancer (PCa) is the most common cancer type in older men and often metastasizes to bone in advanced stages. Wnt proteins are implicated in carcinogenesis and especially WNT5A has been discussed to influence the clinical outcome of various cancer types, including PCa. In addition, WNT5A stimulates osteogenic differentiation and may thus not only be involved in PCa development, but also in the formation of subsequent skeletal metastasis. Here, we determined the role of WNT5A in PCa in vitro and in vivo.
A tissue microarray was created using a cohort of 397 mainly high-risk PCa patients and stained for WNT5A. Effects of WNT5A knock-down or overexpression on proliferation and apoptosis of PCa cell lines (PC3, C42B, MDA-PCa-2b) were examined in vitro. In vivo, WNT5A was overexpressed in luciferase-labeled PC3 cells (PC3-Luc) and injected subcutaneously, intratibially or intracardially into nude mice to determine tumor growth.
Expression of WNT5A was higher in PCa patients as compared to patients with benign prostatic hyperplasia (P<0.05). Patients with high WNT5A levels had a better overall survival than those with low WNT5A expression (P<0.05). In vitro, WNT5A overexpression reduced proliferation by 39% in PC3 cells and simultaneously induced apoptosis twofold (as determined by caspase 3/7 activation, annexin V/PI-positive cells, PARP cleavage, and DNA fragmentation). Knock-down of WNT5A yielded opposite results. Similar effects were seen in C42B and MDA-PCa-2b. In vivo, subcutaneous tumor growth and tumor growth within the bone microenvironment was inhibited in WNT5A-overexpressing PC3-Luc cells as compared to PC3-Luc cells (−90% and −85%, P<0.05). Moreover, while 80% of the mice receiving PC3-Luc cells developed bone metastasis and bone lesions, overexpression of WNT5A abolished this process. These data indicate that WNT5A may act as a tumor suppressor in PCa and suggest that WNT5A may emerge as a novel therapeutic target for prostate cancer and bone metastases.
17 - 20 May 2014
European Calcified Tissue Society