Prostate cancer is the most prevalent cancer in men and metastatic spread to bone is detected in up to 80% of patients with advanced disease at autopsy. PCa can progress from treatable androgen-dependent stage to castration-resistant stage with distant metastases for which novel therapeutic targets and strategies are urgently needed. Here we identify the cell surface/secreted oncoprotein Cripto as a potential target for the diagnosis and treatment of metastatic prostate cancer.
We show that high expression levels of Cripto correlate with poor survival in stratified risk groups of prostate cancer patients and demonstrate that Cripto and its signalling partner Grp78 are highly expressed in prostate cancer bone metastases.
Furthermore Cripto and Grp78 are expressed at substantially higher levels in the metastatic ALDHhigh subpopulation of stem-like PC-3M-Pro4luc2 prostate cancer cells compared to non-metastatic ALDHlow differentiated tumor cells. In order to mimic the endosteal HSC niche in vitro, we cultured the highly osteotropic PC-3M-Pro4luc2 cells with differentiated primary human osteoblasts. This strongly induces CRIPTO and Grp78 expression in the prostate cancer cells and it selectively increases the size of the ALDHhigh subpopulation relative to the ALDHlow cells. Additionally, Cripto or Grp78 knockdown decreases cell proliferation, migration, clonogenicity and the size of the metastasis-initiating ALDHhigh subpopulation. Moreover, Cripto knockdown reduces the dissemination and invasion of PC-3M-Pro4luc2 cells in a zebrafish model and strongly inhibits bone metastasis in a preclinical mouse model.
Taken together, our findings highlight a functional role for Cripto and Grp78 in prostate cancer metastasis and suggest that targeting Cripto /Grp78 signaling may have significant therapeutic potential.
14 May 2016 - 17 May 2016