CRIPTO and its signaling partner GRP78 drive the metastatic phenotype in human osteotropic prostate cancer

• Published in: Oncogene Vol. 36; no. 33; pp. 4739 - 4749
• Main Authors: Zoni, E, Chen, L, Karkampouna, S, Granchi, Z, Verhoef, E I, La Manna, F, Kelber, J, Pelger, R C M, Henry, M D, Snaar-Jagalska, E, van Leenders, G J L H, Beimers, L, Kloen, P, Gray, P C, van der Pluijm, G, Kruithof-de Julio, M
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 17.08.2017
• Subjects: Animals; Bone Neoplasms - metabolism; Bone Neoplasms - secondary; Cancer cells; Care and treatment; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell surface; Comparative analysis; Development and progression; Gene Knockdown Techniques; Genetic aspects; Genotype & phenotype; GPI-Linked Proteins - genetics; GPI-Linked Proteins - metabolism; Health aspects; Heat-Shock Proteins - genetics; Heat-Shock Proteins - metabolism; Humans; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Kaplan-Meier Estimate; Male; Metastases; Metastasis; Mice; Mice, Nude; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neoplasm Transplantation; Original; Osteoblasts; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Risk groups; Stem cells; Transforming growth factors
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2017.87

CRIPTO (CR-1, TDGF1) is a cell surface/secreted oncoprotein actively involved in development and cancer. Here, we report that high expression of CRIPTO correlates with poor survival in stratified risk groups of prostate cancer (PCa) patients. CRIPTO and its signaling partner glucose-regulated protein 78 (GRP78) are highly expressed in PCa metastases and display higher levels in the metastatic ALDH sub-population of PC-3M-Pro4Luc2 PCa cells compared with non-metastatic ALDH . Coculture of the osteotropic PC-3M-Pro4Luc2 PCa cells with differentiated primary human osteoblasts induced CRIPTO and GRP78 expression in cancer cells and increases the size of the ALDH sub-population. Additionally, CRIPTO or GRP78 knockdown decreases proliferation, migration, clonogenicity and the size of the metastasis-initiating ALDH sub-population. CRIPTO knockdown reduces the invasion of PC-3M-Pro4Luc2 cells in zebrafish and inhibits bone metastasis in a preclinical mouse model. These results highlight a functional role for CRIPTO and GRP78 in PCa metastasis and suggest that targeting CRIPTO/GRP78 signaling may have significant therapeutic potential.