title: CRIPTO and its signaling partner GRP78 drive the metastatic phenotype in human osteotropic prostate cancer.
abstract: 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 ALDHhighsub-population of PC-3M-Pro4Luc2 PCa cells compared with non-metastatic ALDHlow. 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 ALDHhighsub-population. Additionally, CRIPTO or GRP78 knockdown decreases proliferation, migration, clonogenicity and the size of the metastasis-initiating ALDHhighsub-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.
authors.affiliation: Department of Urology, Leiden University Medical Centre, Leiden, The Netherlands.|Urology Research Laboratory, Department of Urology and Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: E
authors.initials: E
authors.lastname: Zoni
authors.affiliation: Department of Molecular Cell Biology, Institute of Biology, Leiden University, Leiden, The Netherlands.
authors.forename: L
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Urology, Leiden University Medical Centre, Leiden, The Netherlands.|Urology Research Laboratory, Department of Urology and Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Karkampouna
authors.affiliation: Genome Scan, Leiden, The Netherlands.
authors.forename: Z
authors.initials: Z
authors.lastname: Granchi
authors.affiliation: Department of Pathology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: E I
authors.initials: EI
authors.lastname: Verhoef
authors.affiliation: Department of Urology, Leiden University Medical Centre, Leiden, The Netherlands.|Urology Research Laboratory, Department of Urology and Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: La Manna
authors.affiliation: Department of Biology, California State University Northbridge, Northbridge, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Kelber
authors.affiliation: Department of Urology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: R C M
authors.initials: RCM
authors.lastname: Pelger
authors.affiliation: Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Henry
authors.affiliation: Urology Research Laboratory, Department of Urology and Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: E
authors.initials: E
authors.lastname: Snaar-Jagalska
authors.affiliation: Department of Pathology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: G J L H
authors.initials: GJLH
authors.lastname: van Leenders
authors.affiliation: Department of Orthopedic Surgery, Slotervaart Medical Center, Amsterdam, The Netherlands.
authors.forename: L
authors.initials: L
authors.lastname: Beimers
authors.affiliation: Department of Orthopedic Trauma Surgery, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Kloen
authors.affiliation: Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla CA, USA.
authors.forename: P C
authors.initials: PC
authors.lastname: Gray
authors.affiliation: Department of Urology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: van der Pluijm
authors.affiliation: Department of Urology, Leiden University Medical Centre, Leiden, The Netherlands.|Urology Research Laboratory, Department of Urology and Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Kruithof-de Julio
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism / Q000556:secondary*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D000091342:Endoplasmic Reticulum Chaperone BiP; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D058851:GPI-Linked Proteins; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; C070636:TDGF1 protein, human