title: SOST Inhibits Prostate Cancer Invasion.
abstract: Inhibitors of Wnt signaling have been shown to be involved in prostate cancer (PC) metastasis; however the role of Sclerostin (Sost) has not yet been explored. Here we show that elevated Wnt signaling derived from Sost deficient osteoblasts promotes PC invasion, while rhSOST has an inhibitory effect. In contrast, rhDKK1 promotes PC elongation and filopodia formation, morphological changes characteristic of an invasive phenotype. Furthermore, rhDKK1 was found to activate canonical Wnt signaling in PC3 cells, suggesting that SOST and DKK1 have opposing roles on Wnt signaling in this context. Gene expression analysis of PC3 cells co-cultured with OBs exhibiting varying amounts of Wnt signaling identified CRIM1 as one of the transcripts upregulated under highly invasive conditions. We found CRIM1 overexpression to also promote cell-invasion. These findings suggest that bone-derived Wnt signaling may enhance PC tropism by promoting CRIM1 expression and facilitating cancer cell invasion and adhesion to bone. We concluded that SOST and DKK1 have opposing effects on PC3 cell invasion and that bone-derived Wnt signaling positively contributes to the invasive phenotypes of PC3 cells by activating CRIM1 expression and facilitating PC-OB physical interaction. As such, we investigated the effects of high concentrations of SOST in vivo. We found that PC3-cells overexpressing SOST injected via the tail vein in NSG mice did not readily metastasize, and those injected intrafemorally had significantly reduced osteolysis, suggesting that targeting the molecular bone environment may influence bone metastatic prognosis in clinical settings.
authors.affiliation: Biology and Biotechnology Division, Physical and Life Sciences Directorate, Lawrence Livermore National Laboratories, Livermore, California, United States of America.
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Hudson
authors.affiliation: Biology and Biotechnology Division, Physical and Life Sciences Directorate, Lawrence Livermore National Laboratories, Livermore, California, United States of America.
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Hum
authors.affiliation: Biology and Biotechnology Division, Physical and Life Sciences Directorate, Lawrence Livermore National Laboratories, Livermore, California, United States of America.
authors.forename: Cynthia B
authors.initials: CB
authors.lastname: Thomas
authors.affiliation: Biology and Biotechnology Division, Physical and Life Sciences Directorate, Lawrence Livermore National Laboratories, Livermore, California, United States of America.
authors.forename: Ayano
authors.initials: A
authors.lastname: Kohlgruber
authors.affiliation: Biology and Biotechnology Division, Physical and Life Sciences Directorate, Lawrence Livermore National Laboratories, Livermore, California, United States of America.|School of Natural Sciences, University of California Merced, Merced, California, United States of America.
authors.forename: Aimy
authors.initials: A
authors.lastname: Sebastian
authors.affiliation: Biology and Biotechnology Division, Physical and Life Sciences Directorate, Lawrence Livermore National Laboratories, Livermore, California, United States of America.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Collette
authors.affiliation: Biology and Biotechnology Division, Physical and Life Sciences Directorate, Lawrence Livermore National Laboratories, Livermore, California, United States of America.|Department of Radiation Oncology, University of California Davis Medical Center, Sacramento, California, United States of America.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Coleman
authors.affiliation: Department of Orthopaedic Surgery, University of California Davis Medical Center, Sacramento, California, United States of America.
authors.forename: Blaine A
authors.initials: BA
authors.lastname: Christiansen
authors.affiliation: Biology and Biotechnology Division, Physical and Life Sciences Directorate, Lawrence Livermore National Laboratories, Livermore, California, United States of America.|School of Natural Sciences, University of California Merced, Merced, California, United States of America.
authors.forename: Gabriela G
authors.initials: GG
authors.lastname: Loots
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D052004:Bone Morphogenetic Protein Receptors; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000473:pathology / Q000556:secondary; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D005819:Genetic Markers / Q000235:genetics; D064593:Heterografts; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009368:Neoplasm Transplantation; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D010014:Osteolysis / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D060449:Wnt Signaling Pathway / Q000235:genetics*; D060509:Wnt3A Protein / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; C486175:CRIM1 protein, human; C501126:DKK1 protein, human; D005819:Genetic Markers; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C422903:SOST protein, human; C555510:WNT3A protein, human; D060509:Wnt3A Protein; D052004:Bone Morphogenetic Protein Receptors