title: Prostate cancer cells and bone stromal cells mutually interact with each other through bone morphogenetic protein-mediated signals.
abstract: Functional interactions between cancer cells and the bone microenvironment contribute to the development of bone metastasis. Although the bone metastasis of prostate cancer is characterized by increased ossification, the molecular mechanisms involved in this process are not fully understood. Here, the roles of bone morphogenetic proteins (BMPs) in the interactions between prostate cancer cells and bone stromal cells were investigated. In human prostate cancer LNCaP cells, BMP-4 induced the production of Sonic hedgehog (SHH) through a Smad-dependent pathway. In mouse stromal MC3T3-E1 cells, SHH up-regulated the expression of activin receptor IIB (ActR-IIB) and Smad1, which in turn enhanced BMP-responsive reporter activities in these cells. The combined stimulation with BMP-4 and SHH of MC3T3-E1 cells cooperatively induced the expression of osteoblastic markers, including alkaline phosphatase, bone sialoprotein, collagen type II α1, and osteocalcin. When MC3T3-E1 cells and LNCaP cells were co-cultured, the osteoblastic differentiation of MC3T3-E1 cells, which was induced by BMP-4, was accelerated by SHH from LNCaP cells. Furthermore, LNCaP cells and BMP-4 cooperatively induced the production of growth factors, including fibroblast growth factor (FGF)-2 and epidermal growth factor (EGF) in MC3T3-E1 cells, and these may promote the proliferation of LNCaP cells. Taken together, our findings suggest that BMPs provide favorable circumstances for the survival of prostate cancer cells and the differentiation of bone stromal cells in the bone microenvironment, possibly leading to the osteoblastic metastasis of prostate cancer.
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Hikaru
authors.initials: H
authors.lastname: Nishimori
authors.forename: Shogo
authors.initials: S
authors.lastname: Ehata
authors.forename: Hiroshi I
authors.initials: HI
authors.lastname: Suzuki
authors.forename: Yoko
authors.initials: Y
authors.lastname: Katsuno
authors.forename: Kohei
authors.initials: K
authors.lastname: Miyazono
mesh_terms: D030301:Activin Receptors, Type II / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism*; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000556:secondary; D002114:Calcinosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D059016:Tumor Microenvironment
chemical_list: D000943:Antigens, Differentiation; C525809:BMP4 protein, human; C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D009363:Neoplasm Proteins; C497399:SMAD1 protein, human; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D016222:Fibroblast Growth Factor 2; D004815:Epidermal Growth Factor; D030301:Activin Receptors, Type II; C425584:activin receptor type II-B