title: BMP4 promotes prostate tumor growth in bone through osteogenesis.
abstract: Induction of new bone formation is frequently seen in the bone lesions from prostate cancer. However, whether osteogenesis is necessary for prostate tumor growth in bone is unknown. Recently, 2 xenografts, MDA-PCa-118b and MDA-PCa-133, were generated from prostate cancer bone metastases. When implanted subcutaneously in severe combined immunodeficient (SCID) mice, MDA-PCa-118b induced strong ectopic bone formation while MDA-PCa-133 did not. To identify the factors that are involved in bone formation, we compared the expression of secreted factors (secretome) from MDA-PCa-118b and MDA-PCa-133 by cytokine array. We found that the osteogenic MDA-PCa-118b xenograft expressed higher levels of bone morphogenetic protein BMP4 and several cytokines including interleukin-8, growth-related protein (GRO), and CCL2. We showed that BMP4 secreted from MDA-PCa-118b contributed to about a third of the osteogenic differentiation seen in MDA-PCa-118b tumors. The conditioned media from MDA-PCa-118b induced a higher level of osteoblast differentiation, which was significantly reduced by treatment with BMP4 neutralizing antibody or the small molecule BMP receptor 1 inhibitor LDN-193189. BMP4 did not elicit an autocrine effect on MDA-PCa-118b, which expressed low to undetectable levels of BMP receptors. Treatment of SCID mice bearing MDA-PCa-118b tumors with LDN-193189 significantly reduced tumor growth. Thus, these studies support a role of BMP4-mediated osteogenesis in the progression of prostate cancer in bone.
authors.affiliation: Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, USA.
authors.forename: Yu-Chen
authors.initials: YC
authors.lastname: Lee
authors.forename: Chien-Jui
authors.initials: CJ
authors.lastname: Cheng
authors.forename: Mehmet A
authors.initials: MA
authors.lastname: Bilen
authors.forename: Jing-Fang
authors.initials: JF
authors.lastname: Lu
authors.forename: Robert L
authors.initials: RL
authors.lastname: Satcher
authors.forename: Li-Yuan
authors.initials: LY
authors.lastname: Yu-Lee
authors.forename: Gary E
authors.initials: GE
authors.lastname: Gallick
authors.forename: Sankar N
authors.initials: SN
authors.lastname: Maity
authors.forename: Sue-Hwa
authors.initials: SH
authors.lastname: Lin
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary*; D000818:Animals; D019898:Autocrine Communication; D055415:Bone Morphogenetic Protein 4 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D001859:Bone Neoplasms / Q000188:drug therapy / Q000503:physiopathology / Q000556:secondary*; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism / Q000637:transplantation; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000378:metabolism / Q000502:physiology*; D009999:Ossification, Heterotopic / Q000209:etiology*; D010006:Osteoblasts / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000494:pharmacology; D040521:Subcutaneous Tissue; D023041:Xenograft Model Antitumor Assays
chemical_list: C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D017077:Culture Media, Conditioned; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; C554430:LDN 193189; D009363:Neoplasm Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D011994:Recombinant Proteins; D052005:Bone Morphogenetic Protein Receptors, Type I