title: Semaphorin 4D Promotes Skeletal Metastasis in Breast Cancer.
abstract: Bone density is controlled by interactions between osteoclasts, which resorb bone, and osteoblasts, which deposit it. The semaphorins and their receptors, the plexins, originally shown to function in the immune system and to provide chemotactic cues for axon guidance, are now known to play a role in this process as well. Emerging data have identified Semaphorin 4D (Sema4D) as a product of osteoclasts acting through its receptor Plexin-B1 on osteoblasts to inhibit their function, tipping the balance of bone homeostasis in favor of resorption. Breast cancers and other epithelial malignancies overexpress Sema4D, so we theorized that tumor cells could be exploiting this pathway to establish lytic skeletal metastases. Here, we use measurements of osteoblast and osteoclast differentiation and function in vitro and a mouse model of skeletal metastasis to demonstrate that both soluble Sema4D and protein produced by the breast cancer cell line MDA-MB-231 inhibits differentiation of MC3T3 cells, an osteoblast cell line, and their ability to form mineralized tissues, while Sema4D-mediated induction of IL-8 and LIX/CXCL5, the murine homologue of IL-8, increases osteoclast numbers and activity. We also observe a decrease in the number of bone metastases in mice injected with MDA-MB-231 cells when Sema4D is silenced by RNA interference. These results are significant because treatments directed at suppression of skeletal metastases in bone-homing malignancies usually work by arresting bone remodeling, potentially leading to skeletal fragility, a significant problem in patient management. Targeting Sema4D in these cancers would not affect bone remodeling and therefore could elicit an improved therapeutic result without the debilitating side effects.
authors.affiliation: Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, Baltimore, Maryland, United States of America.
authors.forename: Ying-Hua
authors.initials: YH
authors.lastname: Yang
authors.affiliation: Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, Baltimore, Maryland, United States of America.
authors.forename: Asma
authors.initials: A
authors.lastname: Buhamrah
authors.affiliation: Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, Baltimore, Maryland, United States of America.|Greenebaum Cancer Center, Baltimore, Maryland, United States of America.
authors.forename: Abraham
authors.initials: A
authors.lastname: Schneider
authors.affiliation: Division of Diagnostic and Surgical Sciences, School of Dentistry, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Lin
authors.affiliation: Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, Baltimore, Maryland, United States of America.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, Baltimore, Maryland, United States of America.
authors.forename: Amr
authors.initials: A
authors.lastname: Bugshan
authors.affiliation: Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, Baltimore, Maryland, United States of America.|Greenebaum Cancer Center, Baltimore, Maryland, United States of America.
authors.forename: John R
authors.initials: JR
authors.lastname: Basile
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000556:secondary; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002113:Calcification, Physiologic; D045744:Cell Line, Tumor; D005260:Female; D064593:Heterografts; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D039961:Semaphorins / Q000235:genetics / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; C093224:CD100 antigen; C508606:CXCL8 protein, human; D016209:Interleukin-8; D009363:Neoplasm Proteins; D039961:Semaphorins