title: Osteoprotegerin contributes to the metastatic potential of cells with a dysfunctional TSC2 tumor-suppressor gene.
abstract: In addition to its effects on bone metabolism, osteoprotegerin (OPG), a soluble member of the tumor necrosis factor family of receptors, promotes smooth muscle cell proliferation and migration and may act as a survival factor for tumor cells. We hypothesized that these cellular mechanisms of OPG may be involved in the growth and proliferation of lymphangioleiomyomatosis (LAM) cells, abnormal smooth muscle-like cells with mutations in one of the tuberous sclerosis complex tumor-suppressor genes (TSC1/TSC2) that cause LAM, a multisystem disease characterized by cystic lung destruction, lymphatic infiltration, and abdominal tumors. Herein, we show that OPG stimulated proliferation of cells cultured from explanted LAM lungs, and selectively induced migration of LAM cells identified by the loss of heterozygosity for TSC2. Consistent with these observations, cells with TSC2 loss of heterozygosity expressed the OPG receptors, receptor activator of NF-κB ligand, syndecan-1, and syndecan-2. LAM lung nodules showed reactivities to antibodies to tumor necrosis factor-related apoptosis-inducing ligand, receptor activator of NF-κB ligand, syndecan-1, and syndecan-2. LAM lung nodules also produced OPG, as shown by expression of OPG mRNA and colocalization of reactivities to anti-OPG and anti-gp100 (HMB45) antibodies in LAM lung nodules. Serum OPG was significantly higher in LAM patients than in normal volunteers. Based on these data, it appears that OPG may have tumor-promoting roles in the pathogenesis of lymphangioleiomyomatosis, perhaps acting as both autocrine and paracrine factors.
authors.affiliation: Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892-1590, USA.
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Steagall
authors.forename: Gustavo
authors.initials: G
authors.lastname: Pacheco-Rodriguez
authors.forename: Connie G
authors.initials: CG
authors.lastname: Glasgow
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Jing-Ping
authors.initials: JP
authors.lastname: Lin
authors.forename: Gang
authors.initials: G
authors.lastname: Zheng
authors.forename: Joel
authors.initials: J
authors.lastname: Moss
mesh_terms: D000328:Adult; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000097:blood; D005434:Flow Cytometry; D064368:Healthy Volunteers; D006801:Humans; D019656:Loss of Heterozygosity; D008168:Lung / Q000378:metabolism / Q000473:pathology; D018192:Lymphangioleiomyomatosis / Q000097:blood / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D042282:Microdissection; D008875:Middle Aged; D009362:Neoplasm Metastasis; D053244:Osteoprotegerin / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D058951:gp100 Melanoma Antigen / Q000378:metabolism
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D053244:Osteoprotegerin; D011956:Receptors, Cell Surface; C000624653:TSC2 protein, human; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D058951:gp100 Melanoma Antigen