title: The type III transforming growth factor-β receptor inhibits proliferation, migration, and adhesion in human myeloma cells.
abstract: Transforming growth factor-β (TGF-β) plays an important role in regulating hematopoiesis, inhibiting proliferation while stimulating differentiation when appropriate. We previously demonstrated that the type III TGF-β receptor (TβRIII, or betaglycan) serves as a novel suppressor of cancer progression in epithelial tumors; however, its role in hematologic malignancies is unknown. Here we demonstrate that TβRIII protein expression is decreased or lost in the majority of human multiple myeloma specimens. Functionally, restoring TβRIII expression in myeloma cells significantly inhibited cell growth, proliferation, and motility, largely independent of its ligand presentation role. In a reciprocal fashion, shRNA-mediated silencing of endogenous TβRIII expression enhanced cell growth, proliferation, and motility. Although apoptosis was not affected, TβRIII inhibited proliferation through induction of the cyclin-dependent kinase inhibitors p21 and p27. TβRIII further regulated myeloma cell adhesion, increasing homotypic myeloma cell adhesion while decreasing myeloma heterotropic adhesion to bone marrow stromal cells. Mechanistically, live cell imaging of myeloma and stroma cell cocultures revealed that TβRIII-mediated inhibition of heterotropic adhesion was associated with decreased duration of myeloma/bone marrow stromal cell interaction. These results suggest that loss of TβRIII expression during multiple myeloma progression contributes to disease progression through its functional effects on increased cell growth, proliferation, motility, and adhesion.
authors.affiliation: Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, NC 27708, USA.
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Lambert
authors.forename: Huang
authors.initials: H
authors.lastname: Huang
authors.forename: Karthikeyan
authors.initials: K
authors.lastname: Mythreye
authors.forename: Gerard C
authors.initials: GC
authors.lastname: Blobe
mesh_terms: D001854:Bone Marrow Cells / Q000378:metabolism; D002448:Cell Adhesion; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D018920:Coculture Techniques; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D018450:Disease Progression; D006410:Hematopoiesis; D006801:Humans; D015151:Immunoblotting; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology; D011509:Proteoglycans / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; C071736:betaglycan; D050760:Cyclin-Dependent Kinase Inhibitor p27