Transforming growth factor beta-induced (TGFBI) is an anti-adhesive protein regulating the invasive growth of melanoma cells.
Melanoma is a malignancy characterized by high invasive/metastatic potential, with no efficient therapy after metastasis. Understanding the molecular mechanisms underlying the invasive/metastatic tendency is therefore important. Our genome-wide gene expression analyses revealed that human melanoma cell lines WM793 and especially WM239 (vertical growth phase and metastatic cells, respectively) overexpress the extracellular matrix (ECM) protein transforming growth factor β induced (TGFBI). In adhesion assays, recombinant TGFBI was strongly anti-adhesive for both melanoma cells and skin fibroblasts. TGFBI further impaired the adhesion of melanoma cells to the adhesive ECM proteins fibronectin, collagen-I, and laminin, known to interact with it. Unexpectedly, WM239 cells migrated/invaded more effectively in three-dimensional collagen-I and Matrigel cultures after knockdown of TGFBI by shRNA expression. However, in the physiological subcutaneous microenvironment in nude mice, after TGFBI knockdown, these cells showed markedly impaired tumor growth and invasive capability; the initially formed small tumors later underwent myxoid degeneration and completely regressed. By contrast, the expanding control tumors showed intense TGFBI staining at the tumor edges, co-localizing with the fibrillar fibronectin/tenascin-C/periostin structures that characteristically surround melanoma cells at invasion fronts. Furthermore, TGFBI was found in similar fibrillar structures in clinical human melanoma metastases as well, co-localizing with fibronectin. These data imply an important role for TGFBI in the ECM deposition and invasive growth of melanoma cells, rendering TGFBI a potential target for therapeutic interventions.
Department of Pathology, Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
Pirjo
P
Nummela
Johanna
J
Lammi
Johanna
J
Soikkeli
Olli
O
Saksela
Pirjo
P
Laakkonen
Erkki
E
Hölttä
D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D005109:Extracellular Matrix / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D009368:Neoplasm Transplantation; D011994:Recombinant Proteins / Q000494:pharmacology; D012867:Skin / Q000378:metabolism; D016608:Talin / Q000378:metabolism; D013947:Thymosin / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D000099201:Thymosin beta(4); D000099222:betaIG-H3 Protein
D016326:Extracellular Matrix Proteins; D019012:Integrin beta1; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D016608:Talin; D013947:Thymosin; D016212:Transforming Growth Factor beta; D000099201:Thymosin beta(4); D000099222:betaIG-H3 Protein