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The Melanoma-Associated Antigen A3 Mediates Fibronectin-Controlled Cancer Progression and Metastasis

Departments of ¹ Pathology and ² Medicine, University Health Network, Ontario Cancer Institute, Toronto, Ontario, Canada

Requests for reprints: Shereen Ezzat, Ontario Cancer Institute, 610 University Avenue, #8-327, Toronto, Ontario, Canada M5G 2M9. Phone: 416-946-4501, ext. 2815; Fax: 416-340-5517; E-mail: shereen.ezzat{at}utoronto.ca.

Key Words: Fibronectin • MAGE A3 • p53 • p21 • metastasis • thyroid cancer

Tumor cells frequently exhibit decreased adhesiveness due to failure to deposit stromal fibronectin (FN), permitting more rapid proliferation, migration, invasion, and metastasis. Although up-regulation of FN has been noted in gene profiles of carcinomas compared with normal tissue, reduced FN expression has been described at the peripheral margins of invading tumors. In this study, we investigate the role of FN in cancer behavior. Using human thyroid carcinoma cells with stably down-regulated FN, we performed gene profiling and created an orthotopic mouse model. We stably overexpressed the FN target, MAGE A3, which has also been identified as a target of the breast cancer risk factor fibroblast growth factor receptor 2, and examined the functional effects in vitro and in vivo in a flank model and an orthotopic model of thyroid cancer. Mouse xenografts showed significantly enhanced tumor growth as well as larger and more numerous lung metastases in response to FN silencing. Gene profiling identified the melanoma-associated antigen (MAGE A3) as significantly up-regulated in response to FN silencing. Forced expression of MAGE A3 resulted in p21 down-regulation, accelerated cell cycle progression, increased cell migration rate, and invasion in vitro and in vivo in an orthotopic mouse model where microcomputed tomography confirmed lung metastases that recapitulate the progression of human thyroid cancer. We conclude that MAGE A3 is a functional integrator of diverse signals, including FGFR2 and FN, to modulate cancer progression. [Cancer Res 2008;68(19):8104–12]

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