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Macrophage-Derived SPARC Bridges Tumor Cell-Extracellular Matrix Interactions toward Metastasis

¹ Department of Experimental Oncology, Immunotherapy and Gene Therapy Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori; ² Department of Human Morphology, Universita degli Studi di Milano, Milan, Italy; ³ Department of Oncology and Neurosciences, Surgical Pathology Section, "G. d'Annunzio" University and Ce.S.I. Aging Research Center, "G. d'Annunzio" University Foundation, Chieti, Italy; and ⁴ Departments of Surgery and Pharmacology, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas

Requests for reprints: Mario P. Colombo, Immunotherapy and Gene Therapy Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy. Phone: 39-2-2390-2252; Fax: 39-2-2390-2630; E-mail: mario.colombo{at}istitutotumori.mi.it.

Key Words: Macrophages • Mestastasis • SPARC

Other than genetic imprinting and epithelial to mesenchymal transition, cancer cells need interaction with the nearby stroma toward metastasis. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein known to regulate extracellular matrix (ECM) deposition and cell-ECM interaction. Gene expression profiles associate SPARC to malignant progression. Using reciprocal bone marrow chimeras between SPARC knockout and wild-type mice, we show that SPARC produced by inflammatory cells is necessary for spontaneous, but not experimental, i.v. metastasis. Macrophage-derived SPARC induces cancer cell migration and enhances their migration to other ECM proteins at least through _vβ₅ integrin. Indeed, RNA interference knockdown of β₅ integrin expression reduces cell migration in vitro and metastasis in vivo. Together these results show that macrophage-derived SPARC takes part in metastasis, acting at the step of integrin-mediated migration of invasive cells. [Cancer Res 2008;68(21):9050–9]