1. ¹Department Biological Chemistry, Faculty of Sciences, University of Buenos Aires, Buenos Aires, Argentina
2. ²Inmunopathology Section, Hospital Eva Perón, Buenos Aires, Argentina
3. ³Angelini Farmaceutici ACRAF SpA, S.Palomba-Pomezia, Rome, Italy
4. ⁴Department Molecular Cell Biology, Faculty of Medicine, Amsterdam, The Netherlands
5. ⁵National University of La Plata, Bs. As., Argentina
6. ⁶Istituto Clinico Humanitas, Rozzano, Italy
7. ⁷Cancerology Laboratory, Fundación Instituto Leloir, Buenos Aires, Argentina

Correspondence: Dr Rosa Wainstok, Department of Biological Chemistry, Faculty of Sciences, University of Buenos Aires, Ciudad Universitaria, Pabellon II, 4th floor, Nuñez (1428), Capital Federal, Argentina. E-mail: rwains@qb.fcen.uba.ar

Received 6 September 2006; Revised 5 February 2007; Accepted 9 February 2007; Published online 26 April 2007.

Abstract

Chemokines such as monocyte chemoattractant protein (MCP)-1 are key agonists that attract macrophages to tumors. In melanoma, it has been previously shown that variable levels of MCP-1/CCL2 appear to correlate with infiltrating macrophages and tumor fate, with low to intermediate levels of the chemokine contributing to melanoma development. To work under such conditions, a poorly tumorigenic human melanoma cell line was transfected with an expression vector encoding MCP-1. We found that M2 macrophages are associated to MCP-1⁺ tumors, triggering a profuse vascular network. To target the protumoral macrophages recruitment and reverting tumor growth promotion, clodronate-laden liposomes (Clod-Lip) or bindarit were administered to melanoma-bearing mice. Macrophage depletion after Clod-Lip treatment induced development of smaller tumors than in untreated mice. Immunohistochemical analysis with an anti-CD31 antibody revealed scarce vascular structures mainly characterized by narrow vascular lights. Pharmacological inhibition of MCP-1 with bindarit also reduced tumor growth and macrophage recruitment, rendering necrotic tumor masses. We suggest that bindarit or Clod-Lip abrogates protumoral-associated macrophages in human melanoma xenografts and could be considered as complementary approaches to antiangiogenic therapy.