Targeting tumor-associated macrophages and inhibition of MCP-1 reduce angiogenesis and tumor growth in a human melanoma xenograft.
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.
Gazzaniga
Silvina
S
Department Biological Chemistry, Faculty of Sciences, University of Buenos Aires, Buenos Aires, Argentina.
Bravo
Alicia I
AI
Guglielmotti
Angelo
A
van Rooijen
Nico
N
Maschi
Fabricio
F
Vecchi
Annunciata
A
Mantovani
Alberto
A
Mordoh
José
J
Wainstok
Rosa
R
D000818:Animals; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000502:physiology; D004002:Clodronic Acid / Q000008:administration & dosage*; D006801:Humans; D007191:Indazoles / Q000627:therapeutic use*; D008081:Liposomes; D008264:Macrophages / Q000502:physiology*; D008297:Male; D008546:Melanoma, Experimental / Q000098:blood supply / Q000188:drug therapy*; D051379:Mice; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D011422:Propionates / Q000627:therapeutic use*; D014183:Transplantation, Heterologous
D018932:Chemokine CCL2; D007191:Indazoles; D008081:Liposomes; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011422:Propionates; D004002:Clodronic Acid; C079489:bindarit