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.

Osteosarcoma (OS) is the most common primary tumor of bone, occurring predominantly in the second decade of life. High-dose cytotoxic chemotherapy and surgical resection have improved prognosis, with long-term survival for patients with localized disease. Vanadium is an ultra-trace element that after being absorbed accumulates in bone. Besides, vanadium compounds have been studied during recent years to be considered as representative of a new class of non-platinum antitumor agents. Moreover, flavonoids are a wide family of polyphenolic compounds that display many interesting biological effects. Since coordination of ligands to metals can improve the pharmacological properties, we report herein, for the first time, the in vitro and in vivo effects of an oxidovanadium(IV) complex with the flavonoid chrysin on the new 3D human osteosarcoma and xenograft osteosarcoma mice models. The pharmacological results show that VOchrys inhibited the cell viability affecting the shape and volume of the spheroids and VOchrys suppressed MG-63 tumor growth in the nude mice without inducing toxicity and side effects. As a whole, the results presented herein demonstrate that the antitumor action of the complex was very promissory on human osteosarcoma models, whereby suggesting that VOchrys is a potentially good candidate for future use in alternative antitumor treatments.

There is growing evidence that necrosis, instead of apoptosis, could act as a natural adjuvant, which could activate an immune response. In this work we have investigated if induction of tumor necrosis could trigger the affluence of inflammatory cells at the tumor site, and thus induce an immune response. For this purpose, a liquid N2 spray was applied on human melanoma (IIB-MEL-J cell line) xenografted in nude mice and 24 h later some mice received intratumorally a single 500 U dose of recombinant murine granulocyte macrophage-colony-stimulating factor. 77-100% of the tumor mass underwent necrosis. Congestion, edema, and endothelial cell activation were the first noticeable events. A quick infiltrative response of polymorphonuclear leukocytes around the tumor was detected 24 h after liquid N2 application, peaking at day 3. Massive macrophage recruitment was observed since day 3. An early intratumoral infiltration with inflammatory cells was only detected in the group that received recombinant murine granulocyte macrophage- colony-stimulating factor after necrosis induction by liquid N2. Coexisting DEC 205- and F4/80-positive cells increased in number, and their localization was predominantly peritumoral after necrosis. Antibody response was only detected in the groups with tumor-induced necrosis. Our results suggest that cryosurgery-induced necrosis could be a useful model to analyze the interaction among necrosis, inflammation, and the generation of an immune response.

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