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Comparative characterization of tumor microenvironment and systemic environment in animals with murine melanoma under chemotherapy treatment

Grant number: 07/01713-0
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): October 01, 2007
Effective date (End): September 30, 2008
Field of knowledge:Biological Sciences - Morphology - Cytology and Cell Biology
Principal Investigator:Roger Chammas
Grantee:Ciro Blujus dos Santos Rohde
Home Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Tumors are not only a mass of transformed cells, but also a tissue microenvironment, sharing similar features to either inflammatory microenvironments or regenerating tissues. Under these conditions, host elements as cells from the innate immune system may act favoring tumor growth, either directly, by phagocytosing cell debris or indirectly, as a rich source of secreted pro-angiogenic cytokines. In this sense, a cross-talk between tumor cells and effector elements of the innate immunity exists. This cross-talk, in its turn, could be either local or systemic. Evidence suggest that peripheral lymphoid organs, such as spleen, represent sites for bone marrow-derived cell maturation or commitment. These cells favor both tumor growth and tumor repopulation, a tissue response associated with therapy failure. Tumor repopulation is common upon treatment of tumor-bearing animals with chemotherapeutic agents, such as dacarbazine, a pro-apoptogenic drug. Accumulation of apoptotic cells within the tumor, besides the action of dacarbazine on the tumor vasculature, are followed by the creation of a inflammatory milieu, with recruitment or activation of phagocytes. An immunosuppressive environment is then generated by cytokines produced by these activated cells, thus favoring the growth of dacarbazine-resistant tumor cells. Among the phagocytes, there are macrophages which secrete a variety of molecules, among them PAF-like substances. Recently, in a collaborative study of the group, the therapeutic effect of dacarbazine had improved when used combined with a PAF-Receptor antagonist. In this project, we will analyze both quantitative and qualitatively the leukocyte subpopulations present within tumors and the spleen of animals under different treatment conditions. Analyses will be performed by both immunohistochemistry and flow cytometry. These analyses will allow for the description of the scenario of cellular interactions that are potentially involved with tumor cell repopulation.