title: NFAT1 transcription factor is central in the regulation of tissue microenvironment for tumor metastasis.
abstract: Members of the nuclear factor of activated T cell (NFAT) family of transcription factors were originally described in T lymphocytes but later shown to be expressed in several immune and non-immune cell types. NFAT proteins can modulate cellular transformation intrinsically, and NFAT-deficient (NFAT1-/-) mice are indeed more susceptible to transformation than wild-type counterparts. However, the contribution of an NFAT1-/- microenvironment to tumor progression has not been studied. We have addressed this question by inoculating NFAT1-/- mice with B16F10 melanoma cells intravenously, an established model of tumor homing and growth. Surprisingly, NFAT1-/- animals sustained less tumor growth in the lungs after melanoma inoculation than wild-type counterparts. Even though melanoma cells equally colonize NFAT1-/- and wild-type lungs, tumors do not progress in the absence of NFAT1 expression. A massive mononuclear perivascular infiltrate and reduced expression of TGF-β in the absence of NFAT1 suggested a role for tumor-infiltrating immune cells and the cytokine milieu. However, these processes are independent of an IL-4-induced regulatory tumor microenvironment, since lack of this cytokine does not alter the phenotype in NFAT1-/- animals. Bone marrow chimera experiments meant to differentiate the contributions of stromal and infiltrating cells to tumor progression demonstrated that NFAT1-induced susceptibility to pulmonary tumor growth depends on NFAT1-expressing parenchyma rather than on bone marrow-derived cells. These results suggest an important role for NFAT1 in radio-resistant tumor-associated parenchyma, which is independent of the anti-tumor immune response and Th1 versus Th2 cytokine milieu established by the cancer cells, but able to promote site-specific tumor growth.
authors.affiliation: Division of Cellular Biology, Brazilian National Institute of Cancer (INCA), Rua André Cavalcanti, 37, Centro, Rio de Janeiro, RJ, 20231-050, Brazil.
authors.forename: Miriam B F
authors.initials: MB
authors.lastname: Werneck
authors.forename: Adriana
authors.initials: A
authors.lastname: Vieira-de-Abreu
authors.forename: Roger
authors.initials: R
authors.lastname: Chammas
authors.forename: João P B
authors.initials: JP
authors.lastname: Viola
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016207:Cytokines / Q000096:biosynthesis; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000172:deficiency / Q000276:immunology / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000276:immunology; D009362:Neoplasm Metastasis / Q000276:immunology; D009374:Neoplasms, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: D016207:Cytokines; D050778:NFATC Transcription Factors; C494007:Nfatc2 protein, mouse