Abstract
NFAT (the nuclear factor of activated T cells) upregulation has been linked to cellular transformation intrinsically, but it is unclear whether and how tissue cells with NFAT activation change the local environment for tumor initiation and progression. Direct evidence showing NFAT activation initiates primary tumor formation in vivo is also lacking. Using inducible transgenic mouse systems, we show that tumors form in a subset of, but not all, tissues with NFATc1 activation, indicating that NFAT oncogenic effects depend on cell types and tissue contexts. In NFATc1-induced skin and ovarian tumors, both cells with NFATc1 activation and neighboring cells without NFATc1 activation have significant upregulation of c-Myc and activation of Stat3. Besides known and suspected NFATc1 targets, such as Spp1 and Osm, we have revealed the early upregulation of a number of cytokines and cytokine receptors, as key molecular components of an inflammatory microenvironment that promotes both NFATc1+ and NFATc1− cells to participate in tumor formation. Cultured cells derived from NFATc1-induced tumors were able to establish a tumorigenic microenvironment, similar to that of the primary tumors, in an NFATc1-dependent manner in nude mice with T-cell deficiency, revealing an addiction of these tumors to NFATc1 activation and downplaying a role for T cells in the NFATc1-induced tumorigenic microenvironment. These findings collectively suggest that beyond the cell autonomous effects on the upregulation of oncogenic proteins, NFATc1 activation has non-cell autonomous effects through the establishment of a promitogenic microenvironment for tumor growth. This study provides direct evidence for the ability of NFATc1 in inducing primary tumor formation in vivo and supports targeting NFAT signaling in anti-tumor therapy.
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References
Graef IA, Chen F, Crabtree GR . NFAT signaling in vertebrate development. Curr Opin Genet Dev 2001; 11: 505–512.
Pan M, Winslow MM, Chen L, Kuo A, Felsher D, Crabtree GR . Enhanced NFATc1 nuclear occupancy causes T cell activation independent of CD28 costimulation. J Immunol 2007; 178: 4315–4321.
Neal JW, Clipstone NA . A constitutively active NFATc1 mutant induces a transformed phenotype in 3T3-L1 fibroblasts. J Biol Chem 2003; 278: 17246–17254.
Marafioti T, Pozzobon M, Hansmann ML, Ventura R, Pileri SA, Roberton H et al. The NFATc1 transcription factor is widely expressed in white cells and translocates from the cytoplasm to the nucleus in a subset of human lymphomas. Br J Haematol 2005; 128: 333–342.
Medyouf H, Alcalde H, Berthier C, Guillemin MC, dos Santos NR, Janin A et al. Targeting calcineurin activation as a therapeutic strategy for T-cell acute lymphoblastic leukemia. Nat Med 2007; 13: 736–741.
Pham LV, Tamayo AT, Yoshimura LC, Lin-Lee YC, Ford RJ . Constitutive NF-kappaB and NFAT activation in aggressive B-cell lymphomas synergistically activates the CD154 gene and maintains lymphoma cell survival. Blood 2005; 106: 3940–3947.
Buchholz M, Schatz A, Wagner M, Michl P, Linhart T, Adler G et al. Overexpression of c-myc in pancreatic cancer caused by ectopic activation of NFATc1 and the Ca2+/calcineurin signaling pathway. EMBO J. 2006; 25: 3714–3724.
Jauliac S, Lopez-Rodriguez C, Shaw LM, Brown LF, Rao A, Toker A . The role of NFAT transcription factors in integrin-mediated carcinoma invasion. Nat Cell Biol 2002; 4: 540–544.
Muller MR, Rao A . NFAT, immunity and cancer: a transcription factor comes of age. Nat Rev Immunol 2010; 10: 645–656.
Pan MG, Xiong Y, Chen F . NFAT gene family in inflammation and cancer. Curr Mol Med (in press).
Zhao H, Kegg H, Grady S, Truong HT, Robinson ML, Baum M et al. Role of fibroblast growth factor receptors 1 and 2 in the ureteric bud. Dev Biol 2004; 276: 403–415.
Guo Q, Tripathi P, Poyo E, Wang Y, Austin PF, Bates CM et al. Cell death serves as a single etiological cause of a wide spectrum of congenital urinary tract defects. J Urol 2011; 185: 2320–2328.
Anderson B, Turner DA, Benda J . Ovarian sarcoma. Gynecol Oncol 1987; 26: 183–192.
Horsley V, Aliprantis AO, Polak L, Glimcher LH, Fuchs E . NFATc1 balances quiescence and proliferation of skin stem cells. Cell 2008; 132: 299–310.
Yasaka N, Furue M, Tamaki K . CD44 expression in normal human skin and skin tumors. J Dermatol 1995; 22: 88–94.
Lin C, Yin Y, Chen H, Fisher AV, Chen F, Rauchman M et al. Construction and characterization of a doxycycline-inducible transgenic system in Msx2 expressing cells. Genesis 2009; 47: 352–359.
Lesina M, Kurkowski MU, Ludes K, Rose-John S, Treiber M, Kloppel G et al. Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell 2011; 19: 456–469.
Torti D, Trusolino L . Oncogene addiction as a foundational rationale for targeted anti-cancer therapy: promises and perils. EMBO Mol Med 2011; 3: 623–636.
McCormick F . Cancer therapy based on oncogene addiction. J Surg Oncol 2011; 103: 464–467.
Graef IA, Chen F, Chen L, Kuo A, Crabtree GR . Signals transduced by Ca(2+)/calcineurin and NFATc3/c4 pattern the developing vasculature. Cell 2001; 105: 863–875.
Chang CP, McDill BW, Neilson JR, Joist HE, Epstein JA, Crabtree GR et al. Calcineurin is required in urinary tract mesenchyme for the development of the pyeloureteral peristaltic machinery. J Clin Invest 2004; 113: 1051–1058.
Li SZ, McDill BW, Kovach PA, Ding L, Go WY, Ho SN et al. Calcineurin-NFATc signaling pathway regulates AQP2 expression in response to calcium signals and osmotic stress. Am J Physiol Cell Physiol 2007; 292: C1606–C1616.
Wang Y, Jarad G, Tripathi P, Pan M, Cunningham J, Martin DR et al. Activation of NFAT signaling in podocytes causes glomerulosclerosis. J Am Soc Nephrol 2010; 21: 1657–1666.
Sansone P, Bromberg J . Environment, inflammation, and cancer. Curr Opin Genet Dev 2011; 21: 80–85.
Wu H, Peisley A, Graef IA, Crabtree GR . NFAT signaling and the invention of vertebrates. Trends Cell Biol 2007; 17: 251–260.
Rao A . Signaling to gene expression: calcium, calcineurin and NFAT. Nat Immunol. 2009; 10: 3–5.
Barriere C, Santamaria D, Cerqueira A, Galan J, Martin A, Ortega S et al. Mice thrive without Cdk4 and Cdk2. Mol Oncol 2007; 1: 72–83.
Li W, Kotoshiba S, Berthet C, Hilton MB, Kaldis P . Rb/Cdk2/Cdk4 triple mutant mice elicit an alternative mechanism for regulation of the G1/S transition. Proc Natl Acad Sci USA 2009; 106: 486–491.
Wong SY, Reiter JF . Wounding mobilizes hair follicle stem cells to form tumors. Proc Natl Acad Sci USA 2011; 108: 4093–4098.
Belteki G, Haigh J, Kabacs N, Haigh K, Sison K, Costantini F et al. Conditional and inducible transgene expression in mice through the combinatorial use of Cre-mediated recombination and tetracycline induction. Nucleic Acids Res 2005; 33: e51.
Janik P, Briand P, Hartmann NR . The effect of estrone-progesterone treatment on cell proliferation kinetics of hormone-dependent GR mouse mammary tumors. Cancer Res 1975; 35: 3698–3704.
McDill BW, Li SZ, Kovach PA, Ding L, Chen F . Congenital progressive hydronephrosis (cph) is caused by an S256L mutation in aquaporin-2 that affects its phosphorylation and apical membrane accumulation. Proc Natl Acad Sci USA 2006; 103: 6952–6957.
Acknowledgements
We thank Dr Crabtree for providing the TetO-NFATc1Nuc mice and Dr Yuan Zhu for helpful discussion of the study. FC is supported in part by institutional funds from the Department of Medicine at Washington University School of Medicine and NIH grants (DK81592 and DK67386). We also thank the George M. O’Brien Center for Kidney Disease Research at Washington University (P30DK079333) for core services. We thank Michael Heinz from the Genome Technology Access Center (P30 CA91842, UL1RR024992) in the Department of Genetics at Washington University School of Medicine for help with gene expression analysis.
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Tripathi, P., Wang, Y., Coussens, M. et al. Activation of NFAT signaling establishes a tumorigenic microenvironment through cell autonomous and non-cell autonomous mechanisms. Oncogene 33, 1840–1849 (2014). https://doi.org/10.1038/onc.2013.132
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DOI: https://doi.org/10.1038/onc.2013.132
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