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. Author manuscript; available in PMC: 2010 May 10.
Published in final edited form as: Nat Rev Cancer. 2009 Nov;9(11):810–820. doi: 10.1038/nrc2735

Figure 3. NFAT promotes tumor cell migration through paracrine and autocrine mechanisms.

Figure 3

Subsequent to genetic and epigenetic deregulation, epithelial cells that reside on the basement membrane undergo a fundamental change in morphology adopting a mesenchymal architecture, concomitant with acquisition of a motile phenotype. This ordered series of events is collectively termed the epithelial to mesenchymal transition (EMT). Subsequently, the tumor cells degrade the basement membrane and this facilitates cancer invasion into connective tissue that is comprised primarily of extracellular membrane (ECM) proteins. NFAT promotes migration and invasion through multiple non-redundant mechanisms. Engagement of integrins such as α6β4 on tumor cells promotes NFAT nuclear translocation likely through calcium flux. Nuclear NFAT transactivates numerous genes, including those that encode the autotaxin and cyclooxygenase (COX-2) proteins. Autotaxin and COX-2 are secreted proteins and catalyze the synthesis of lysophosphatidic acid (LPA) and prostaglandin E2 (PGE2) respectively. Both LPA and PGE2 are potent motogens and mitogens that act in both paracrine and autocrine signaling through binding Edg (endothelial differentiation gene) and prostaglandin E2 (EP) receptors, respectively, to promote the invasive migration of tumor cells through the ECM.