Activation of NFAT signaling establishes a tumorigenic microenvironment through cell autonomous and non-cell autonomous mechanisms

Abstract

NFAT 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.

Camphor white oil induces tumor regression through cytotoxic T cell‐dependent mechanisms

“…In the hair cycle, NFAT signaling promotes bulge stem cell quiescence by inhibiting the cell cycle regulator CDK4 . By contrast, overactivation of NFAT in epidermal cells promotes keratinocyte hyperproliferation . The latter report is consistent with our finding that CWO increases proliferation of normal human keratinocytes.…”

“…NFAT activity has context‐dependent effects on keratinocyte proliferation, both maintaining stem cell quiescence and inducing keratinocyte proliferation . We postulated that CWO might also alter the cell cycle through NFAT activity.…”

Nuclear factor of activated T cells in cancer development and treatment

“…As the downstream of bone morphogenetic protein 4, NFAT2 inhibits CDK4 to maintain skin stem cell dormancy [6]. Another study demonstrated that constitutively activated NFAT2 leads to significant expansion of CD34 + cells and initiates skin squamous cell-like carcinoma [66]. NFAT2 may be involved in acquiring stem cell-like properties and self-renewal capacity, including tumor cell epithelial to mesenchymal transition (EMT) [67] (Table 1).…”

“…Meanwhile, several cytokines and cytokine receptors are upregulated and contribute to the inflammatory microenvironment. In conclusion, NFAT2 activation possesses both cell autonomous and cell non-autonomous mechanisms for establishing the tumor microenvironment in situ [66]. Studies have also been performed examining the microenvironment of the premetastatic site or niche.…”

Cell Proliferation and Epithelia Profile in Prostate Cancer and Benign Prostatic Hyperplasia

“…This cytoskeletal adhesion, however, is necessary to stabilize the epithelial structure. The cadherin molecules are important in maintaining the adherent junctions via calcium mediated cell-cell interaction [17]. One of the most predominant cadherin molecules is E-Cadherin, a transmembrane protein that creates ECAD interaction between 2 cells (calcium dependent) [1,11].…”