Tyrosine kinase oncoprotein, RET/PTC3, induces the secretion of myeloid growth and chemotactic factors

Abstract

Differentiated thyroid carcinomas are the most frequent endocrine neoplasms, but account for few cancer-related deaths. Although the indolent growth of these cancers correlates well with longevity, the biological basis for this good prognosis is not known. In contrast, two of the most frequent autoimmune diseases involve the thyroid suggesting a high propensity for this organ to invoke destructive immunity. Unfortunately, the mechanism linking malignancy and autoimmunity is not clear, although the expression of the oncogenic fusion protein RET/PTC3 (RP3) in both of these disorders may provide a clue. Interestingly, the signaling caused by activated RET kinase involves overlapping pathways and some common to the inflammatory response. Accordingly, we analyzed the function of RP3 and a mutant RP3 molecule to induce proinflammatory pathways in thyroid epithelial cells. Indeed, we find that RP3 alone causes increases in nuclear NF-jB activity and secretion of MCP-1 and GM-CSF. Finally, transfer of RP3-expressing thyrocytes into mice in vivo attracted dense macrophage infiltrates, which lead to rapid thyroid cell death. Further, cytokine synthesis and inflammation was largely abrogated by mutation of RP3 Tyr 588 ; an important protein-binding site for downstream signaling. Together, these studies implicate oncogeneinduced cytokine-signaling pathways in a new mechanism linking inflammation with cancer.

TIMP3 regulates migration, invasion and in vivo tumorigenicity of thyroid tumor cells

“…In several human tumors, including thyroid cancer and related animal models, it has been observed that tumor angiogenesis correlates with the extent of macrophage infiltration (Russell et al, 2003;Detoraki et al, 2009). To investigate the presence of infiltrating macrophages in our in vivo tumor model, we evaluated their presence at tumor edges by immunohistochemistry with F4/80 antibodies.…”

Interleukin 24 is induced by the RET/PTC3 oncoprotein and is an autocrine growth factor for epithelial cells

“…The association of RET/PTC with HT suggested that oncoproteins may be one component involved in promoting organ-specific inflammation. While the mechanism of how RET/PTC contributes to autoimmune thyroiditis is not clear, the activated tyrosine kinase activity associated with RET/PTC has been shown to support the production of inflammatory mediators and induce inflammation (Russell et al, 2003). One member of this oncoprotein family RP3 (RP3) can induce nuclear NF-kB activity and the downstream effects of this activation including the production of the Gmcsf and Mcp1 from thyroid cells in vitro and in vivo (Russell et al, 2003(Russell et al, , 2004.…”

“…While the mechanism of how RET/PTC contributes to autoimmune thyroiditis is not clear, the activated tyrosine kinase activity associated with RET/PTC has been shown to support the production of inflammatory mediators and induce inflammation (Russell et al, 2003). One member of this oncoprotein family RP3 (RP3) can induce nuclear NF-kB activity and the downstream effects of this activation including the production of the Gmcsf and Mcp1 from thyroid cells in vitro and in vivo (Russell et al, 2003(Russell et al, , 2004. Furthermore, cytokine synthesis was largely dependent on a tyrosine at position 588 of RET/PTC, which corresponds to tyrosine 1062 of c-RET, a Shc docking site critical for downstream signaling (Russell et al, 2003).…”

Thyroid cancer and inflammation

“…M a n u s c r i p t Russell et al, 2003Russell et al, , 2004Puxeddu et al, 2005; A c c e p t e d M a n u s c r i p t Small cytokine belonging to the CXC chemokine which activate leukocytes and is often induced by proinflammatory stimuli. It is the key enzyme in prostaglandin biosynthesis.…”