RET-mediated modulation of tumor microenvironment and immune response in multiple endocrine neoplasia type 2 (MEN2)

Abstract

Medullary thyroid carcinomas (MTC) arise from thyroid parafollicular, calcitoninproducing C-cells and can occur either as sporadic or as hereditary diseases in the context of familial syndromes, including multiple endocrine neoplasia 2A (MEN2A), multiple endocrine neoplasia 2B (MEN2B) and familial MTC (FMTC). In a large fraction of sporadic cases, and virtually in all inherited cases of MTC, activating point mutations of the RET proto-oncogene are found. RET encodes for a receptor tyrosine kinase protein endowed with transforming potential on thyroid parafollicular cells. As in other cancer types, microenvironmental factors play a critical role in MTC. Tumor-associated extracellular matrix, stromal cells and immune cells interact and influence the behavior of cancer cells both in a tumor-promoting and in a tumor-suppressing manner. Several studies have shown that, besides the neoplastic transformation of thyroid C-cells, a profound modification of tumor microenvironment has been associated to the RET FMTC/MEN2-associated oncoproteins. They influence the surrounding stroma, activating cancerassociated fibroblasts (CAFs), promoting cancer-associated inflammation and suppressing anti-cancer immune response. These mechanisms might be exploited to develop innovative anti-cancer therapies and novel prognostic tools in the context of familial, RET-associated MTC.

A dual mechanism of activation of the Sonic Hedgehog pathway in anaplastic thyroid cancer: crosstalk with RAS-BRAF-MEK pathway and ligand secretion by tumor stroma

“…A growing body of evidences indicates the stroma as a key player in tumorigenesis to support the growth, maintenance and progression of cancer. In thyroid cancers, stroma composition changes among the different histotypes being mainly characterized by immune/inflammatory cells in PTC and by a desmoplastic stromal reaction in ATC and MTC as well as in metastatic PTC, where it correlates to aggressiveness and lymph node metastasis [ 22 – 26 ]. Recent reports in cancer models have suggested a crucial role for the Shh pathway in tumor-stroma interaction.…”

A Nationwide Study of Multiple Endocrine Neoplasia Type 2A in Norway: Predictive and Prognostic Factors for the Clinical Course of Medullary Thyroid Carcinoma

“…TKI is today the only systemic treatment and are indicated at metastatic progressive MTC. The treatment effect is increased PFS with transient effect, the side effects are profound (237,238,299).…”

“…Combinations of targeted therapies with other agents, including immunotherapy has shown to enhance drug efficacy, overcoming resistance and reducing side effects (299,305). Treatment with TKI together with immunotherapy in MTC should be explored even more.…”

GDNF and the RET Receptor in Cancer: New Insights and Therapeutic Potential

“…Interactions of tumor cells and their environment can result in reciprocal remodeling that enhances the ability of the tumor to grow, and invade surrounding tissues or escape immune response and initiate metastasis. In multiple cancers, stimulation of RET activity leads to changes in expression of transcription factors (e.g., SLUG, SNAIL, ZEB, TWIST), adhesion proteins (e.g., E-cadherin, N-cadherin, vimentin) and matrix remodeling proteins (e.g., matrix metalloproteases) that can cause cancer cells to take on more mesenchymal phenotypes (Melillo et al, 2005; Lian et al, 2017; Castellone and Melillo, 2018). Cells undergoing RET-mediated epithelial to mesenchymal transition (EMT) remodel their actin cytoskeleton and lose cell polarity, becoming more motile, and have enhanced abilities to degrade the ECM to promote cell invasion (Tang et al, 1998; Asai et al, 1999; Melillo et al, 2005; Lian et al, 2017).…”