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

  1. Rosa Marina Melillo1,2
  1. 1Istituto di Endocrinologia ed Oncologia Sperimentale del CNR ‘G. Salvatore’, Naples, Italy
  2. 2Dipartimento di Medicina Molecolare e Biotecnologie Mediche, University of Naples ‘Federico II’, Naples, Italy
  1. Correspondence should be addressed to R M Melillo: rosmelil{at}
  1. Figure 1

    A representative scheme of RET receptor tyrosine kinase structure is depicted. The RET gene is located on chromosome 10q11.12. RET encodes for a receptor tyrosine kinase (RTK) with quite peculiar features: RET extracellular domain contains 4 cadherin-homology domains and a cysteine-rich region. Its tyrosine kinase domain contains two subdomains divided by a short kinase insert. Specific structural domains are indicated: CHD, cadherin-homology domain; CRD, cysteine-rich domain; CTD, carboxy-terminal domain; JMD, juxta-membrane domain; TKD, tyrosine kinase domain; TMD, trans-membrane domain. Selected heritable mutations identified in patients with MEN2A/FMTC (red stars) or MEN2B (black stars) are shown. Substitutions involving C634 and M918 (highlighted in red) are the most common mutations involved in MEN2A and MEN2B syndromes, respectively. RET tyrosines phosphorylated upon activation are indicated as yellow circles. Y900 and Y905 represent autocatalityc tyrosines, whereas Y1015 and Y1062 represent major docking sites for signaling proteins. Y1015- and Y1062-binding proteins are indicated in red boxes, and the activated downstream signaling pathways are indicated in blue boxes.

  2. Figure 2

    RET MEN2-associated mutants shape tumor microenvironment in MTC. Activation of RET in MEN2 results not only in the oncogenic conversion of the C-cell, but also in the production of factors that influence tumor microenvironment. RET-transformed C-cells can produce Tenascin C (TnC), collagens (COL1A1/2), vimentin, matrix metalloproteases (MMps) and cytokines (SDF-1, TGFβ). These factors induce fibroblast conversion into myofibroblasts, also defined as cancer-activated fibroblasts (CAFs), desmoplastic reaction and the epithelial-to-mesenchymal transition (EMT). Activated RET in the context of MEN2-associarted MTC can induce the production of immune-inflammatory molecules that can recruit and activate immune cells. CX3CL1 is induced by RET MEN2A and is involved in the recruitment of NK and CTLs. Signaling pathways activated by RET MEN2B can induce immunosuppression by recruiting Tregs and by the expression of immunomodulatory molecules, including PD L1/2. IL23 and IL17 are expressed in MTCs and can be responsible for Th17 presence and activity into tumor site. Some factors, including osteopontin (OPN), IL8 and stromal cell-derived growth factor 1 (SDF1), can increase the malignant potential of MTC cells by autocrine activation of cognate receptors.

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