The genetic mechanisms underlying the multistep process of medullary thyroid carcinoma (MTC) development is at present largely unknown. About 60% of all MTCs occur as sporadic cancer and the remaining 40% occur as familial cancer. Activation of RET, a receptor tyrosine kinase, initiates hereditary MTC development and could be involved in sporadic MTC development as well. Additional oncogenic events are required, but remain to be elucidated. In chapter 1, an overview is provided of all RET and non-RET genetic alterations detected in human MTCs. In addition, an overview of all RET and non-RET mouse models that develop MTC, is provided. Genes affected in these non-RET models might be involved in human MTC tumorigenesis as well, which should be further investigated. In chapter 2, we show the presence of somatic inactivating mutations in P18 in human sporadic and MEN 2-associated MTCs, and MEN 2-associated pheochromocytomas (PCs). Each mutation causes an amino acid substitution in the cyclin dependent kinase-interacting region of P18. We have shown that these mutations inhibit P18 function and cause reduced stability. Our findings implicate P18 as a tumor suppressor gene involved in human MTC and PC development. In chapter 3, we describe the detection of a synergistic effect of oncogenic RET and loss of p18 on MTC development, age-of-onset and MTC size. In addition, somatic loss of p18 expression, correlating with MTC growth, has been detected, indicating that loss of p18 in combination with oncogenic RET not only increases the risk for MTC development, it also enhances MTC progression. In chapter 4, we demonstrate nuclear localization in MEN 2-associated primary MTCs and their metastases. We show that RET is able to interact with, and tyrosine phosphorylate beta-catenin. As a result, beta-catenin escapes cytosolic downregulation by the APC/AXIN/GSK3 complex and accumulates in the nucleus, where it stimulates transcriptional programs. Downregulation of beta-catenin activity decreases RET-mediated cell proliferation, colony formation, and tumor growth in nude mice. These data show that the RET kinase-beta-catenin pathway is a critical contributor to the development and metastasis of human MTC. Thirty to 55% of sporadic MTC patients are not cured after initial surgical treatment. A literature study, described in chapter 5, revealed that re-operation of patients with postoperative hypercalcitoninemia results in low biochemical cure rates. This chapter provides an overview of currently used and putative novel biomarkers, like RET, plasma CT and CEA, radiopharmaceuticals and regulatory peptides, for the diagnosis, treatment and prediction of progression of MTC. Chapter 6 provides an integrated model describing our current knowledge of the molecular mechanisms underlying multistep MTC tumorigenesis. Via several downstream pathways, RET signaling may be involved in all the essential steps for tumorigenesis. These pathways may involve activation of beta-Catenin-mediated signaling through tyrosine phosphorylation by RET. In addition, loss of G1/S transition control, e.g. via inactivation of P18 or loss of RB, might be an important step in MTC tumorigenesis
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