RET-mediated modulation of tumor microenvironment and immune response in multiple endocrine neoplasia type 2 (MEN2)
Medullary thyroid carcinomas (MTC) arise from thyroid parafollicular, calcitonin-producing 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 facto...
Source: Endocrine-Related Cancer - January 18, 2018 Category: Endocrinology Authors: Castellone, M. D., Melillo, R. M. Tags: Thematic Review Source Type: research
Non-mammalian models of multiple endocrine neoplasia type 2
Twenty-five years ago, RET was identified as the primary driver of multiple endocrine neoplasia type 2 (MEN2) syndrome. MEN2 is characterized by several transformation events including pheochromocytoma, parathyroid adenoma and, especially penetrant, medullary thyroid carcinoma (MTC). Overall, MTC is a rare but aggressive type of thyroid cancer for which no effective treatment currently exists. Surgery, radiation, radioisotope treatment and chemotherapeutics have all shown limited success, and none of these approaches have proven durable in advanced disease. Non-mammalian models that incorporate the oncogenic RET isoforms a...
Source: Endocrine-Related Cancer - January 18, 2018 Category: Endocrinology Authors: Das, T. K., Cagan, R. L. Tags: Thematic Review Source Type: research
Structure and function of RET in multiple endocrine neoplasia type 2
It has been twenty-five years since the discovery of oncogenic germline RET mutations as the cause of multiple endocrine neoplasia type 2 (MEN2). Intensive work over the last two and a half decades on RET genetics, signaling and cell biology has provided the current bases for the genotype–phenotype and functional correlations within this cancer syndrome. On the contrary, the structural and molecular basis for RET tyrosine kinase domain activation and oncogenic deregulation has remained largely elusive. Recent studies with a strong crystallographic and biochemical focus have started to elucidate key insights into such...
Source: Endocrine-Related Cancer - January 18, 2018 Category: Endocrinology Authors: Plaza-Menacho, I. Tags: Thematic Review Source Type: research
Patient quality of life and prognosis in multiple endocrine neoplasia type 2
Multiple endocrine neoplasia type 2 (MEN2) refers to the autosomal-dominant neuroendocrine tumour syndromes, MEN type 2A (MEN2A) and MEN type 2B (MEN2B). They are typified by the development of medullary thyroid cancer (MTC), phaeochromocytoma and parathyroid hyperplasia in MEN2A and MTC, phaeochromocytomas, ganglioneuromatosis and skeletal abnormalities in MEN2B. The aggressiveness of MTC is variable according to genotype, and although it is still the major cause of mortality in both conditions, prognosis has improved dramatically in those diagnosed and treated at a young age thanks to predictive genetic testing. Neverthe...
Source: Endocrine-Related Cancer - January 18, 2018 Category: Endocrinology Authors: Grey, J., Winter, K. Tags: Thematic Review Source Type: research
Novel targeted therapeutics for MEN2
The rearranged during transfection (RET) proto-oncogene was recognized as the multiple endocrine neoplasia type 2 (MEN2) causing gene in 1993. Since then, much effort has been put into a clear understanding of its oncogenic signaling, its biochemical function and ways to block its aberrant activation in MEN2 and related cancers. Several small molecules have been designed, developed or redirected as RET inhibitors for the treatment of MEN2 and sporadic MTC. However, current drugs are mostly active against several other kinases, as they were not originally developed for RET. This limits efficacy and poses safety issues. Ther...
Source: Endocrine-Related Cancer - January 18, 2018 Category: Endocrinology Authors: Redaelli, S., Plaza-Menacho, I., Mologni, L. Tags: Thematic Review Source Type: research
Advances in risk-oriented surgery for multiple endocrine neoplasia type 2
Genetic association studies hinge on definite clinical case definitions of the disease of interest. This is why more penetrant mutations were overrepresented in early multiple endocrine neoplasia type 2 (MEN2) studies, whereas less penetrant mutations went underrepresented. Enrichment of genetic association studies with advanced disease may produce a flawed understanding of disease evolution, precipitating far-reaching surgical strategies like bilateral total adrenalectomy and 4-gland parathyroidectomy in MEN2. The insight into the natural course of the disease gleaned over the past 25 years caused a paradigm shift in MEN2...
Source: Endocrine-Related Cancer - January 18, 2018 Category: Endocrinology Authors: Machens, A., Dralle, H. Tags: Thematic Review Source Type: research
A comprehensive review on MEN2B
MEN2B is a very rare autosomal dominant hereditary tumor syndrome associated with medullary thyroid carcinoma (MTC) in 100% cases, pheochromocytoma in 50% cases and multiple extra-endocrine features, many of which can be quite disabling. Only few data are available in the literature. The aim of this review is to try to give further insights into the natural history of the disease and to point out the missing evidence that would help clinicians optimize the management of such patients. MEN2B is mainly characterized by the early occurrence of MTC, which led the American Thyroid Association to recommend preventive thyroidecto...
Source: Endocrine-Related Cancer - January 18, 2018 Category: Endocrinology Authors: Castinetti, F., Moley, J., Mulligan, L., Waguespack, S. G. Tags: Thematic Review Source Type: research
Looking beyond the thyroid: advances in the understanding of pheochromocytoma and hyperparathyroidism phenotypes in MEN2 and of non-MEN2 familial forms
Over the last years, the knowledge of MEN2 and non-MEN2 familial forms of pheochromocytoma (PHEO) has increased. In MEN2, PHEO is the second most frequent disease: the penetrance and age at diagnosis depend on the mutation of RET. Given the prevalence of bilateral PHEO (50% by age 50), adrenal sparing surgery, aimed at sparing a part of the adrenal cortex to avoid adrenal insufficiency, should be systematically considered in patients with bilateral PHEO. Non-MEN2 familial forms of PHEO now include more than 20 genes: however, only small phenotypic series have been reported, suggesting that phenotypic features of isolated h...
Source: Endocrine-Related Cancer - January 18, 2018 Category: Endocrinology Authors: Guerin, C., Romanet, P., Taieb, D., Brue, T., Lacroix, A., Sebag, F., Barlier, A., Castinetti, F. Tags: Thematic Review Source Type: research
Advances in the management of MEN2: from improved surgical and medical treatment to novel kinase inhibitors
Medullary thyroid carcinoma (MTC), a tumor derived from the neural crest, occurs either sporadically or as the dominant component of the type 2 multiple endocrine neoplasia (MEN) syndromes, MEN2A and MEN2B. The discovery that mutations in the RET protooncogene cause hereditary MTC was of great importance, since it led to the development of novel methods of diagnosis and treatment. For example, the detection of a mutated RET allele in family members at risk for inheriting MEN2A or MEN2B signaled that they would develop MTC, and possibly other components of the syndromes. Furthermore, the detection of a mutated allele create...
Source: Endocrine-Related Cancer - January 18, 2018 Category: Endocrinology Authors: Wells, S. A. Tags: Thematic Review Source Type: research
The evolving clinical, genetic and therapeutic landscape of multiple endocrine neoplasia type 2
(Source: Endocrine-Related Cancer)
Source: Endocrine-Related Cancer - January 18, 2018 Category: Endocrinology Authors: Moodley, S., Weber, F., Mulligan, L. M. Tags: Editorials Source Type: research
A unifying biology of sex steroid-induced apoptosis in prostate and breast cancers
Prostate and breast cancer are the two cancers with the highest incidence in men and women, respectively. Here, we focus on the known biology of acquired resistance to antihormone therapy of prostate and breast cancer and compare laboratory and clinical similarities in the evolution of the disease. Laboratory studies and clinical observations in prostate and breast cancer demonstrate that cell selection pathways occur during acquired resistance to antihormonal therapy. Following sex steroid deprivation, both prostate and breast cancer models show an initial increased acquired sensitivity to the growth potential of sex ster...
Source: Endocrine-Related Cancer - January 16, 2018 Category: Endocrinology Authors: Maximov, P. Y., Abderrahman, B., Curpan, R. F., Hawsawi, Y. M., Fan, P., Jordan, V. C. Tags: Review Source Type: research
Long noncoding RNAs: emerging players in thyroid cancer pathogenesis
Thyroid cancer continues to be the most common malignancy of endocrine glands. The incidence of thyroid cancer has risen significantly over the past 4 decades and has emerged as a major health issue. In recent years, significant progress has been achieved in our understanding of the molecular mechanisms of thyroid carcinogenesis, resulting in significant diagnostic, prognostic and therapeutic implications; yet, it has not reached a satisfactory level. Identifying novel molecular therapeutic targets and molecules for diagnosis and prognosis is expected to advance the overall management of this common malignancy. Long noncod...
Source: Endocrine-Related Cancer - January 16, 2018 Category: Endocrinology Authors: Murugan, A. K., Munirajan, A. K., Alzahrani, A. S. Tags: Review Source Type: research
Characterization of neuroendocrine tumors in heterozygous mutant MENX rats: a novel model of invasive medullary thyroid carcinoma
Rats affected by the MENX syndrome spontaneously develop multiple neuroendocrine tumors (NETs) including adrenal, pituitary and thyroid gland neoplasms. MENX was initially reported to be inherited as a recessive trait and affected rats were found to be homozygous for the predisposing Cdkn1b mutation encoding p27. We here report that heterozygous MENX-mutant rats (p27+/mut) develop the same spectrum of NETs seen in the homozygous (p27mut/mut) animals but with slower progression. Consequently, p27+/mut rats have a significantly shorter lifespan compared with their wild-type (p27+/+) littermates. In the tumors of p27+/mut rat...
Source: Endocrine-Related Cancer - January 10, 2018 Category: Endocrinology Authors: Molatore, S., Kugler, A., Irmler, M., Wiedemann, T., Neff, F., Feuchtinger, A., Beckers, J., Robledo, M., Roncaroli, F., Pellegata, N. S. Tags: Research Source Type: research
Classification of gastrointestinal stromal tumor syndromes
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, thought to derive from neoplastic outgrowth of the interstitial cells of Cajal. Building on recent advances in recognition, classification and diagnosis, the past two decades have seen a changing paradigm with molecular diagnostics and targeted therapies. KIT and PDGFRA mutations account for 85–90% of GIST carcinogenesis. However, the remaining 10–15% of GISTs, which until recently were called KIT/PDGFRA wild-type GISTs, have been found to have one of the several mutations, including in the SDHA, B, C, ...
Source: Endocrine-Related Cancer - January 10, 2018 Category: Endocrinology Authors: Gopie, P., Mei, L., Faber, A. C., Grossman, S. R., Smith, S. C., Boikos, S. A. Tags: Review Source Type: research
Notch pathway inhibition targets chemoresistant insulinoma cancer stem cells
This study was aimed to characterise and target INS CSCs in order to develop novel targeted therapies. Highly invasive and tumourigenic human and canine INS CSC-like cells were successfully isolated. These cells expressed stem cell markers (OCT4, SOX9, SOX2, CD133 and CD34), exhibited greater resistance to 5-fluorouracil (5-FU) and demonstrated a more invasive and tumourigenic phenotype in vivo compared to bulk INS cells. Here, we demonstrated that Notch-signalling-related genes (NOTCH2 and HES1) were overexpressed in INS CSC-like cells. Protein analysis showed an active NOTCH2-HES1 signalling in INS cell lines, especially...
Source: Endocrine-Related Cancer - January 8, 2018 Category: Endocrinology Authors: Capodanno, Y., Buishand, F. O., Pang, L. Y., Kirpensteijn, J., Mol, J. A., Argyle, D. J. Tags: Research Source Type: research
