Medullary Thyroid Cancer: A Promising Model for Targeted Therapy

Torino, Francesco; Paragliola, Rosa Maria; Barnabei, Agnese; Corsello, Salvatore Maria

doi:10.2174/156652410792630607

Cited by 19 publications

(12 citation statements)

References 133 publications

(189 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…MEN syndrome includes the following three subtypes: MEN2A (association between medullary thyroid carcinoma [MTC], PHEO and primary hyperparathyroidism); familial medullary thyroid cancer and MEN2B. The latter represents a less common but more aggressive form and it is characterized by the association between MTC and PHEO with other particular features such as mucosal neuromas, intestinal ganglioneuromas, and marfanoid habitus with skeletal deformations and joint laxity [3]. …”

Section: Introductionmentioning

confidence: 99%

A rare case of juvenile hypertension: coexistence of type 2 multiple endocrine neoplasia -related bilateral pheochromocytoma and reninoma in a young patient with ACE gene polymorphism

et al. 2015

View full text Add to dashboard Cite

BackgroundPheochromocytoma and reninoma represent two rare diseases causing hypertension. We here reported a rare case of association between type 2 multiple endocrine neoplasia related bilateral pheochromocytoma and reninoma. Moreover, polymorphism of ACE gene, which is known to be related to an increase of cardiovascular risk, has been found in the same patient.Case presentationA 24 year old Caucasian man came to our attention for severe hypertension, resistant to anti-hypertensive polytherapy. At the age of twenty he had undergone total thyroidectomy with lymphadenectomy for medullary carcinoma. Genetic testing showed a RET mutation of codon 918 (exon 16) not documented in other family members. During the follow-up, a progressive increase of urinary metanephrines and catecholamines was recorded. Our evaluation confirmed the presence of severe hypertension (220/140 mmHg) and a severe increase of urinary catecholamines and metanephrines. Due to the presence of hypokalemia, other causes of hypertension were researched leading to the discovery of hyperreninemia (236 μUI/ml) with mild hyperaldosteronism, and a mild increase of the renal artery resistance at ultrasound. An abdominal MRI showed multiple adrenal masses and a right kidney nodular lesion of about 2 cm.The patient underwent bilateral adrenalectomy and right nephrectomy, and histology confirmed the presence of bilateral pheochromocytoma and right reninoma. The post-surgery laboratory evaluation showed a rapid reduction of the urinary metanephrines while plasma renin level remained low in spite of the bilateral adrenalectomy without any mineralocorticoid supplementation. To further investigate these unusual feature, we performed genetic testing for the ACE gene, which revealed the presence of ACE I/D polymorphism.ConclusionThis unique report describes the association between two rare causes of hypertension in the same patient. Furthermore, the absence of requirement of mineralocorticoid supplementation in spite of bilateral adrenalectomy, represent an uncommon and interest finding.

show abstract

Section: Introductionmentioning

confidence: 99%

A rare case of juvenile hypertension: coexistence of type 2 multiple endocrine neoplasia -related bilateral pheochromocytoma and reninoma in a young patient with ACE gene polymorphism

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Activation of the Raf1 signaling pathway has been shown to inhibit growth in SCLC, MTC, and carcinoid cells in vitro [6,25,26], and we showed that doxycycline-induced MEK expression also led to inhibition of cell growth in MTC cells. Taken together, these results suggest that components of the MEK signaling pathway tightly regulate the MTC phenotype.…”

Section: Discussionmentioning

confidence: 56%

“…MTC cells produce several hormones and NE markers such as calcitonin, Chromogranin A (CgA) [5], and Achaete Scute Complex-Like 1 (ASCL1), also known as human ASH1 (Achaete Scute Homolog-1) [6,7]. ASCL1 is involved in C-cell expansion and is critical for neuroendocrine cell differentiation and MTC tumor growth.…”

Section: Introductionmentioning

confidence: 99%

“…MTC is the end result of an oncogenic activation of protein cascades in the NE cells of the thyroid gland [3]. Hence, understanding the molecular pathways that control C-cell proliferation is vital for developing novel therapies for patients with advanced MTC [4].MTC cells produce several hormones and NE markers such as calcitonin, Chromogranin A (CgA) [5], and Achaete Scute Complex-Like 1 (ASCL1), also known as human ASH1 (Achaete Scute Homolog-1) [6,7]. ASCL1 is involved in C-cell expansion and is critical for neuroendocrine cell differentiation and MTC tumor growth.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Activation of Mek Alters Morphology and Neuroendocrine Phenotype in Medullary Thyroid Cancer Cell

Alhefdhi¹,

Kunnimalaiyaan²,

Chen³

2016

EMIJ

View full text Add to dashboard Cite

SynopsisActivation of the MEK pathway in MTC cells elicited similar effects of raf-1 pathway activation, resulting in cell growth suppression. Therefore, MEK may serve as a molecular target and a therapeutic strategy to treat patients with MTC. IntroductionMedullary thyroid cancer (MTC) is a neuroendocrine (NE) tumor that arises from the parafollicular cells (C-cells) of the thyroid gland [1]. MTC accounts for 5-10% of all thyroid malignancies and responds poorly to chemotherapy [2]. Thus, the only curative option for MTC is surgical resection [1]. MTC is the end result of an oncogenic activation of protein cascades in the NE cells of the thyroid gland [3]. Hence, understanding the molecular pathways that control C-cell proliferation is vital for developing novel therapies for patients with advanced MTC [4].MTC cells produce several hormones and NE markers such as calcitonin, Chromogranin A (CgA) [5], and Achaete Scute Complex-Like 1 (ASCL1), also known as human ASH1 (Achaete Scute Homolog-1) [6,7]. ASCL1 is involved in C-cell expansion and is critical for neuroendocrine cell differentiation and MTC tumor growth. The importance of ASCL1 for C-cell growth was observed in transgenic mice with an ASCL1 knockout gene, which failed to develop thyroid C-cells [1]. Moreover, ASCL1 has been found to be involved in the development of other NE cells such as pulmonary endocrine cells and chromaffin cells [1]. AbstractBackground: Medullary thyroid cancer (MTC) is a neuroendocrine (NE) tumor of the thyroid C cells. Surgery is the only curative therapy. Activation of raf-1 in MTC cells resulted in growth suppression and NE marker reduction. However, the exact mediator of this effect is not clearly understood. We hypothesize that MEK, a key downstream target of raf-1 pathway, may be involved in the effect seen with raf-1 activation in MTC. To determine the role of MEK, we established a doxycyclineinducible MEK in MTC TT cells and assessed the effects on morphology and NE phenotype.Methods: Doxycycline-inducible TT-MEK cells were created by stable transfection of a pRevTRE-MEK plasmid in TT cells expressing a Tet responsive protein. TT-MEK cells were treated with 0-1.0μg/ml of doxycycline for four days. The level of total and active MEK expression was determined by western blot analysis using MEK and phosphorylated ERK1/2 antibodies. In addition, the lysates were analyzed for levels of the NE markers achaete-scute complex like 1 (ASCL1) and Chromogranin A (CgA). Morphology of the treated and control cells was observed under a light microscope.Results: Treatment of TT-MEK cells with doxycycline led to an induction of MEK protein, which is associated with activation of ERK1/2 in a dose-dependent manner. Importantly, the levels of NE markers were reduced by increasing MEK activation. Similar to RAF-1 activation, there was a striking morphological change with activation of MEK1/2, with a decrease in horizontal spread of each cell resulting in rounder, larger cells. Conclusion:We demonstrate, for the first time, that the over exp...

show abstract

“…These agents target various tyrosine kinases including MET, RET, and VEGFR-2 (190)(191)(192)(193)(194)(195).…”

Section: Prognosis and Risk Stratification Based On Genetic Testingmentioning

confidence: 99%

C-cells and their associated lesions and conditions: a pathologists perspective

Baloch¹,

LiVolsi²

2015

TJPATH

View full text Add to dashboard Cite

This paper updates the histopathology and cytopathology of thyroid tumors and proliferations derived from the para-follicular or C cells. Beginning with an historical over view, including the recognition of medullary thyroid carcinoma as a distinct histologic entity, its relationship to the hormone, calcitonin, (which was discovered in the same decade) and to thyroid C cells, medullary carcinoma and its variants are reviewed. The molecular biology of the tumors and the associated mutations in the tumors (somatic mutations) are discussed. Additionally the genetic features (germline mutations) including familial clusters and associations with other endocrine and neuroendocrine lesions are reviewed. Screening for the tumor and its precursors is included with a review of the latest American Thyroid Association guidelines for treatment as well as timing and approach to surgery. Tabular data of specific germline mutations and their relationships to tumor virulence, and prognosis are illustrated. Precursor and early C cell lesions such as C-cell hyperplasia and micro-medullary carcinoma are discussed. Difficulties and controversies in the definition of C-cell proliferations which are neoplastic and those which are "reactive" are reviewed. The entity of medullary microcarcinoma or medullary microcarcinoma is illustrated and the distinction between C cell nodules and microcarcinoma is defined using the latest available criteria. Finally the latest approved chemotherapeutic agents and their results in metastatic medullary thyroid carcinoma are included.

show abstract

Medullary Thyroid Cancer: A Promising Model for Targeted Therapy

Cited by 19 publications

References 133 publications

A rare case of juvenile hypertension: coexistence of type 2 multiple endocrine neoplasia -related bilateral pheochromocytoma and reninoma in a young patient with ACE gene polymorphism

A rare case of juvenile hypertension: coexistence of type 2 multiple endocrine neoplasia -related bilateral pheochromocytoma and reninoma in a young patient with ACE gene polymorphism

Activation of Mek Alters Morphology and Neuroendocrine Phenotype in Medullary Thyroid Cancer Cell

C-cells and their associated lesions and conditions: a pathologists perspective

Contact Info

Product

Resources

About