New Continuous Cell-Line From Human Medullary-Thyroid Carcinoma - Sinj - Phenotypic Analysis and Invivo Carcinogenesis

Pfragner, Roswitha; Wirnsberger, Gerhard; Behmel, Annemarie; Wolf, G.; Passath, A; Ingoliç, Elisabeth; Adamiker, D; Schauenstein, Konrad

doi:10.3892/ijo.2.5.831

Cited by 9 publications

(6 citation statements)

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“…With these positive results in hand, MTC-SK and SIN-J were selected as representative for further analysis. MTC-SK cells were derived from a solid sporadic MTC tumor while SIN-J cells originated from metastatic sporadic MTC (Pfragner et al, 1990; Pfragner et al, 1993). Both have been characterized for their close similarity to MTC tumor cells and express appreciable levels of Cdk5, p35, and p25.…”

Section: Resultsmentioning

confidence: 99%

The Role of Cdk5 in Neuroendocrine Thyroid Cancer

et al. 2013

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SUMMARY Medullary thyroid carcinoma (MTC) is a neuroendocrine cancer that originates from calcitonin-secreting parafollicular cells, or C cells. We found that Cdk5 and its cofactors, p35 and p25, are highly expressed in human MTC and that Cdk5 activity promotes MTC proliferation. A conditional MTC mouse model was generated and corroborated the role of aberrant Cdk5 activation in MTC. C cell-specific overexpression of p25 caused rapid C cell hyperplasia leading to lethal MTC, which was arrested by repressing p25 overexpression. A comparative phosphoproteomic screen between proliferating and arrested MTC identified the retinoblastoma protein (Rb) as a crucial Cdk5 downstream target. Prevention of Rb phosphorylation at Ser807/811 attenuated MTC proliferation. These findings implicate Cdk5 signaling via Rb as critical to MTC tumorigenesis and progression.

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Section: Resultsmentioning

confidence: 99%

The Role of Cdk5 in Neuroendocrine Thyroid Cancer

et al. 2013

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“…comm. ), SHER‐I,11, 12, 14–16 SINJ12, 17 and OEE‐III18 (Table 1) were analyzed by Multiplex‐FISH and array‐CGH. The cell lines were checked for MTC markers when they were established.…”

Section: Methodsmentioning

confidence: 99%

High‐resolution analysis of alterations in medullary thyroid carcinoma genomes

Flicker

Ulz

Höger

et al. 2011

Intl Journal of Cancer

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Hereditary and sporadic medullary thyroid carcinoma (MTC) are closely associated with RET proto-oncogene mutations. However, the role of additional changes in the tumor genomes remains unclear. Our objective was the identification of chromosomal regions involved in MTC tumorigenesis and to assess their significance by using MTC-derived cell lines. We used array-CGH (comparative genomic hybridization) to map chromosomal imbalances in 52 primary tumors and ten metastases. Eleven tumors (11/52, 21%) were hereditary and 41 (41/52, 79%) were sporadic. Among the latter, 15 tumors (15/41, 37%) harbored RET mutations. Furthermore, we characterized five MTC cell lines in detail and evaluated the tumorigenicity by severe combined immunodeficiency (SCID)-mouse experiments. Most MTCs had only few copy number changes, and losses of chromosomes 1p, 4q, 19p and 22q were observed most frequently. The number of chromosomal aberrations increased in metastases. Twenty-three percent (12/52) of the primary tumors did not even show any chromosomal gains and losses. We injected three cell lines (two of these were without chromosomal changes and pathogenic RET mutations) into immune deficient SCID mice, and in each case, we observed rapid tumor growth at the injection sites. Our data suggest that MTCs-in contrast to most other tumor entities-do not acquire a multitude of genomic imbalances. SCID mouse experiments performed with chromosomally normal cell lines and without RET mutations suggest that presently unknown submicroscopic genomic changes are sufficient in MTC tumorigenesis.Human medullary thyroid carcinoma (MTC) is a calcitoninproducing tumor originating from the parafollicular C-cells. It constitutes about 5-8% of all thyroid cancers and may occur sporadic (70-80% of cases) or hereditary (20-30%). 1Hereditary MTC is inherited in an autosomal-dominant pattern, either as familial MTC (FMTC) without other endocrinopathies or as part of multiple endocrine neoplasia syndrome type 2A (MEN-2A), or in multiple endocrine neoplasia type 2B (MEN-2B). 2As the disease may develop over many years without clinical signs, lymph node metastasis are documented in more than 50% of patients, and distant metastasis are found in at least in one quarter of patients at the time of diagnosis. With 5-and 10-year survival reported at 86% and 78%, respectively, prognosis is less favorable than for follicular cellderived carcinomas. Patients with distant metastases have only a 35% survival after 5 years. MTC, both in patients and in preclinical models, is resistant to chemotherapy and radiation therapy. Surgical removal of all malignant tissue is the only potentially curative treatment in localized disease.1 Management guidelines for treatment of MTC were recently published by the American Thyroid Association. 3MTC is closely associated with mutations in the REarranged during Transfection (RET) proto-oncogene in chromosome 10q11.2. The hereditary variants MEN-2/FMTC are associated with activating germline point mutations in the RET proto-oncogene and near...

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“…Directly after transportation, tissue was treated for 20 min with PBS containing 1000 IU penicillin/ml and 1000 g streptomycin/ml. Previously described techniques for primary and continuous cultivation of MTC were applied (8,9). Briefly, tissue was dissociated mechanically, and erythrocyte lysis buffer was applied for 15 min.…”

Section: Cell Cultivationmentioning

confidence: 99%

Cytotoxic Activity of Camptothecin and Paclitaxel in Newly Established Continuous Human Medullary Thyroid Carcinoma Cell Lines

Kaczirek

Schindl

Weinhäusel

et al. 2004

The Journal of Clinical Endocrinology &Amp; Metabolism

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At the time of diagnosis, more than one quarter of patients with medullary thyroid carcinoma (MTC) has distant metastases. Only few of these patients can be cured by surgery. Standard chemotherapy is characterized by low response rates and short response time. The establishment of eight human MTC cell lines provides a new basis for in vitro investigation of cytotoxic drugs. Camptothecin (CPT) and paclitaxel, which never have been investigated in the treatment of MTC, were tested for their cytotoxic profile in comparison with the clinically ineffective dacarbazine. Eight MTC cell lines were established from seven patients with MTC. IC(50) values were calculated from dose-response relationships using cell counts and a formazan dye assay (WST-1). IC(50) values were 3.5 +/- 1.2 nmol/liter for CPT and 8.2 +/- 1.9 nmol/liter for paclitaxel. Dacarbazine showed no reduction of cell proliferation at concentrations 10-fold higher than clinically achievable. Given peak plasma concentrations of 65 +/- 20 nmol/liter for CPT and 1 micro mol/liter for paclitaxel, these promising in vitro results provide a basis for the performance of clinical trials in patients with advanced MTC.

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New Continuous Cell-Line From Human Medullary-Thyroid Carcinoma - Sinj - Phenotypic Analysis and Invivo Carcinogenesis

Cited by 9 publications

References 0 publications

The Role of Cdk5 in Neuroendocrine Thyroid Cancer

The Role of Cdk5 in Neuroendocrine Thyroid Cancer

High‐resolution analysis of alterations in medullary thyroid carcinoma genomes

Cytotoxic Activity of Camptothecin and Paclitaxel in Newly Established Continuous Human Medullary Thyroid Carcinoma Cell Lines

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