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A Perren, S Schmid, T Locher, P Saremaslani, C Bonvin, P U Heitz and P Komminoth

The tumorigenesis of sporadic endocrine tumors is still not fully understood. Activating point mutations of the serine/threonine kinase gene BRAF located on 7q34 are found in a wide range of malignancies, with the highest frequency (66%) occurring in malignant melanomas. Melanomas are tumors of neural-crest-derived cells as are medullary thyroid carcinomas, pheochromocytomas and paragangliomas. BRAF has not been examined in endocrine tumors of the diffuse neuroendocrine system or of neural-crest-derived cells.

We examined 130 endocrine tumors of the pancreas, parathyroid gland, adrenal medulla, paraganglia, lung and gastrointestinal tract as well as follicular and c-cell-derived thyroid tumors. We found a high rate of V559E mutations in papillary thyroid carcinomas (47%), one V599E mutation in a well-differentiated gastric endocrine carcinoma (malignant carcinoid), but no activating BRAF mutations in all other endocrine tumors examined. These results point towards different pathways in tumorigenesis of endocrine tumors of various localizations and only rare involvement of the MAP kinase (MAPK) pathway in a subset of malignant neuroendocrine tumors.

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S Latteyer, S Christoph, S Theurer, G S Hönes, K W Schmid, D Führer and L C Moeller

Thyroid hormones are important for physiology and homeostasis. In addition to nuclear thyroid hormone receptors, the plasma membrane protein integrin αvβ3 has been recognized as a receptor for both thyroxine (T4) and triiodothyronine (T3). Here, we studied whether thyroid hormone promotes growth of murine lung cancer via αvβ3 in vivo. Murine Lewis lung carcinoma cells (3LL), stably transfected with luciferase, were injected into mouse lungs. Tumor growth in untreated mice was compared to hypothyroid mice and hypothyroid mice treated with T3 or T4 with or without the αvβ3 inhibitor 3,5,3′,5′-tetraiodothyroacetic acid (Tetrac). Tumor progression was determined by serial in vivo imaging of bioluminescence emitted from the tumor. Tumor weight was recorded at the end of the experiment. Neoangiogenesis was determined by immunohistochemistry for CD31. Tumor growth was reduced in hypothyroidism and increased by T4 treatment. Strikingly, only T4 but not T3 treatment promoted tumor growth. This T4 effect was abrogated by the αvβ3 inhibitor Tetrac. Tumor weight and neoangiogenesis were also significantly increased only in T4-treated mice. The T4 effect on tumor weight and neoangiogenesis was abolished by Tetrac. In vitro, T4 did not stimulate 3LL cell proliferation or signaling pathway activation. We conclude that T4 promotes lung cancer growth in this orthotopic mouse model. The tumor-promoting effect is mediated via the plasma membrane integrin αvβ3 and increased neoangiogenesis rather than direct stimulation of 3LL cells. These data suggest that such effects of levothyroxine may need to be considered in cancer patients on T4 substitution.

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M Montani, A M Schmitt, S Schmid, T Locher, P Saremaslani, P U Heitz, P Komminoth and A Perren

Germline mutations of the three succinate dehydrogenase subunits SDHB, SDHC and SDHD have recently been associated with familial pheochromocytoma and paraganglioma. Several reasons make these genes candidate tumor suppressor genes for medullary thyroid carcinoma (MTC): (1) SDHB lies on chromosome 1p, the region known to be deleted most frequently in MTC, (2) MTCs develop from neural crest-derived cells, as do pheochromocytomas and paragangliomas and (3) patients with germline mutations of the Ret-protooncogene develop MTCs as well as pheochromocytomas, indicating a relationship of these tumors on a genetic level. Therefore, we attempted to determine whether the tumor suppressor genes SDHB, SDHC and SDHD are involved in sporadic and familial MTC. Somatic mutations of the SDH subunits were absent in all 35 investigated MTCs. Loss of heterozygosity was found in 27% (SDHB) and 4% (SDHD) respectively. While the frequency of non-coding, intronic polymorphisms did not differ in MTC patients compared with a control population, an accumulation of amino-acid coding polymorphisms (S163P in SDHB as well as G12S and H50R in SDHD) was found among MTC patients especially patients with familial tumors, suggesting a functional connection of coding SDH polymorphisms to activating Ret mutations.

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A M Schmitt, S Schmid, T Rudolph, M Anlauf, C Prinz, G Klöppel, H Moch, P U Heitz, P Komminoth and A Perren

A small subset of familial pancreatic endocrine tumors (PET) arises in patients with von Hippel–Lindau syndrome and these tumors may have an adverse outcome compared to other familial PET. Sporadic PET rarely harbors somatic VHL mutations, but the chromosomal location of the VHL gene is frequently deleted in sporadic PET. A subset of sporadic PET shows active hypoxia signals on mRNA and protein level. To identify the frequency of functionally relevant VHL inactivation in sporadic PET and to examine a possible prognostic significance we correlated epigenetic and genetic VHL alterations with hypoxia signals. VHL mutations were absent in all 37 PETs examined. In 2 out of 35 informative PET (6%) methylation of the VHL promoter region was detected and VHL deletion by fluorescence in situ hybridization was found in 14 out of 79 PET (18%). Hypoxia inducible factor 1α (HIF1-α), carbonic anhydrase 9 (CA-9), and glucose transporter 1 (GLUT-1) protein was expressed in 19, 27, and 30% of the 152 PETs examined. Protein expression of the HIF1-α downstream target CA-9 correlated significantly with the expression of CA-9 RNA (P<0.001), VHL RNA (P<0.05), and VHL deletion (P<0.001) as well as with HIF1-α (P<0.005) and GLUT-1 immunohistochemistry (P<0.001). These PET with VHL alterations and signs of hypoxia signalling were characterized by a significantly shortened disease-free survival. We conclude that VHL gene impairment by promoter methylation and VHL deletion in nearly 25% of PET leads to the activation of the HIF-pathway. Our data suggest that VHL inactivation and consecutive hypoxia signals may be a mechanism for the development of sporadic PET with an adverse outcome.

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Y M H Jonkers, S M H Claessen, A Perren, S Schmid, P Komminoth, A A Verhofstad, L J Hofland, R R de Krijger, P J Slootweg, F C S Ramaekers and E-J M Speel

Endocrine pancreatic tumors (EPTs) comprise a highly heterogeneous group of tumors with different clinical behavior and genetic makeup. Insulinomas represent the predominant syndromic subtype of EPTs. The metastatic potential of insulinomas can frequently not be predicted using histopathological criteria, and also molecular markers indicating malignant progression are unreliable because of the small number of cases per subtype studied so far. For the identification of reliable indicators of metastatic disease, we investigated 62 sporadic insulinomas (44 benign and 18 tumors with metastases) by means of comparative genomic hybridization (CGH). In addition, the role of MEN1 (multiple endocrine neoplasia type 1) gene mutations was determined to assess specific chromosomal alterations associated with dysfunction of this endocrine tumor-related tumor suppressor gene. Only one case with a somatic MEN1 mutation was identified (1527del7bp), indicating that the MEN1 gene plays a minor pathogenic role in sporadic insulinomas. CGH analysis revealed that the total number of aberrations per tumor differs strongly between the benign and the malignant group (4.2 vs 14.1; P<0.0001). Furthermore, chromosome 9q gain was found to be the most frequent aberration in both benign and malignant insulinomas, whereas chromosome 6q losses and 12q, 14q and 17pq gains are strongly associated with metastatic disease. Our study shows that chromosomal instability, as defined by ≥5 gains together with ≥5 losses, or total number of gains and losses ≥8, rather than parameters such as tumor size and proliferation index, is the most powerful indicator for the development of metastatic disease in patients with sporadic insulinoma.