Overexpression and activation of EGFR and VEGFR2 in medullary thyroid carcinomas is related to metastasis
Por:
Rodriguez-Antona, C, Pallares, J, Montero-Conde, C, Inglada-Perez, L, Castelblanco, E, Landa, I, Leskela, S, Leandro-Garcia, LJ, Lopez-Jimenez, E, Leton, R, Cascon, A, Lerma, E, Martin, MC, Carralero, MC, Mauricio, D, Cigudosa, JC, Matias-Guiu, X, Robledo, M
Publicada:
1 mar 2010
Resumen:
Therapeutic options for patients with metastatic medullary thyroid carcinoma (MTC) are limited due to lack of effective treatments. Thus, there is a need to thoroughly characterize the pathways of molecular pathogenesis and to identify potential targets for therapy in MTC. Since epidermal growth factor receptor (EGFR) seems to play a crucial role for RET activation, a key feature of MTCs, and several promising EGFR/vascular endothelial growth factor receptor 2 (VEGFR2)-targeted drugs have been developed, the present study was designed to investigate whether these proteins are altered in MTCs. We used a well-characterized series of 153 MTCs to evaluate EGFR activation by sequencing and FISH analysis, and to perform EGFR and VEGFR2 immunohistochemistry. EGFR tyrosine kinase domain mutations were not a feature of MTCs; however, EGFR polysomy and a strong EGFR expression were detected in 15 and 13% of the tumors respectively. Interestingly, EGFR was significantly overexpressed in metastases compared with primary tumors (35 vs 9%, P=0.002). We also studied whether specific RET mutations were associated with EGFR status, and found a decrease in EGFR polysomies (P=0.006) and a tendency towards lower EGFR expression for the most aggressive RET mutations (918, 883). Concerning VEGFR2, metastasis showed a higher expression than primary tumors (P=2.8 x 10(-8)). In this first study investigating the relationship between EGFR, RET, and VEGFR2 in a large MTC series, we found an activation of EGFR and VEGFR2 in metastasis, using both independent and matched primary/metastasis samples. This suggests that some MTC patients may benefit from existing anti-EGFR/VEFGR2 therapies, although additional preclinical and clinical evidence is needed. Endocrine-Related Cancer (2010) 17 7-16
Filiaciones:
Rodriguez-Antona, C:
Spanish Natl Canc Ctr CNIO, Hereditary Endocrine Canc Grp, Human Canc Genet Programme, Madrid 28029, Spain
ISCIII Ctr Biomed Res Rare Dis CIBERER, Madrid, Spain
Pallares, J:
Univ Lleida, IRBLLEIDA, Hosp Univ Arnau Vilanova, Dept Pathol & Mol Genet, Lleida, Spain
Montero-Conde, C:
Spanish Natl Canc Ctr CNIO, Hereditary Endocrine Canc Grp, Human Canc Genet Programme, Madrid 28029, Spain
Inglada-Perez, L:
Spanish Natl Canc Ctr CNIO, Hereditary Endocrine Canc Grp, Human Canc Genet Programme, Madrid 28029, Spain
ISCIII Ctr Biomed Res Rare Dis CIBERER, Madrid, Spain
Castelblanco, E:
Univ Lleida, IRBLLEIDA, Hosp Univ Arnau Vilanova, Dept Pathol & Mol Genet, Lleida, Spain
Univ Lleida, Hosp Univ Amau Vilanova, Dept Endocrinol, IRBLLEIDA, Lleida, Spain
Landa, I:
Spanish Natl Canc Ctr CNIO, Hereditary Endocrine Canc Grp, Human Canc Genet Programme, Madrid 28029, Spain
Leskela, S:
Spanish Natl Canc Ctr CNIO, Hereditary Endocrine Canc Grp, Human Canc Genet Programme, Madrid 28029, Spain
Leandro-Garcia, LJ:
Spanish Natl Canc Ctr CNIO, Hereditary Endocrine Canc Grp, Human Canc Genet Programme, Madrid 28029, Spain
Lopez-Jimenez, E:
Spanish Natl Canc Ctr CNIO, Hereditary Endocrine Canc Grp, Human Canc Genet Programme, Madrid 28029, Spain
Leton, R:
Spanish Natl Canc Ctr CNIO, Hereditary Endocrine Canc Grp, Human Canc Genet Programme, Madrid 28029, Spain
Cascon, A:
Spanish Natl Canc Ctr CNIO, Hereditary Endocrine Canc Grp, Human Canc Genet Programme, Madrid 28029, Spain
ISCIII Ctr Biomed Res Rare Dis CIBERER, Madrid, Spain
Lerma, E:
Santa Creu & St Pau Hosp, Pathol Serv, Barcelona, Spain
Martin, MC:
Spanish Natl Canc Ctr CNIO, Mol Cytogenet Grp, Human Canc Genet Programme, Madrid 28029, Spain
Carralero, MC:
Spanish Natl Canc Ctr CNIO, Mol Cytogenet Grp, Human Canc Genet Programme, Madrid 28029, Spain
Mauricio, D:
Univ Lleida, Hosp Univ Amau Vilanova, Dept Endocrinol, IRBLLEIDA, Lleida, Spain
Cigudosa, JC:
ISCIII Ctr Biomed Res Rare Dis CIBERER, Madrid, Spain
Spanish Natl Canc Ctr CNIO, Mol Cytogenet Grp, Human Canc Genet Programme, Madrid 28029, Spain
Matias-Guiu, X:
Univ Lleida, IRBLLEIDA, Hosp Univ Arnau Vilanova, Dept Pathol & Mol Genet, Lleida, Spain
Robledo, M:
Spanish Natl Canc Ctr CNIO, Hereditary Endocrine Canc Grp, Human Canc Genet Programme, Madrid 28029, Spain
ISCIII Ctr Biomed Res Rare Dis CIBERER, Madrid, Spain
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