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Activation of the mTOR Pathway in Primary Medullary Thyroid Carcinoma and Lymph Node Metastases.
MedLine Citation:
PMID:  22753663     Owner:  NLM     Status:  In-Data-Review    
PURPOSE: Understanding the molecular pathogenesis of medullary thyroid carcinoma (MTC) is prerequisite to the design of targeted therapies for patients with advanced disease.
EXPERIMENTAL DESIGN: We studied by immunohistochemistry the phosphorylation status of proteins of the RAS/MEK/ERK and PI3K/AKT/mTOR pathways in 53 MTC tissues (18 hereditary, 35 sporadic), including 51 primary MTCs and 2 cases with only lymph node metastases (LNM). We also studied 21 autologous LNMs, matched to 21 primary MTCs. Staining was graded on a 0 to 4 scale (S score) based on the percentage of positive cells. We also studied the functional relevance of the mTOR pathway by measuring cell viability, motility, and tumorigenicity upon mTOR chemical blockade.
RESULTS: Phosphorylation of ribosomal protein S6 (pS6), a downstream target of mTOR, was evident (S ≥ 1) in 49 (96%) of 51 primary MTC samples. This was associated with activation of AKT (phospho-Ser473, S > 1) in 79% of cases studied. Activation of pS6 was also observed (S ≥ 1) in 7 (70%) of 10 hereditary C-cell hyperplasia specimens, possibly representing an early stage of C-cell transformation. It is noteworthy that 22 (96%) of 23 LNMs had a high pS6 positivity (S ≥ 3), which was increased compared with autologous matched primary MTCs (P = 0.024). Chemical mTOR blockade blunted viability (P < 0.01), motility (P < 0.01), and tumorigenicity (P < 0.01) of human MTC cells.
CONCLUSION: The AKT/mTOR pathway is activated in MTC, particularly, in LNMs. This pathway sustains malignant features of MTC cell models. These findings suggest that targeting mTOR might be efficacious in patients with advanced MTC. Clin Cancer Res; 18(13); 3532-40. ©2012 AACR.
Anna Tamburrino; Alfredo A Molinolo; Paolo Salerno; Rebecca D Chernock; Mark Raffeld; Liqiang Xi; J Silvio Gutkind; Jeffrey F Moley; Samuel A Wells; Massimo Santoro
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Clinical cancer research : an official journal of the American Association for Cancer Research     Volume:  18     ISSN:  1078-0432     ISO Abbreviation:  Clin. Cancer Res.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-07-03     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9502500     Medline TA:  Clin Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3532-40     Citation Subset:  IM    
Authors' Affiliations: Center for Cancer Research, Laboratory of Pathology, National Cancer Institute; National Institute of Dental and Craniofacial Research, Bethesda, Maryland; Washington University School of Medicine, St. Louis, Missouri; and Dipartimento di Biologia e Patologia Cellulare e Molecolare, Universitá di Napoli Federico II, Napoli, Italy.
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