Cell Survival in MEN2 Thyroid and Adrenal Medullary Neoplasms: Role of PI3 Kinase/AKT Pathways.
Tania Ioannidis, Ringo Lam, Lok Lam, Alfredo Blanes, Salvador J Diaz-Cano. King's College Hospital, London, United Kingdom; University of Malaga School of Medicine, Spain
Background: The cell survival in tumors is heterogeneous and includes PI3 kinase/AKT, JAK/SRC, and NFkB pathways. The contributions of these pathways in MEN related tumors and the differential expression in pheochromocytomas and medullary thyroid carcinomas remain unknown.
Design: We selected small (1-2cm) familial (MEN2A and MEN2B) pheochromocytomas (PCC, 29) and medullary thyroid carcinomas (MTC, 35), diagnosed and classified according to WHO criteria. We analyzed in a low-density selective cDNA array (LD-SelGEA): BCL2, CCND1, FN1, F13A, JUN, MMP7 (matrilysin), MYC (PI3 Kinase / AKT Pathway): BCL2, BCL2L1 (Jak / Src Pathway): BCL2A1 (Bfl-1/A1), BIRC2 (c-IAP2), BIRC3 (c-IAP1), NAIP (BIRC1), TERT (NFκB Pathway); and CXCL12, CXCR4 (basic regulators of stem cell phenotype). Total RNA was extracted, cleaned from normal and neoplastic tissues (RNeasy columns), first-strand cDNA synthesized using T7-(dT24)-oligomer and used as template for cRNA synthesis. The cRNA was fragmented, Cy3-/Cy5-labeled, and hybridized to LD-SelGEA noncompetitively, cross-validating the results (expression factor>2, significance<0.01). Variables were studied regarding the histological diagnosis and the familial syndrome (MEN2A/MEN2B). Significant variables were then tested on tissue sections by immunohistochemistry.
Results: Statistical significant differences (expression factor>2 at least) were observed for CCND1 (cyclin D1 – up-regulated in MTC), FN1 (fibronectin – up-regulated in MTC), CXCL12/CXCR4 (up-regulated in MTC), and F13A (coagulation factor XIII A – up-regulated in PCC). All other genes showed no statistically significant differences by histological subtypes and no significant differences were observed for each diagnostic group by the DNA genotype (MEN2A vs. MEN2B).
Conclusions: Cell survival is differentially promoted in MEN2 thyroid and adrenal medullary neoplasm: (a) MTC cell survival depends on the PI3 kinase/AKT pathways (cyclin D1, fibronectin) and basic regulators of stem cell phenotype (CXCL12/CXCR4). (b) PCC tumor cell promotion is mainly dependent on the vascular supply and the role coagulation factor XIII A subunit. The cell survival mechanism is independent of the familial genotype.
Tuesday, March 1, 2011 1:00 PM
Poster Session IV # 46, Tuesday Afternoon