Primary Benign Parathyroid Proliferative Lesions: Growth Factor Pathways and Stromal Interaction Responsible of the Growth Patterns
Ringo Lam, Alfredo Blanes, Salvador J Diaz-Cano. King's College Hospital, London, United Kingdom; University of Malaga School of Medicine, Malaga, Spain
Background: The distinction of primary benign parathyroid proliferative lesions is a challenge with a difficult pathological answer, for which the contributions of cell growth-proliferation, TGFβ and calcium-protein kinase C pathways in this biological process remain unknown.
Design: We selected primary benign parathyroid proliferative lesions with irregularly hyperplastic parenchyma (PTNH, 27) and atrophic peritumoral parenchyma surrounding single (adenomas, PTA, 64) or multiple (MPTA, 16) autonomous lesions (WHO criteria) to analyze cell growth-proliferation (MKI67, AKT1, TERT, CAV2, EGFR, ERBB3, FGFR2, FGFBP1, FOXC2, IGFBP4, MST1R, PDGFRB,TIMP1), TGFβ (TGFB1, TGFB2, TGFB3, SMAD1, SMAD2, SMAD3, SMAD4, CDKN1A, CDKN1B, CDKN2A, CDKN2B) and calcium-protein kinase C (CSF2, FOS, IL2, JUN, MYC, ODC1, PRKCA, PRKCE, TFRC) pathways in a low-density selective cDNA array. 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 arrays noncompetitively, cross-validating the results (expression factor>2, significance<0.01). Variables were studied regarding histological diagnosis. Significant variables were then tested on tissue sections by in-situ techniques.
Results: PTA and MPTA revealed significant upregulation (expression factor>2, significance<0.01) of TGFB1, SMAD2, and SMAD4 when compared with PTNH, whereas MPTA differentially overexpressed FN1 and FOS. PTNH showed significant overexpression of CDKN1B, FOXC2, IGFBP4, MST1R, and underexpression of FGFR2 when compared with PTA and MPTA. Remaining genes showed no significant differences.
Conclusions: PTNH growth depends on the balanced interaction with stroma and the insulin-like growth factor pathway (IGFBP4, FGFR2 and MST1R), whereas the autonomous proliferation of adenomas is driven by TGFB pathway. The presence of multiple adenomas is related with abnormal cell adhesion and migration processes (FN1).
Tuesday, March 20, 2012 1:00 PM
Poster Session IV # 38, Tuesday Afternoon