Hypoxia-Inducible Factor (HIF) and Mammalian Target of Rapamycin (mTOR) Pathway Markers in Ovarian Clear Cell Carcinoma
G Han, RA Soslow, VE Reuter, E Oliva, CB Gilks, H Asad, SK Tickoo. Memorial Sloan-Kettering Cancer Center, New York; Massachusetts General Hospital, Boston; Vancouver General Hospital, Vancouver, Canada
Background: Studies report that ovarian clear cell carcinoma (OCC) have gene expression profiles similar to clear cell renal cell carcinoma (CRCC). Targeted therapies against HIF and mTOR pathway molecules have recently shown to be effective in metastatic CRCC. We studied the expression of HIF and mTOR pathway markers in OCC to investigate the justification for potential utility of similar therapies.
Design: Immunohistochemistry using antibodies against HIF pathway markers HIF-1α, vascular endothelial growth factor-receptor 2 (VEGF R2), carbonic anhydrase IX (CA IX), and activated mTOR pathway markers phospho-S6 (p-S6) and phospho-4E biding protein 1 (p-4E BP1) were performed on tissue microarrays consisting of OCC (n=64). Positivity was graded as 0-3 (0 = 0-5%, 1 = 6-25%, 2 = 26-50%, 3 >50% tumor cells positive) for p-S6 (cytoplasmic), p-4E BP1 (nuclear and/or cytoplasmic), HIF-1α (nuclear), and CA IX (membranous). VEGF R2 was graded on the intensity of cytoplasmic staining in tumor vessels (0 = absent, 1 = weak, 2 = intense).
Results: The percentage of cases showing ≥2 staining for HIF-1α, VEGF R2, p-S6, and p-4E BP1 are comparable to those previously reported in CRCC (Table 1). Similar to CRCC, VEGF R2 positivity was observed in OCC tumor vessels, not in tumor cells. CA IX positivity was observed only in a small number of cases. Spearman's correlation coefficient analyses indicated significant relationships (p <0.05) between the expression of HIF1α and VEGF R2 (rho = 0.628), p-S6 and p-4E BP1 (rho = 0.779), HIF-1α and p-4E BP1 (rho = 0.354), VEGF R2 and p-4E BP1 (rho = 0.332), and VEGF R2 and p-S6 (rho = 0.266). There was no significant correlation of expression between HIF-1α and p-S6, or CA IX and any other marker.
|Grade||HIF-1α/%||VEGF R2/%||CA IX/%||p-S6/%||p-4E BP1/%|