mTOR and HIF-1 Pathway Inhibitors: Exploring the Potential in Clear Cell Carcinoma Variant of Ovary and Endometrium, Comparing with That of Kidney
Hayan Jaratli, Tarek Jazaerly, Kinda Hayek, Sudeshna Bandyopadhyay, Tamar Giorgadze, Rouba Ali-Fehmi. Wayne State University, Detroit, MI
Background: The inhibitors of mammalian target of rapamycin (mTOR) and hypoxia-inducible factor-1α (HIF-1α) pathway molecules have been approved to treat advanced clear cell renal cell carcinoma (RCC). Ovarian clear cell carcinoma (OCC) and endometrial clear cell carcinoma (ECC) exhibit similar morphology and have been reported to share overlapping gene expression profiles with clear cell RCC. Our objective was to study the expression of HIF and mTOR pathway markers in OCC and ECC, and to compare the patterns to those present in clear cell RCC as a rationale for investigating potentially similar treatment approaches for OCC and ECC.
Design: Immunohistochemical staining using antibodies against mTOR pathway markers mTOR, PTEN, phospho-S (p-S6), and phosphor-4E binding protein 1(p-4E BP1); and HIF-1 pathway marker Glucose transporter-1 (Glut1) were performed on tissue microarrays constructed from 39 clear cell RCC, 33 OCC, and 29 ECC. Nuclear and/or cytoplasmic expression was evaluated for p-S6, p-4E BP1, Glut1 and P27 markers based on the intensity of staining (graded 0-3) and the percentage of positive cells. PTEN immunostain was assessed as expressed or not. Fisher's exact test with two tails was used to compare expression levels of markers between clear cell RCC and OCC, and between clear cell RCC and ECC. The level of significance was assigned at P <0.05.
Results: Comparing clear cell RCC to OCC and ECC, a high expression of p-4E BP1 in all three tumor system was noted. However, OCC and ECC revealed a significantly higher expression of mTOR (P <0.0001 for OCC, 0.001 for ECC), p-S6 (P =0.04 for OCC, 0.0008 for ECC), and Glut1 (P =0.006 for OCC, 0.0006 for ECC) than clear cell RCC, while loss of PTEN expression was significantly higher in clear cell RCC than in OCC and ECC (P =0.0006 for OCC, 0.0008 for ECC).
|clear cell RCC||OCC||ECC|
|p-4E BP1||71% (n 38)||76% (n 17)||79 % (n 28)|
|p-S6||54% (n 37)||78% (n 32)||93% (n 27)|
|PTEN (loss of expression)||82% (n 39)||42% (n 33)||37.5% (n 24)|
|mTOR||28% (n39)||78% (n32)||70% (n27)|
|Glut1||49% (n 39)||82% (n 33)||90% (n 29)|