Abstract 96: Estrogen modulates cellular and molecular markers of hypoxic tumor microenvironment in thyroid cancer.

Abstract

Abstract Thyroid proliferative diseases are three to four times more prevalent in women than in men. Our laboratory has systemically elucidated the role of estrogen in thyroid cancer as a promoter of increased aggressiveness, however the role of estrogen within the hypoxic environment of thyroid cancer is not known. Based on our observation that estrogen promotes neo-vascularization of thyroid tumors by modulating angiogenic factors, vascular endothelial growth factors (VEGF) and matrix metalloproteinases (MMPs), we hypothesize that tumor hypoxia synergizes with estrogen to produce an inflammatory microenvironment that helps the progression of thyroid cancer. We observed that thyroid cancer cells are responsive to hypoxic conditions and estrogen induces hypoxia inducible factor-1α (HIF-1α) nuclear translocation in these cells. Furthermore, estrogen and hypoxia modulate the HIF-1 signaling in thyroid cancer cells which is abrogated by the anti-estrogen fulvestrant and the HIF-1 inhibitor YC-1 (3-(5’-hydroxymethyl-2’-furyl)-1-benzylindazole). Conditioned medium from estrogen treated thyroid cancer cells lead to enhanced migration and tubulogenesis of human umbilical vein endothelial cells (HUVECs), due to secretion of hypoxia and estrogen responsive proteins by thyroid cancer cells leading to increased angiogenesis of endothelial cells. This phenomenon was abrogated by HIF-1 inhibitor. These results demonstrate for the first time that estrogen signaling pathways mimic the signaling pathways in the hypoxic environment in thyroid cancer cells, thus suggesting that estrogen potentially mimics oxygen deprivation at the molecular level to produce an inflammatory tumor microenvironment thus fostering the progression of thyroid cancer. We conclude that apart from the direct activity of estrogen on thyroid cancer phenotype, estrogen also modulates the tumor microenvironment specifically maintaining hypoxic conditions which may be essential for thyroid cancer progression and/or metastases. Citation Format: Shilpi Rajoria, Elyse Hanly, Andrea George, Robert Suriano, Jan Geliebter, Masoud Saman, Stimson Schantz, Raj K. Tiwari. Estrogen modulates cellular and molecular markers of hypoxic tumor microenvironment in thyroid cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 96. doi:10.1158/1538-7445.AM2013-96