Abstract IA15: HIFs, hypoxia, and tumor progression

Abstract

Abstract Intratumoral hypoxia and expression of Hypoxia Inducible Factor 1α (HIF1α) correlate with metastasis and poor survival in sarcoma patients. We demonstrate here that hypoxia controls sarcoma cell metastasis through a novel mechanism in which HIF1α induces the expression of the intracellular enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2). PLOD2 hydroxylates procollagen, consequently altering the structure of extracellular collagen fibers along which transformed cells migrate in primary tumors. We show that loss of HIF1α or PLOD2 expression disrupts collagen deposition, cell migration and pulmonary metastasis (but not primary tumor growth) in allograft and autochthonous LSL-KrasG12D/+; Trp53fl/fl murine sarcoma models. Furthermore, ectopic PLOD2 expression restores migration and metastatic potential in HIF1α-deficient cells and tumors, and microarray analyses of human sarcomas reveal elevated HIF1α and PLOD2 expression in metastatic primary lesions. Collectively, these data indicate that whereas HIF1α activity modifies pre-metastatic niches in carcinomas, it controls sarcoma metastasis through PLOD2-dependent collagen deposition in primary tumors. Therefore, we conclude that PLOD2 is a novel therapeutic target in sarcomas and successful inhibition of this enzyme may reduce tumor cell dissemination. Citation Format: M. Celeste Simon. HIFs, hypoxia, and tumor progression. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr IA15.