Abstract B48: The effects of different types of hypoxia on tumor progression in breast cancer

Hypoxia, the state of low oxygen conditions, occurs frequently in solid tumors and is a poor prognostic factor. The expression of Hif-1α,the main mediator of the hypoxic response pathway, and the subsequent up-regulation of its target genes have been implicated in tumor growth, invasion, angiogenesis, therapy resistance and metastasis. There are two forms of hypoxia present in a growing tumor: chronic hypoxia (caused by limitations in oxygen diffusion from abnormal tumor vasculature) and intermittent hypoxia (caused by the aberrant, repeated and temporary closing and re-opening of blood vessels, leading to fluctuations in oxygen supply). This study investigates the phenotypes endowed by different forms of hypoxia that mediate metastatic potential in a syngeneic mouse model of breast cancer. By exposing murine breast cancer cells to 9 days of 20% O 2 (normoxia), 1% O 2 (chronic hypoxia) or alternating 24 hour cycles in 20% O 2 and 1% O 2 (intermittent hypoxia), we observe that intermittent hypoxia produces tumor cells with greater metastatic potential. These treatments produce no difference in primary tumor growth when orthotopically injected into the mammary fat pad of female C57Bl/6 mice. However, intermittent hypoxia-treated cells give rise to a greater number of and larger lung metastases when injected intravenously via the tail-vein of female C57Bl/6 mice. Intermittent hypoxia, but not chronic hypoxia, up-regulated the expression of genes that predict lung metastasis in breast cancer, endowed cells with an enhanced ability for anchorage-independent growth and produced greater clonal diversity. Furthermore, intermittent hypoxia also caused a switch to glycolysis in cells and induced a pro-tumorigenic, immunosuppressive secretory profile in vitro. Finally, intermittent hypoxia up-regulated the expression of mammary stem cell genes, increased expression of stem cell marker Sca-1 as well as CD14, and generated tumor-initiating cells at a higher frequency as evidenced by in vivo limiting dilution assays. This work demonstrates that intermittent hypoxia enhances metastatic seeding and outgrowth by priming cells intrinsically to metastasize, while activating co-operating factors that act extrinsically to form a permissive, immunosuppressive microenvironment. By delineating the contributions of different forms of hypoxia to metastasis, critical molecular mediators can be identified in aid of the development of efficacious therapies that could inhibit, prevent or cure metastatic disease. Citation Format: Anna Chen, Jaclyn Sceneay, Nathan Godde, Erik Thompson, Patrick Humbert, Andreas Moller. The effects of different types of hypoxia on tumor progression in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B48.