Abstract B61: Intratumoral oxygen gradients mediate sarcoma cell invasion
Lewis, DM; Park, KM; Eisinger-Mathason, TSK; Simon, C; Gerecht, S
Published in: Cancer Research
Hypoxia is a critical factor in the progression and metastasis of many cancers including soft tissue sarcomas. Frequently, oxygen (O2) gradients develop in tumors as they grow beyond their vascular supply leading to heterogeneous areas of O2 depletion. Here we report the impact of hypoxic O2 gradients on sarcoma cell invasion and migration. O2 gradient measurements showed that large sarcoms mouse tumors (>300mm3) contain a severely hypoxic core (≤0.1% pO2) whereas smaller tumors possessed hypoxic gradients throughout the tumor mass (0.1%-6% pO2). To analyze tumor invasion, we utilized O2-controllable hydrogels to recreate the physio-pathological O2 levels in vitro. Small tumor grafts encapsulated in the hydrogels revealed increased invasion that was both faster and extended over a longer-distance in the hypoxic hydrogels compared to nonhypoxic hydrogels. To accurately model the effect of the O2 gradient, we examined individual sarcoma cells embedded in the O2-controllable hydrogel. We observed that hypoxic gradients guide sarcoma cell motility and matrix remodeling through HIF1α activation. We further found that in the hypoxic gradient, individual cells migrate more quickly, across longer distances, and in the direction of increasing O2 tension. Treatment with minoxidil, inhibitor of hypoxia-induced sarcoma metastasis, abrogated cell migration and matrix remodeling in the hypoxic gradient. Overall, we show that O2 acts as a 3D physico-tactic agent during sarcoma tumor invasion and propose the O2-controllable hydrogels as a predictive system to study early stages of the metastatic process and therapeutic targets.Citation Format: Daniel M. Lewis, Kyung Min Park, T.S. Karin Eisinger-Mathason, Celeste Simon, Sharon Gerecht. Intratumoral oxygen gradients mediate sarcoma cell invasion. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B61.
