Intratumoral oxygen gradients mediate sarcoma cell invasion

Hypoxia is a critical factor in the progression and metastasis of many cancers, including soft tissue sarcomas. Frequently, oxygen (O-2) gradients develop in tumors as they grow beyond their vascular supply, leading to heterogeneous areas of O-2 depletion. Here, we report the impact of hypoxic O-2 gradients on sarcoma cell invasion and migration. O-2 gradient measurements showed that large sarcoma mouse tumors (>300 mm(3)) contain a severely hypoxic core [<= 0.1% partial pressure of O-2 (pO(2))] whereas smaller tumors possessed hypoxic gradients throughout the tumor mass (0.1-6% pO(2)). To analyze tumor invasion, we used O-2-controllable hydrogels to recreate the physiopathological O-2 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 with nonhypoxic hydrogels. To model the effect of the O-2 gradient accurately, we examined individual sarcoma cells embedded in the O-2-controllable hydrogel. We observed that hypoxic gradients guide sarcoma cell motility and matrix remodeling through hypoxia-inducible factor-1 alpha (HIF-1 alpha) activation. We further found that in the hypoxic gradient, individual cells migrate more quickly, across longer distances, and in the direction of increasing O-2 tension. Treatment with minoxidil, an inhibitor of hypoxia-induced sarcoma metastasis, abrogated cell migration and matrix remodeling in the hypoxic gradient. Overall, we show that O-2 acts as a 3D physicotactic agent during sarcoma tumor invasion and propose the O-2-controllable hydrogels as a predictive system to study early stages of the metastatic process and therapeutic targets.