title: Intratumoral oxygen gradients mediate sarcoma cell invasion.
abstract: 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 sarcoma mouse tumors (>300 mm(3)) contain a severely hypoxic core [≤0.1% partial pressure of O2 (pO2)] whereas smaller tumors possessed hypoxic gradients throughout the tumor mass (0.1-6% pO2). To analyze tumor invasion, we used O2-controllable hydrogels to recreate the physiopathological 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 with nonhypoxic hydrogels. To model the effect of the O2 gradient accurately, we examined individual sarcoma cells embedded in the O2-controllable hydrogel. We observed that hypoxic gradients guide sarcoma cell motility and matrix remodeling through hypoxia-inducible factor-1α (HIF-1α) 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, an 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 physicotactic 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.
authors.affiliation: Department of Chemical and Biomolecular Engineering, Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218;
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Lewis
authors.affiliation: Department of Chemical and Biomolecular Engineering, Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218;
authors.forename: Kyung Min
authors.initials: KM
authors.lastname: Park
authors.affiliation: Department of Chemical and Biomolecular Engineering, Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218;
authors.forename: Vitor
authors.initials: V
authors.lastname: Tang
authors.affiliation: Department of Chemical and Biomolecular Engineering, Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218;
authors.forename: Yu
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; Sarcoma Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Koreana
authors.initials: K
authors.lastname: Pak
authors.affiliation: Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; Sarcoma Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: T S Karin
authors.initials: TS
authors.lastname: Eisinger-Mathason
authors.affiliation: Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: M Celeste
authors.initials: MC
authors.lastname: Simon
authors.affiliation: Department of Chemical and Biomolecular Engineering, Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218; Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD 21218 gerecht@jhu.edu.
authors.forename: Sharon
authors.initials: S
authors.lastname: Gerecht
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D002465:Cell Movement; D020100:Hydrogels; D051379:Mice; D008914:Minoxidil / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D010100:Oxygen / Q000378:metabolism*; D012509:Sarcoma / Q000473:pathology*
chemical_list: D020100:Hydrogels; D008914:Minoxidil; D010100:Oxygen
keywords: gradients; hydrogel; hypoxia; migration; sarcoma