Hypoxia is a hallmark of tumor microenvironments, exerting wide-ranging impacts on key processes of tumor progression and metastasis. However, our understanding of how hypoxia regulates these processes has been based primarily on studying the effects of hypoxia within the primary tumor. Recently, an increasing number of studies have suggested the importance of hypoxic regulation within metastatic target organs, but hypoxic metastatic niches in the body are difficult to access with current imaging techniques, hampering detailed in vivo investigation of hypoxia at metastatic sites. Here, we report an engineered biomaterial scaffold that is able to establish an in vivo hypoxic metastatic niche in a readily accessible area, enabling the investigation of hypoxic regulation at a metastatic site. We engineered hypoxic environments within microporous poly(lactide-co-glycolide) (PLG) scaffolds, which have previously been shown to act as premetastatic niche mimics, via the addition of CoCl2, a hypoxia-mimetic agent. When implanted into the subcutaneous region of mice, CoCl2-containing PLG (Co-PLG) scaffolds established hypoxic microenvironments, as evidenced by the stabilization of hypoxia-inducible factor 1α (HIF1α) and increased blood vessel formation in vitro and in vivo. Furthermore, implanted Co-PLG scaffolds were able to recruit 4T1 metastatic breast cancer cells. These results demonstrate that Co-PLG scaffolds can establish an in vivo hypoxic metastatic niche, providing a novel platform to investigate hypoxic regulation of disseminated tumor cells (DTCs) at target organs.
Bibliographical noteFunding Information:
This work was supported by the University of Minnesota, the Dr. Ralph and Marian Falk Medical Research Trust Bank of America, N.A., and the Kwanjeong Educational Foundation (H.R.L.).
The authors would like to thank Elizabeth Lundstrom for assistance with ICP-OES measurement, Colleen Forster and Lori Holm for histology training and assistance, and Buck O’Flanagan for help with animal surgeries. Parts of this work were carried out in the Characterization Facility, University of Minnesota, which receives partial support from the National Science Foundation through the MRSEC program. Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health, United States, Award No. UL1TR000114. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Copyright © 2019 American Chemical Society.
- biomaterial scaffolds
- disseminated tumor cells
- metastatic niche
- tumor microenvironment