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In this study, we investigated the activity of intratumoral hypoxia\u2010inducible factor (HIF), which functions as a master regulator of the cellular response to hypoxia and inflammation. We constructed the HIF activity\u2010monitoring reporter gene hypoxia\u2010response element\u2010Venus\u2010Akaluc (<jats:italic>HVA<\/jats:italic>) that expresses the green fluorescent protein Venus and modified firefly luciferase Akaluc in a HIF activity\u2010dependent manner, and created transgenic mice harboring HVA transgene (HVA\u2010Tg). In HVA\u2010Tg, HIF\u2010active cells can be visualized using AkaBLI, an ultra\u2010sensitive in vivo bioluminescence imaging technology that produces an intense near\u2010infrared light upon reaction of Akaluc with the D\u2010luciferin analog AkaLumine\u2010HCl. By orthotopic transplantation of E0771, a mouse triple negative breast cancer cell line without a reporter gene, into HVA\u2010Tg, we succeeded in noninvasively monitoring bioluminescence signals from HIF\u2010active stromal cells as early as 8\u2009days after transplantation. The HIF\u2010active stromal cells initially clustered locally and then spread throughout the tumors with growth. Immunohistochemistry and flow cytometry analyses revealed that CD11b<jats:sup>+<\/jats:sup>F4\/80<jats:sup>+<\/jats:sup> macrophages were the predominant HIF\u2010active stromal cells in E0771 tumors. These results indicate that HVA\u2010Tg is a useful tool for spatiotemporal analysis of HIF\u2010active tumor stromal cells, facilitating investigation of the roles of HIF\u2010active tumor stromal cells in tumor growth and malignant progression.<\/jats:p>","DOI":"10.1111\/cas.15907","type":"journal-article","created":{"date-parts":[[2023,7,22]],"date-time":"2023-07-22T09:24:49Z","timestamp":1690017889000},"page":"3935-3945","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["In vivo optical imaging of tumor stromal cells with hypoxia\u2010inducible factor activity"],"prefix":"10.1111","volume":"114","author":[{"given":"Hitomi","family":"Miyabara","sequence":"first","affiliation":[{"name":"School of Life Science and Technology Tokyo Institute of Technology  Yokohama Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryuichiro","family":"Hirano","sequence":"additional","affiliation":[{"name":"School 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