Tumor hypoxia, observed in all types of human tumors, is an independent prognosticator of malignant progression and poor patient survival. The conventional wisdom is that hypoxic tumor cells are resistant to conventional therapy and is highly metastatic. Therefore, targeting hypoxic tumor cells has inevitably become a focus of current cancer treatment plans as well as drug development efforts. Unfortunately, there remains a lack of definitive answers about the true malignant phenotypes and characteristics of hypoxic tumor cells in vivo, which partly explains the lack of convincing benefits of targeting hypoxic tumor cells in clinical trials so far. To addrss these pertinent questions, we propose an innovative approach to specifically mark hypoxic cells for in vivo identification or ex vivo isolation, as well as to follow their metastatic journey and o monitor cell fate after anti-cancer treatment in vivo. We will also use this innovative strategy to conduct targeted investigation of signaling pathways specifically in hypoxic cells in vivo without the unwanted interference from the adjacent non-hypoxic tumor cells.

Public Health Relevance

The project will provide direct in vivo evidence about the contribution of hypoxic tumor cells to malignant progression and therapy resistance, which will have a tremendous impact on how hypoxic tumors should be treated in clinics. The new methodology developed in this application will have the potential to positively change the way hypoxia research is conducted in the future.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Radiation Therapeutics and Biology Study Section (RTB)
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Bernhard, Eric J
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Yale University
Schools of Medicine
New Haven
United States
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Kim, Hoon; Lin, Qun; Yun, Zhong (2018) The hypoxic tumor microenvironment in vivo selects tumor cells with increased survival against genotoxic stresses. Cancer Lett 431:142-149
Kim, Hoon; Lin, Qun; Glazer, Peter M et al. (2018) The hypoxic tumor microenvironment in vivo selects the cancer stem cell fate of breast cancer cells. Breast Cancer Res 20:16
Li, Quhuan; Lin, Qun; Kim, Hoon et al. (2017) The anti-protozoan drug nifurtimox preferentially inhibits clonogenic tumor cells under hypoxic conditions. Am J Cancer Res 7:1084-1095
Li, Quhuan; Lin, Qun; Yun, Zhong (2016) Hypoxia-activated cytotoxicity of benznidazole against clonogenic tumor cells. Cancer Biol Ther 17:1266-1273
Yun, Zhong; Glazer, Peter M (2015) Tumor suppressor p53 stole the AKT in hypoxia. J Clin Invest 125:2264-6
Liu, Chao; Lin, Qun; Yun, Zhong (2015) Cellular and molecular mechanisms underlying oxygen-dependent radiosensitivity. Radiat Res 183:487-96
Lin, Qun; Gao, Zhanguo; Alarcon, Rodolfo M et al. (2009) A role of miR-27 in the regulation of adipogenesis. FEBS J 276:2348-58