Tumor hypoxia promotes resistance to radiotherapy and chemotherapy, and selects for the emergence of highly malignant cells. The Hypoxia Inducible Factors (HIFs) are the primary transcriptional regulators mediating cellular adaptation to tissue hypoxia, and HIFs are highly expressed in many human cancers. HIFs contribute to tumor progression and metastasis by promoting the growth, metabolism, and survival of cancer cells, as well as modulating the recruitment and function of tumor-associated stromal cells. HIFs have therefore been proposed as an attractive therapeutic target, and significant effort has been focused on identifying HIF inhibitors for cancer therapy. The rationale for this approach has become controversial, however, as distinct HIF complexes have been recently shown to either promote or suppress tumor growth and progression in different cellular contexts. The majority of HIF responses are mediated by two independent transcriptional complexes containing either HIF-1? or HIF-2?, each of which binds the constitutively expressed subunit ARNT (also called HIF-1?). Although they fulfill some redundant functions, HIF-1? and HIF-2? also antagonize each other's effects on tumor metabolism, angiogenesis, and immune responses. To date, genetically engineered murine cancer models have investigated the effects of deleting only HIF-1? or HIF-2? independently, without assessing the functional importance of the remaining HIF-? subunit, which may act to either promote or suppress tumor progression. Consequently, the impact of full HIF-deficiency in cancer cells and associated stromal cells cannot be accurately predicted, and could result in unintended tumor progression in specific settings. In this proposal, we will use tissue-specific Cre expression to delete the Arnt/Hif-1? gene (and both HIF-1? and HIF-2? function) in murine colon carcinoma cells and tumor-associated macrophages (TAMs). This approach will, for the first time, model the impact of pan-HIF inhibition in an autochthonous murine tumor model. This work will also inform ongoing efforts to develop pharmacological HIF inhibitors as safe and effective cancer therapies.

Public Health Relevance

The Hypoxia Inducible Factor (HIF) proteins allow cancer cells to adapt to stressful tumor micro- environments, and drugs that inhibit HIFs are being developed as cancer therapies. However, recent data show that different HIFs can actually suppress tumor growth in some settings, suggesting that HIF inhibition could consequently promote tumor growth in some contexts. The proposed experiments will, for the first time, use a mouse model of cancer to test the impact of inhibiting multiple HIFs simultaneously.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Tumor Progression and Metastasis Study Section (TPM)
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Thomas, John
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University of Pennsylvania
Anatomy/Cell Biology
Schools of Medicine
United States
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Lin, Nan; Simon, M Celeste (2016) Hypoxia-inducible factors: key regulators of myeloid cells during inflammation. J Clin Invest 126:3661-3671
Lee, Kyoung Eun; Spata, Michelle; Bayne, Lauren J et al. (2016) Hif1a Deletion Reveals Pro-Neoplastic Function of B Cells in Pancreatic Neoplasia. Cancer Discov 6:256-69
Wong, Waihay J; Richardson, Theresa; Seykora, John T et al. (2015) Hypoxia-inducible factors regulate filaggrin expression and epidermal barrier function. J Invest Dermatol 135:454-61
Krock, Bryan L; Eisinger-Mathason, Tzipora S; Giannoukos, Dionysios N et al. (2015) The aryl hydrocarbon receptor nuclear translocator is an essential regulator of murine hematopoietic stem cell viability. Blood 125:3263-72
Lee, Kyoung Eun; Simon, M Celeste (2015) SnapShot: Hypoxia-Inducible Factors. Cell 163:1288-1288.e1
Majmundar, Amar J; Lee, David S M; Skuli, Nicolas et al. (2015) HIF modulation of Wnt signaling regulates skeletal myogenesis in vivo. Development 142:2405-12
Shay, Jessica E S; Imtiyaz, Hongxia Z; Sivanand, Sharanya et al. (2014) Inhibition of hypoxia-inducible factors limits tumor progression in a mouse model of colorectal cancer. Carcinogenesis 35:1067-77
Wagage, Sagie; John, Beena; Krock, Bryan L et al. (2014) The aryl hydrocarbon receptor promotes IL-10 production by NK cells. J Immunol 192:1661-70
Thompson, A A Roger; Elks, Philip M; Marriott, Helen M et al. (2014) Hypoxia-inducible factor 2α regulates key neutrophil functions in humans, mice, and zebrafish. Blood 123:366-76
Shay, Jessica E S; Celeste Simon, M (2012) Hypoxia-inducible factors: crosstalk between inflammation and metabolism. Semin Cell Dev Biol 23:389-94

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