Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy

Semenza, Gregg L.

doi:10.1016/j.tips.2012.01.005

Cited by 1,514Cancer, Hypoxia, and MetabolismAngiogenesis and VEGF in CancerErythropoietin and Anemia Treatment

Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy

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Semenza, Gregg L.·2012·Trends in Pharmacological Sciences

DOI 10.1016/j.tips.2012.01.005PMC PMC3437546

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Abstract

Hypoxia-inducible factors (HIFs) mediate adaptive physiological responses to hypoxia. In human cancers that are accessible for O(2) electrode measurements, intratumoral hypoxia is common and severe hypoxia is associated with increased risk of mortality. HIF activity in regions of intratumoral hypoxia mediates angiogenesis, epithelial-mesenchymal transition, stem-cell maintenance, invasion, metastasis, and resistance to radiation therapy and chemotherapy. A growing number of drugs have been identified that inhibit HIF activity by a variety of molecular mechanisms. Because many of these drugs are already FDA-approved for other indications, clinical trials can (and should) be initiated to test the hypothesis that incorporation of HIF inhibitors into current standard-of-care therapy will increase the survival of cancer patients.

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Several approaches for targeting hypoxic tumor cells have been proposed including hypoxia-activated prodrugs, gene therapy, recombinant anaerobic bacteria, specific targeting of HIFs, or targeting pathways important in hypoxic cells such as the mTOR and UPR pathways.
“Several approaches for targeting hypoxic tumor cells have been proposed including hypoxia-activated prodrugs, gene therapy, recombinant anaerobic bacteria, specific targeting of HIFs, or targeting pathways important in hypoxic cells such as the mTOR and UPR pathways (Melillo, 2007;Wilson & Hay, 2011;Semenza, 2012).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Semenza, 2012
The “HIF-1 inhibitors for cancer therapy” section supports targeting HIFs, and its “HIF-1α synthesis” subsection identifies mTOR inhibitors as one approach (page numbers unavailable). The passages do not support the other listed approaches—hypoxia-activated prodrugs, gene therapy, recombinant anaerobic bacteria, or targeting the UPR pathway—as claims attributable to this source. (LLM, conf=0.85)
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HIF1α is a key regulator of the Warburg effect and regulates expression of a variety of metabolism-related proteins.
“HIF1α is a key regulator of the Warburg effect and regulates the expression of a variety of metabolism-related proteins61.”
From RETRACTED ARTICLE: Fasting inhibits aerobic glycolysis and proliferation in colorectal cancer via the Fdft1-mediated AKT/mTOR/HIF1α pathway suppression (2020) · cites this paper as [61]

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Mitochondrial Autophagy Is an HIF-1-dependent Adaptive Metabolic Response to Hypoxia
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Lysyl oxidase is essential for hypoxia-induced metastasis
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RETRACTED: Acriflavine inhibits HIF-1 dimerization, tumor growth, and vascularization
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RETRACTED ARTICLE: HIF-1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs
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RETRACTED: Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells
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Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1
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Carbonaro, M., O’Brate, A., & Giannakakou, P. (2011) · The Journal of Cell Biology · doi:10.1083/jcb.201004145 · Cited by 95 · see citing works
Radiosensitization and Stromal Imaging Response Correlates for the HIF-1 Inhibitor PX-478 Given with or without Chemotherapy in Pancreatic Cancer
Schwartz, D. L., Bankson, J. A., Lemos, R., Lai, S. Y., Thittai, A. K., He, Y., Hostetter, G. H., Demeure, M. J., Hoff, D. D. V., & Powis, G. (2010) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-09-0768 · Cited by 94 · see citing works
The role of erythropoietin and its receptor in growth, survival and therapeutic response of human tumor cells
Szenajch, J., Wcisło, G., Jeong, J., Szczylik, C. A., & Feldman, L. (2010) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2010.04.002 · Cited by 87 · see citing works
Endothelins and hypoxia-inducible factor in cancer
Grimshaw, M. J. (2007) · Endocrine Related Cancer · doi:10.1677/erc-07-0057 · Cited by 83 · see citing works
Treatment regimen determines whether an HIF-1 inhibitor enhances or inhibits the effect of radiation therapy
Harada, H., Itasaka, S., Zhu, Y., Zeng, L., Xie, X., Morinibu, A., Shinomiya, K., & Hiraoka, M. (2009) · British Journal of Cancer · doi:10.1038/sj.bjc.6604939 · Cited by 82 · see citing works
Emerging Roles of microRNAs in the Molecular Responses to Hypoxia
Crosby, M. E., Devlin, C. M., Glazer, P. M., Calin, G. A., & Ivan, M. (2009) · Current Pharmaceutical Design · doi:10.2174/138161209789649367 · Cited by 77 · see citing works
Metastasis and stem cell pathways
Barnhart, B. C., & Simon, M. C. (2007) · Cancer and Metastasis Reviews · doi:10.1007/s10555-007-9053-3 · Cited by 71 · see citing works
Spermidine/Spermine N1-Acetyltransferase-1 Binds to Hypoxia-inducible Factor-1α (HIF-1α) and RACK1 and Promotes Ubiquitination and Degradation of HIF-1α
Baek, J. H., Liu, Y. V., McDonald, K. R., Wesley, J. B., Zhang, H., & Semenza, G. L. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m705627200 · Cited by 69 · see citing works
Self-citation
Se-methylselenocysteine sensitizes hypoxic tumor cells to irinotecan by targeting hypoxia-inducible factor 1α
Chintala, S., Tóth, K., Cao, S., Durrani, F. A., Vaughan, M. M., Jensen, R. L., & Rustum, Y. M. (2010) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-009-1238-8 · Cited by 68 · see citing works
Metabolic reprogramming by HIF-1 promotes the survival of bone marrow–derived angiogenic cells in ischemic tissue
Rey, S., Luo, W., Shimoda, L. A., & Semenza, G. L. (2011) · Blood · doi:10.1182/blood-2010-11-321190 · Cited by 68 · see citing works
Self-citation
Hypoxia prevents etoposide-induced DNA damage in cancer cells through a mechanism involving hypoxia-inducible factor 1
Sullivan, R., & Graham, C. H. (2009) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-08-1090 · Cited by 65 · see citing works
Molecular Pathways: Targeting Proteasomal Protein Degradation in Cancer
Molineaux, S. M. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-0853 · Cited by 63 · see citing works
Functional significance of vascular endothelial growth factor receptors on gastrointestinal cancer cells
Dallas, N. A., Fan, F., Gray, M. J., et al. (2007) · Cancer and Metastasis Reviews · doi:10.1007/s10555-007-9070-2 · Cited by 61 · see citing works
Impaired DNA double-strand break repair contributes to chemoresistance in HIF-1 -deficient mouse embryonic fibroblasts
Wirthner, R., Wrann, S., Balamurugan, K., Wenger, R. H., & Stiehl, D. P. (2008) · Carcinogenesis · doi:10.1093/carcin/bgn231 · Cited by 51 · see citing works
Cell Type–Specific, Topoisomerase II–Dependent Inhibition of Hypoxia-Inducible Factor-1α Protein Accumulation by NSC 644221
Creighton-Gutteridge, M., Cardellina, J. H., Stephen, A. G., Rapisarda, A., Uranchimeg, B., Hite, K. M., Denny, W. A., Shoemaker, R. H., & Melillo, G. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-2301 · Cited by 51 · see citing works
Adrenomedullin, an autocrine/paracrine factor induced by androgen withdrawal, stimulates ‘neuroendocrine phenotype’ in LNCaP prostate tumor cells
Berenguer‐Daizé, C., Boudouresque, F., Dussert, C., Daniel, L., Muracciole, X., Grino, M., Rossi, D., Mabrouk, K., Figarella-Branger, D. F., Martin, P.-M., et al. (2007) · Oncogene · doi:10.1038/sj.onc.1210656 · Cited by 49 · see citing works
Antitumor agent PX-12 inhibits HIF-1α protein levels through an Nrf2/PMF-1-mediated increase in spermidine/spermine acetyl transferase
Kim, Y. H., Coon, A., Baker, A. F., & Powis, G. (2011) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-010-1500-0 · Cited by 45 · see citing works
FDA cancels approval for bevacizumab in advanced breast cancer
Tanne, J. H. (2011) · BMJ · doi:10.1136/bmj.d7684 · Cited by 38 · see citing works
Analysis of Hypoxia‐Inducible Factor 1α Expression and its Effects on Invasion and Metastasis
Krishnamachary, B., & Semenza, G. L. (2007) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(07)35017-9 · Cited by 32 · see citing works
Self-citation
Antiangiogenic agents and HIF-1 inhibitors meet at the crossroads
Rapisarda, A., Shoemaker, R. H., & Melillo, G. (2009) · Cell Cycle · doi:10.4161/cc.8.24.10145 · Cited by 25 · see citing works
G-rich Oligonucleotides Inhibit HIF-1α and HIF-2α and Block Tumor Growth
Guan, Y., Reddy, K. R., Zhu, Q., et al. (2009) · Molecular Therapy · doi:10.1038/mt.2009.219 · Cited by 24 · see citing works
ACRIFLAVINE AS A URINARY ANTISEPTIC
Assinder, E. W. (1936) · The Lancet · doi:10.1016/s0140-6736(00)56423-x · Cited by 19 · see citing works

Flagged first, then by citations

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ROS function in redox signaling and oxidative stress
Schieber, M., & Chandel, N. S. (2014) · Current Biology · doi:10.1016/j.cub.2014.03.034 · Cited by 6,931 · see citing works
Combination therapy in combating cancer
Mokhtari, R. B., Homayouni, T. S., Baluch, N., Morgatskaya, E., Kumar, S., Das, B., & Yeger, H. (2017) · Oncotarget · doi:10.18632/oncotarget.16723 · Cited by 2,543 · see citing works
The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy
Muz, B., de la Puente, P., Azab, F., & Azab, A. K. (2015) · Hypoxia · doi:10.2147/hp.s93413 · Cited by 2,066 · see citing works
“Moreover, HIF-α contributes to cancer metastasis by altering cancer cell adhesion and motility through regulation of epithelial-to-mesenchymal transition (EMT) and E-cad, ZEB1, -2 and TCF3 expression,(58) as well as migration and invasion abilities through CXCR4,(59) CAIX,(60) LOX,(61) MMP-2, and MMP-9.(47,62,63)”
Background
Hypoxia and the extracellular matrix: drivers of tumour metastasis
Gilkes, D. M., Semenza, G. L., & Wirtz, D. (2014) · Nature Reviews Cancer · doi:10.1038/nrc3726 · Cited by 1,520 · see citing works
Self-citation
Cancer metabolism: a therapeutic perspective
Martinez-Outschoorn, U. E., Peiris-Pagés, M., Pestell, R. G., Sotgia, F., & Lisanti, M. P. (2017) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2016.60 · Cited by 1,505 · see citing works
Normalizing Tumor Microenvironment to Treat Cancer: Bench to Bedside to Biomarkers
Jain, R. K. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2012.46.3653 · Cited by 1,248 · see citing works
Hypoxia and Metabolic Adaptation of Cancer Cells
Eales, K. L., Hollinshead, K. E. R., & Tennant, D. A. (2016) · Oncogenesis · doi:10.1038/oncsis.2015.50 · Cited by 724 · see citing works
Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer
Wigerup, C., Påhlman, S., & Bexell, D. (2016) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2016.04.009 · Cited by 687 · see citing works
“Several approaches for targeting hypoxic tumor cells have been proposed including hypoxia-activated prodrugs, gene therapy, recombinant anaerobic bacteria, specific targeting of HIFs, or targeting pathways important in hypoxic cells such as the mTOR and UPR pathways (Melillo, 2007; Wilson & Hay, 2011; Semenza, 2012).”
Background
Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis
Wang, T., Gilkes, D. M., Takano, N., Xiang, L., Luo, W., Bishop, C. J., Chaturvedi, P., Green, J. J., & Semenza, G. L. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1410041111 · Cited by 493 · see citing works
Self-citation
RETRACTED: Hypoxia-inducible factors are required for chemotherapy resistance of breast cancer stem cells
Samanta, D., Gilkes, D. M., Chaturvedi, P., Xiang, L., & Semenza, G. L. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1421438111 · Cited by 460 · see citing works
Self-citation
Retracted
The pre-metastatic niche: finding common ground
Sceneay, J., Smyth, M. J., & Möller, A. (2013) · Cancer and Metastasis Reviews · doi:10.1007/s10555-013-9420-1 · Cited by 422 · see citing works
SomaticHIF2AGain-of-Function Mutations in Paraganglioma with Polycythemia
Zhuang, Z., Yang, C., Lorenzo, F., Merino, M., Fojo, T., Kebebew, E., Popovic, V., Stratakis, C. A., Prchal, J. T., & Pacak, K. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1205119 · Cited by 397 · see citing works
Structural integration in hypoxia-inducible factors
Wu, D., Potluri, N., Lu, J., Kim, Y., & Rastinejad, F. (2015) · Nature · doi:10.1038/nature14883 · Cited by 346 · see citing works
Gold Nanoparticles as Radiosensitizers in Cancer Radiotherapy
Chen, Y., Yang, J., Fu, S., & Wu, J. (2020) · International Journal of Nanomedicine · doi:10.2147/ijn.s272902 · Cited by 319 · see citing works
Allosteric inhibition of hypoxia inducible factor-2 with small molecules
Scheuermann, T. H., Li, Q., Ma, H.-W., Key, J., Zhang, L., Chen, R., Garcia, J. A., Naidoo, J., Longgood, J., Frantz, D. E., et al. (2013) · Nature Chemical Biology · doi:10.1038/nchembio.1185 · Cited by 315 · see citing works
Oxygen sensing and hypoxia signalling pathways in animals: The implications of physiology for cancer
Ratcliffe, P. J. (2013) · The Journal of Physiology · doi:10.1113/jphysiol.2013.251470 · Cited by 294 · see citing works
Pharmacologic Targeting of Hypoxia-Inducible Factors
Semenza, G. L. (2019) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010818-021637 · Cited by 288 · see citing works
Self-citation
HIF-1 in cancer therapy: two decade long story of a transcription factor
Soni, S., & Padwad, Y. S. (2017) · Acta Oncologica · doi:10.1080/0284186x.2017.1301680 · Cited by 251 · see citing works
Recent progress of hypoxia-modulated multifunctional nanomedicines to enhance photodynamic therapy: Opportunities, challenges, and future development
Sun, Y., Zhao, D., Wang, G., Wang, Y., Cao, L., Sun, J., Jiang, Q., & He, Z. (2020) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2020.01.004 · Cited by 250 · see citing works
Hypoxia induces myeloid-derived suppressor cell recruitment to hepatocellular carcinoma through chemokine (C-C motif) ligand 26
Chiu, D. K., Xu, I. M., Lai, R. K., Tse, A. P., Wei, L. L., Koh, H., Li, L. L., Lee, D., Lo, R. C., Wong, C., et al. (2016) · Hepatology · doi:10.1002/hep.28655 · Cited by 241 · see citing works
Targeting hypoxia-inducible factors: therapeutic opportunities and challenges
Yuan, X., Ruan, W., Bobrow, B., Carmeliet, P., & Eltzschig, H. K. (2024) · Nature Reviews Drug Discovery · doi:10.1038/s41573-023-00848-6 · Cited by 245 · see citing works
RETRACTED ARTICLE: Fasting inhibits aerobic glycolysis and proliferation in colorectal cancer via the Fdft1-mediated AKT/mTOR/HIF1α pathway suppression
Weng, M.-L., Chen, W.-K., Chen, X.-Y., Lu, H., Sun, Z.-R., Yu, Q., Sun, P.-F., Xu, Y.-J., Zhu, M.-M., Jiang, N., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-15795-8 · Cited by 242 · see citing works
Retracted
The Effect of Hypoxia on Mesenchymal Stem Cell Biology
Ejtehadifar, M., Shamsasenjan, K., Movassaghpour, A., Akbarzadehlaleh, P., Dehdilani, N., Abbasi, P., Molaeipour, Z., & Saleh, M. (2015) · Advanced Pharmaceutical Bulletin · doi:10.15171/apb.2015.021 · Cited by 235 · see citing works
Hypoxia-inducible factor-dependent signaling between triple-negative breast cancer cells and mesenchymal stem cells promotes macrophage recruitment
Chaturvedi, P., Gilkes, D. M., Takano, N., & Semenza, G. L. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1406655111 · Cited by 226 · see citing works
Self-citation
UCHL1 provides diagnostic and antimetastatic strategies due to its deubiquitinating effect on HIF-1α
Goto, Y., Zeng, L., Yeom, C. J., Zhu, Y., Morinibu, A., Shinomiya, K., Kobayashi, M., Hirota, K., Itasaka, S., Yoshimura, M., et al. (2015) · Nature Communications · doi:10.1038/ncomms7153 · Cited by 229 · see citing works
Histone demethylase JMJD2C is a coactivator for hypoxia-inducible factor 1 that is required for breast cancer progression
Luo, W., Chang, R., Zhong, J., Pandey, A., & Semenza, G. L. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1217394109 · Cited by 228 · see citing works
Self-citation
Hypoxia-inducible factor 1-dependent expression of platelet-derived growth factor B promotes lymphatic metastasis of hypoxic breast cancer cells
Schito, L., Rey, S., Tafani, M., Zhang, H., Wong, C. C.-L., Russo, A., Russo, M. A., & Semenza, G. L. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1214019109 · Cited by 224 · see citing works
Self-citation
Prostate cancer cell malignancy via modulation of HIF-1α pathway with isoflurane and propofol alone and in combination
Huang, H., Benzonana, L. L., Zhao, H., Watts, H. R., Perry, N. J. S., Bevan, C., Brown, R., & Ma, D. (2014) · British Journal of Cancer · doi:10.1038/bjc.2014.426 · Cited by 223 · see citing works
HIF-2α activation potentiates oxidative cell death in colorectal cancers by increasing cellular iron
Singhal, R., Mitta, S. R., Das, N. K., Kerk, S. A., Sajjakulnukit, P., Solanki, S., Andren, A., Kumar, R., Olive, K. P., Banerjee, R., et al. (2021) · Journal of Clinical Investigation · doi:10.1172/jci143691 · Cited by 215 · see citing works
Intermittent Hypoxia-induced Changes in Tumor-associated Macrophages and Tumor Malignancy in a Mouse Model of Sleep Apnea
Almendros, I., Wang, Y., Becker, L., Lennon, F. E., Zheng, J., Coats, B. R., Schoenfelt, K. S., Carreras, A., Hakim, F., Zhang, S. X., et al. (2014) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201310-1830oc · Cited by 201 · see citing works
Hypoxia-inducible factors: a central link between inflammation and cancer
Triner, D., & Shah, Y. M. (2016) · Journal of Clinical Investigation · doi:10.1172/jci84430 · Cited by 199 · see citing works
Hypoxia-regulated target genes implicated in tumor metastasis
Tsai, Y.-P., & Wu, K.-J. (2012) · Journal of Biomedical Science · doi:10.1186/1423-0127-19-102 · Cited by 190 · see citing works
Nanoformulations for combination or cascade anticancer therapy
Miao, L., Guo, S., Lin, C. M., Liu, Q., & Huang, L. (2017) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2017.06.003 · Cited by 178 · see citing works
Hypoxia-inducible factor-1 promotes pancreatic ductal adenocarcinoma invasion and metastasis by activating transcription of the actin-bundling protein fascin
Zhao, X., Gao, S., Ren, H., Sun, W., Zhang, H., Sun, J., Yang, S., & Hao, J. (2014) · Cancer Research · doi:10.1158/0008-5472.can-13-3009 · Cited by 163 · see citing works
TET1 regulates hypoxia-induced epithelial-mesenchymal transition by acting as a co-activator
Tsai, Y.-P., Chen, H.-F., Chen, S.-Y., Cheng, W.-C., Wang, H.-W., Shen, Z.-J., Song, C., Teng, S.-C., He, C., & Wu, K.-J. (2014) · Genome biology · doi:10.1186/s13059-014-0513-0 · Cited by 152 · see citing works
Hypoxia Inducible Factor Pathway Inhibitors as Anticancer Therapeutics
Burroughs, S. K., Kaluz, S., Wang, D., Wang, K., Van Meir, E. G., & Wang, B. (2013) · Future Medicinal Chemistry · doi:10.4155/fmc.13.17 · Cited by 140 · see citing works
Intermittent hypoxia induces a metastatic phenotype in breast cancer
Chen, A., Sceneay, J., Gödde, N., Kinwel, T., Ham, S., Thompson, E. W., Humbert, P. O., & Möller, A. (2018) · Oncogene · doi:10.1038/s41388-018-0259-3 · Cited by 133 · see citing works
Hypoxia Dictates Metabolic Rewiring of Tumors: Implications for Chemoresistance
Belisario, D. C., Kopecka, J., Pasino, M., Akman, M., De Smaele, E., Donadelli, M., & Riganti, C. (2020) · Cells · doi:10.3390/cells9122598 · Cited by 133 · see citing works
Impact of hypoxic tumor microenvironment and tumor cell plasticity on the expression of immune checkpoints
Lequeux, A., Noman, M. Z., Xiao, M., Sauvage, D., Van Moer, K., Viry, E., Bocci, I., Hasmim, M., Bosseler, M., Berchem, G., et al. (2019) · Cancer Letters · doi:10.1016/j.canlet.2019.05.021 · Cited by 117 · see citing works
Targeting HIF-1 alpha transcriptional activity drives cytotoxic immune effector cells into melanoma and improves combination immunotherapy
Lequeux, A., Noman, M. Z., Xiao, M., Van Moer, K., Hasmim, M., Benoit, A., Bosseler, M., Viry, E., Arakelian, T., Berchem, G., et al. (2021) · Oncogene · doi:10.1038/s41388-021-01846-x · Cited by 129 · see citing works
CD44 interacts with HIF-2α to modulate the hypoxic phenotype of perinecrotic and perivascular glioma cells
Johansson, E., Grassi, E. S., Pantazopoulou, V., Tong, B., Lindgren, D., Berg, T. J., Pietras, E. J., Axelson, H., & Pietras, A. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.07.049 · Cited by 121 · see citing works
K63-polyubiquitinated HAUSP deubiquitinates HIF-1α and dictates H3K56 acetylation promoting hypoxia-induced tumour progression
Wu, H.-T., Kuo, Y.-C., Hung, J.-J., Huang, C.-H., Chen, W.-Y., Chou, T.-Y., Chen, Y., Chen, Y.-J., Chen, Y.-J., Cheng, W.-C., et al. (2016) · Nature Communications · doi:10.1038/ncomms13644 · Cited by 129 · see citing works
Structural characterization of mammalian bHLH-PAS transcription factors
Wu, D., & Rastinejad, F. (2017) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2016.09.011 · Cited by 122 · see citing works
The Histone Deacetylase Inhibitor, Vorinostat, Represses Hypoxia Inducible Factor 1 Alpha Expression through Translational Inhibition
Hutt, D. M., Roth, D. M., Vignaud, H., Cullin, C., & Bouchecareilh, M. (2014) · PLoS ONE · doi:10.1371/journal.pone.0106224 · Cited by 109 · see citing works
“HIF-1 is a heterodimeric complex composed of the HIF-1a and HIF-1b subunits and a central regulator of angiogenesis and energy metabolism in tumors [18–20].”
Background
A 3D microvascular network model to study the impact of hypoxia on the extravasation potential of breast cell lines
Song, J., Miermont, A., Lim, C. T., & Kamm, R. D. (2018) · Scientific Reports · doi:10.1038/s41598-018-36381-5 · Cited by 87 · see citing works
Tumor heterogeneity in VHL drives metastasis in clear cell renal cell carcinoma
Hu, J., Tan, P., Ishihara, M., Bayley, N. A., Schokrpur, S., Reynoso, J. G., Zhang, Y., Lim, R. J., Dumitras, C., Yang, L., et al. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01362-2 · Cited by 85 · see citing works
Toward the broad adoption of 3D tumor models in the cancer drug pipeline
Cox, M. C., Reese, L. M., Bickford, L. R., & Verbridge, S. S. (2015) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.5b00172 · Cited by 80 · see citing works
Identification of Cys255 in HIF‐1α as a novel site for development of covalent inhibitors of HIF‐1α/ARNT PasB domain protein–protein interaction
Cardoso, R., Love, R., Nilsson, C. L., Bergqvist, S., Nowlin, D., Yan, J., Liu, K. K. ‐., Zhu, J., Chen, P., Deng, Y., et al. (2012) · Protein Science · doi:10.1002/pro.2172 · Cited by 79 · see citing works
HIF-1α and TAZ serve as reciprocal co-activators in human breast cancer cells
Xiang, L., Gilkes, D. M., Hu, H., Luo, W., Bullen, J. W., Liang, H., & Semenza, G. L. (2015) · Oncotarget · doi:10.18632/oncotarget.4190 · Cited by 73 · see citing works
Self-citation
Restoring physiological levels of ascorbate slows tumor growth and moderates HIF‐1 pathway activity in Gulo−/− mice
Campbell, E. J., Vissers, M. C. M., Bozonet, S., Dyer, A., Robinson, B. A., & Dachs, G. U. (2015) · Cancer Medicine · doi:10.1002/cam4.349 · Cited by 59 · see citing works
Hypoxia-inducible factors as key regulators of tumor inflammation
Mamlouk, S., & Wielockx, B. (2013) · International Journal of Cancer · doi:10.1002/ijc.27901 · Cited by 61 · see citing works
The Hypoxia-inducible Factor Renders Cancer Cells More Sensitive to Vitamin C-induced Toxicity
Tian, W., Wang, Y., Xu, Y., Guo, X., Wang, B., Sun, L., Liu, L., Cui, F., Zhuang, Q., Bao, X., et al. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.538157 · Cited by 59 · see citing works
A novel HIF-1α-integrin-linked kinase regulatory loop that facilitates hypoxia-induced HIF-1α expression and epithelial-mesenchymal transition in cancer cells
Chou, C.-C., Chuang, H.-C., Salunke, S. B., Kulp, S. K., & Chen, C.-S. (2015) · Oncotarget · doi:10.18632/oncotarget.3186 · Cited by 50 · see citing works
Decursin promotes HIF-1α proteasomal degradation and immune responses in hypoxic tumour microenvironment
Ge, Y., Yoon, S.-H., Jang, H., Jeong, J.-H., & Lee, Y.-M. (2020) · Phytomedicine · doi:10.1016/j.phymed.2020.153318 · Cited by 49 · see citing works
Lactylation modification of HIF-1α enhances its stability by blocking VHL recognition
Li, C., Fu, C., Zhou, W., Li, H., Liu, Z., Wu, G., He, T., Shen, M., & Liu, H. (2025) · Cell Communication and Signaling · doi:10.1186/s12964-025-02366-x · Cited by 45 · see citing works
Hypoxia inducible factor (HIF) as a model for studying inhibition of protein–protein interactions
Burslem, G. M., Kyle, H. F., Nelson, A., Edwards, T. A., & Wilson, A. J. (2017) · Chemical Science · doi:10.1039/c7sc00388a · Cited by 39 · see citing works
Intratumoral Hypoxia Reduces IFN-γ–Mediated Immunity and MHC Class I Induction in a Preclinical Tumor Model
Murthy, A., Gerber, S. A., Koch, C. J., & Lord, E. M. (2019) · ImmunoHorizons · doi:10.4049/immunohorizons.1900017 · Cited by 36 · see citing works
Quantitative design strategies for fine control of oxygen in microfluidic systems
Shirure, V. S., Lam, S. F., Shergill, B., Chu, Y. E., Ng, N. R., & George, S. C. (2020) · Lab on a Chip · doi:10.1039/d0lc00350f · Cited by 21 · see citing works
Hypoxic microenvironment in cancer: role in metabolic reprogramming
Sureka, N., Maheshwari, R., Agravat, A., Singhal, S., Zaman, S., Rishi, B., Siraj, F., Zaheer, S., & Misra, A. (2026) · Frontiers in Oncology · doi:10.3389/fonc.2026.1771365 · Cited by 11 · see citing works

lncRNAs HIF1A-AS2 facilitates the up-regulation of HIF-1α by sponging to miR-153-3p, whereby promoting angiogenesis in HUVECs in hypoxia
Li, L., Wang, M., Mei, Z., Cao, W., Yang, Y., Wang, Y., & An, W. (2017) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2017.09.113 · Cited by 128 · see citing works
Defective carotid body function and impaired ventilatory responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1α
Kline, D. D., Peng, Y., Manalo, D. J., Semenza, G. L., & Prabhakar, N. R. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.022634199 · Cited by 263 · see citing works
Self-citation
Characterization of tumor hypoxia by 31P MR spectroscopy.
Steen, R. G. (1991) · American Journal of Roentgenology · doi:10.2214/ajr.157.2.1853799 · Cited by 28 · see citing works
Hypoxia-inducible factor-1,a novel target for cancer cell apoptosis and angiogenesis
Chen, Y. (2008) · Zhonghua zhongliu fangzhi zazhi · Cited by 1 · see citing works
The role of hypoxia‐inducible factor‐2 alpha in angiogenesis
Befani, C. D., & Liakos, P. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.26805 · Cited by 118 · see citing works

Authors: Semenza, G. L.
Affiliations: Johns Hopkins University (US)
Corresponding author: Semenza, Gregg L.
ORCID: Semenza, Gregg L.
Venue: Trends in Pharmacological Sciences
Publisher: Elsevier BV
Published: 2012-04
Volume: 33
Issue: 4
Pages: 207-214
ISSN: 0165-6147 (ISSN-L)
DOI: 10.1016/j.tips.2012.01.005
PMC: PMC3437546
OpenAlex: W2118655588
Cited by: 1,514
References: 91
Citations by year: 2026: 45 · 2025: 78 · 2024: 89 · 2023: 82 · 2022: 132 · 2021: 124 · 2020: 145 · 2019: 108 · 2018: 100 · 2017: 97 · 2016: 130 · 2015: 106 · 2014: 130 · 2013: 115 · 2012: 33
FWCI: 8.90
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Trends in Pharmacological Sciences (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: American Cancer Society
Johns Hopkins University
National Cancer Institute (U54CA143868)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
Keywords: hypoxia-inducible factor, intratumoral hypoxia, tumor progression, HIF inhibitors, angiogenesis, epithelial-mesenchymal transition, cancer stem cells, metastasis, radioresistance (biology), chemoresistance, cancer therapy
MeSH terms: Animals, Antineoplastic Agents, Humans, Neoplasms, Cell Hypoxia, Disease Progression, Hypoxia-Inducible Factor 1, Molecular Targeted Therapy

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Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy

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