The role of hypoxia-inducible factors in tumorigenesis

Rankin, E B; Giaccia, A J

doi:10.1038/cdd.2008.21

Cited by 808Cancer, Hypoxia, and MetabolismAngiogenesis and VEGF in CancerErythropoietin and Anemia Treatment

The role of hypoxia-inducible factors in tumorigenesis

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Rankin, E B, Giaccia, A J·2008·Cell Death & Differentiation

DOI 10.1038/cdd.2008.21PMC PMC3050610

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Abstract

Hypoxia-inducible factors (HIFs) are essential mediators of the cellular oxygen-signaling pathway. They are heterodimeric transcription factors consisting of an oxygen-sensitive alpha subunit (HIF-alpha) and a constitutive beta subunit (HIF-beta) that facilitate both oxygen delivery and adaptation to oxygen deprivation by regulating the expression of genes that control glucose uptake, metabolism, angiogenesis, erythropoiesis, cell proliferation, and apoptosis. In most experimental models, the HIF pathway is a positive regulator of tumor growth as its inhibition often results in tumor suppression. In clinical samples, HIF is found elevated and correlates with poor patient prognosis in a variety of cancers. In summary, HIF regulates multiple aspects of tumorigenesis, including angiogenesis, proliferation, metabolism, metastasis, differentiation, and response to radiation therapy, making it a critical regulator of the malignant phenotype.

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HIF-1 controls the expression of genes involved in tumor cell immortalization, stem cell maintenance/de-differentiation, genetic instability, autocrine growth, invasion/metastasis, and treatment failure.
“HIF-1 also controls the expression of genes involved in tumor cell immor- talization, stem cell maintenance/de-differentiation, genetic in- stability, autocrine growth, invasion/metastasis, and treatment failure (6, 7).”
From Digoxin and other cardiac glycosides inhibit HIF-1α synthesis and block tumor growth (2008) · cites this paper as [7]
The Figure 3 caption (Angiogenesis section; page not provided) says HIF-regulated genes contribute to proliferation, invasion, and metastasis, and the Differentiation discussion links HIF signaling to an undifferentiated state. But the review does not establish that HIF-1 controls genes for every listed outcome: it attributes direct Oct4 regulation to HIF-2, does not substantiate immortalization or genetic instability, and describes HIF-1’s effects on radiotherapy response as mixed rather than simply causing treatment failure. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Activation of HIF-1α directly augments transcription of genes involved in angiogenesis and metastasis, such as VEGF, MMP-9, lysyl oxidase, and carbonic anhydrase IX.
“Activation of HIF-1α will directly augment the transcription of genes involved in angiogenesis and metastasis, such as VEGF, MMP-9, lysyl oxidase and carbonic anhydrase IX (Rankin and Giaccia, 2008).”
From SirT3 suppresses hypoxia inducible factor 1α and tumor growth by inhibiting mitochondrial ROS production (2011) · cites this paper as Rankin and Giaccia, 2008
Clinically, hypoxia is associated with HIF activation, metastasis, resistance to chemotherapy and radiotherapy, and poor patient survival.
“Clinically, hypoxia is associated with HIF activation, metastasis, and resistance to chemotherapy and radiotherapy, as well as poor patient survival”
From Hypoxic control of metastasis (2016) · cites this paper as [4]

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Hickey, M. M., & Simon, M. C. (2006) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/s0070-2153(06)76007-0 · Cited by 268 · see citing works
Regulation of E-cadherin Expression by VHL and Hypoxia-Inducible Factor
Esteban, M. A., Tran, M. G. B., Harten, S. K., Hill, P., Castellanos, M. C., Chandra, A., Raval, R., O'Brien, T. S., & Maxwell, P. H. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-2670 · Cited by 262 · see citing works
VHL Promotes E2 Box-Dependent E-Cadherin Transcription by HIF-Mediated Regulation of SIP1 and Snail
Evans, A. J., Russell, R. C., Roche, O., Burry, T. N., Fish, J. E., Chow, V. W. K., Kim, W. Y., Saravanan, A., Maynard, M. A., Gervais, M. L., et al. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.00892-06 · Cited by 248 · see citing works
The Transcriptional Activator Hypoxia Inducible Factor 2 (HIF-2/EPAS-1) Regulates the Oxygen-Dependent Expression of Erythropoietin in Cortical Astrocytes
Chavez, J. C., Baranova, O. V., Lin, J. C.-H., & Pichiule, P. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.2838-06.2006 · Cited by 240 · see citing works
Hypoxia-Inducible Factor 1? Expression Correlates with Angiogenesis and Unfavorable Prognosis in Bladder Cancer
Theodoropoulos, V. (2004) · European Urology · doi:10.1016/j.eururo.2004.04.008 · Cited by 223 · see citing works
Hypoxia promotes a dedifferentiated phenotype in ductal breast carcinoma in situ.
Helczynska, K., Kronblad, Å., Jögi, A., Nilsson, E., Beckman, S., Landberg, G., & Påhlman, S. (2003) · PubMed · Cited by 202 · see citing works
Genetic evidence for a tumor suppressor role of HIF-2α
Acker, T., Díez‐Juan, A., Aragonés, J., Tjwa, M., Brusselmans, K., Moons, L., Fukumura, D., Moreno-Murciano, P., Herbert, J., Burger, A. M., et al. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.07.003 · Cited by 184 · see citing works
Prognostic Impact of Hypoxia-Inducible Factors 1α and 2α in Colorectal Cancer Patients
Yoshimura, H., Dhar, D. K., Kohno, H., Kubota, H., Fujii, T., Ueda, S., Kinugasa, S., Tachibana, M., & Nagasue, N. (2004) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-0946-03 · Cited by 174 · see citing works
Expression of HIF-1α, CA IX, VEGF, and MMP-9 in surgically resected non-small cell lung cancer
Kim, S. J., Rabbani, Z. N., Dewhirst, M. W., Vujašković, Ž., Vollmer, R. T., Schreiber, E.-G., Oosterwijk, E., & Kelley, M. J. (2005) · Lung Cancer · doi:10.1016/j.lungcan.2005.03.036 · Cited by 166 · see citing works
Identification of Transactivation and Repression Functions of the Dioxin Receptor and Its Basic Helix-Loop-Helix/PAS Partner Factor Arnt: Inducible versus Constitutive Modes of Regulation
Whitelaw, M. L., Gustafsson, J.-Α., & Poellinger, L. (1994) · Molecular and Cellular Biology · doi:10.1128/mcb.14.12.8343 · Cited by 161 · see citing works
Loss of pVHL is sufficient to cause HIF dysregulation in primary cells but does not promote tumor growth
Mack, F. A., Rathmell, W. K., Arsham, A. M., Gnarra, J., Keith, B., & Simon, M. C. (2003) · Cancer Cell · doi:10.1016/s1535-6108(02)00240-4 · Cited by 160 · see citing works
Hypoxia-inducible factors 1?? and 2?? are related to vascular endothelial growth factor expression and a poorer prognosis in nodular malignant melanomas of the skin
Giatromanolaki, A. N., Sivridis, E., Kouskoukis, C., Gatter, K. C., Harris, A. L., & Koukourakis, M. I. (2003) · Melanoma Research · doi:10.1097/00008390-200310000-00008 · Cited by 152 · see citing works
Prognostic significance of HIF-1 alpha overexpression in human pancreatic cancer.
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VHL-mediated hypoxia regulation of cyclin D1 in renal carcinoma cells.
Bindra, R. S., Vasselli, J. R., Stearman, R. S., Linehan, W. M., & Klausner, R. D. (2002) · PubMed · Cited by 127 · see citing works
Nucleotide Sequence, Chromosomal Assignment and mRNA Expression of Mouse Hypoxia-Inducible Factor-1α
Wenger, R. H., Rolfs, A., Marti, H. H., Guénet, J., & Gassmann, M. (1996) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1996.0845 · Cited by 122 · see citing works
Targeted Replacement of Hypoxia-Inducible Factor-1α by a Hypoxia-Inducible Factor-2α Knock-in Allele Promotes Tumor Growth
Covello, K. L., Simon, M. C., & Keith, B. (2005) · Cancer Research · doi:10.1158/0008-5472.can-04-3246 · Cited by 121 · see citing works
Expression of hypoxia-inducible factor 1α, hypoxia-inducible factor 2α, and von Hippel–Lindau protein in epithelial ovarian neoplasms and allelic loss of von Hippel-Lindau gene: nuclear expression of hypoxia-inducible factor 1α is an independent prognostic factor in ovarian carcinoma
Osada, R., Horiuchi, A., Kikuchi, N., Yoshida, J., Hayashi, A., Ota, M., Katsuyama, Y., Mellilo, G., & Konishi, I. (2007) · Human Pathology · doi:10.1016/j.humpath.2007.02.010 · Cited by 120 · see citing works
Vhlh Gene Deletion Induces Hif-1-Mediated Cell Death in Thymocytes
Biju, M. P., Neumann, A. K., Bensinger, S. J., Johnson, R. S., Turka, L. A., & Haase, V. H. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.20.9038-9047.2004 · Cited by 110 · see citing works
Prognostic significance of HIF-2α/EPAS1 expression in hepatocellular carcinoma
Bangoura, G. (2007) · World Journal of Gastroenterology · doi:10.3748/wjg.v13.i23.3176 · Cited by 106 · see citing works
The Role of ARNT2 in Tumor Angiogenesis and the Neural Response to Hypoxia
Maltepe, E., Keith, B., Arsham, A. M., Brorson, J. R., & Simon, M. C. (2000) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2000.2928 · Cited by 103 · see citing works
The relation between hypoxia‐inducible factor (HIF)‐1α and HIF‐2α expression with anemia and outcome in surgically treated head and neck cancer
Winter, S. C., SHAH, K. A., Han, C., Campo, L., Turley, H., Leek, R., Corbridge, R., Cox, G. J., & Harris, A. L. (2006) · Cancer · doi:10.1002/cncr.21983 · Cited by 94 · see citing works
Clinical Importance and Therapeutic Implications of the Pivotal CXCL12-CXCR4 (Chemokine Ligand-Receptor) Interaction in Cancer Cell Migration
Arya, M., Ahmed, H. U., Silhi, N., Williamson, M. P., & Patel, H. (2007) · Tumor Biology · doi:10.1159/000102979 · Cited by 81 · see citing works
Overexpression of Hypoxia-Inducible Factor-1α in Human Osteosarcoma: Correlation with Clinicopathological Parameters and Survival Outcome
Yang, Q., Zeng, B., Dong, Y., Shi, Z., Jiang, Z.-M., & Huang, J. (2007) · Japanese Journal of Clinical Oncology · doi:10.1093/jjco/hyl137 · Cited by 75 · see citing works
Radiation and inhibition of angiogenesis by canstatin synergize to induce HIF-1α–mediated tumor apoptotic switch
Magnon, C., Opolon, P., Ricard, M., Connault, E., Ardouin, P., Galaup, A., Métivier, D., Bidart, J., Germain, S., Perricaudet, M., et al. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30269 · Cited by 65 · see citing works
Hypoxia-induced dedifferentiation in neuroblastoma cells
Jögi, A., Øra, I., Nilsson, H., Poellinger, L., Axelson, H., & Påhlman, S. (2003) · Cancer Letters · doi:10.1016/s0304-3835(03)00095-8 · Cited by 46 · see citing works
Molecular Genetics of Sporadic and Familial Renal Cell Carcinoma
Linehan, W. M. (2000) · doi:10.1007/978-1-4613-1101-0_3 · Cited by 44 · see citing works
Protocol of radiotherapy for glioblastoma according to the expression of HIF-1
Irie, N., Matsuo, T., & Nagata, I. (2004) · Brain Tumor Pathology · doi:10.1007/bf02482169 · Cited by 40 · see citing works
MOLECULAR GENETIC STUDIES OF SPORADIC AND FAMILIAL RENAL CELL CARCINOMA
Gnarra, J. R., Glenn, G. M., Latif, F., Anglard, P., Lerman, M. I., Zbar, B., & Linehan, W. M. (1993) · Urologic Clinics of North America · doi:10.1016/s0094-0143(21)00481-x · Cited by 40 · see citing works
Protection of HIF-1-deficient primary renal tubular epithelial cells from hypoxia-induced cell death is glucose dependent
Biju, M. P., Akai, Y., Shrimanker, N., & Haase, V. H. (2005) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00233.2005 · Cited by 35 · see citing works
Characteristic Chromosomal Aberrations in Sporadic Cerebellar Hemangioblastomas Revealed by Comparative Genomic Hybridization
Sprenger, S. H. E., Gijtenbeek, J. M. M., Wesseling, P., Sciot, R., Calenbergh, F. V., Lammens, M. M. Y., & Jeuken, J. W. M. (2001) · Journal of Neuro-Oncology · doi:10.1023/a:1010623119469 · Cited by 32 · see citing works
Relationship of hypoxia-inducible factor 1α and p21WAF1/CIP1 expression to cell apoptosis and clinical outcome in patients with gastric cancer
Mizokami, K., Kakeji, Y., Oda, S., & Maehara, Y. (2006) · World Journal of Surgical Oncology · doi:10.1186/1477-7819-4-94 · Cited by 24 · see citing works

Flagged first, then by citations

Sorted by citations

HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression
Keith, B., Johnson, R. S., & Simon, M. C. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3183 · Cited by 1,693 · see citing works
Hypoxic control of metastasis
Rankin, E. B., & Giaccia, A. J. (2016) · Science · doi:10.1126/science.aaf4405 · Cited by 1,340 · see citing works
Self-citation
Defining normoxia, physoxia and hypoxia in tumours—implications for treatment response
McKeown, S. R. (2014) · The British Journal of Radiology · doi:10.1259/bjr.20130676 · Cited by 1,050 · see citing works
Oxidative Stress and Oxidative Damage in Carcinogenesis
Klaunig, J. E., Kamendulis, L. M., & Hocevar, B. A. (2009) · Toxicologic Pathology · doi:10.1177/0192623309356453 · Cited by 960 · see citing works
“2006) as well as hypoxia-inducible transcription factor 1 a (HIF-1a; Rankin and Giaccia 2008).”
BackgroundMethod
Hypoxia-inducible factors enhance the effector responses of CD8(+) T cells to persistent antigen
Doedens, A. L., Phan, A. T., Stradner, M. H., Fujimoto, J. K., Nguyen, J. V., Yang, E., Johnson, R. S., & Goldrath, A. W. (2013) · Nature Immunology · doi:10.1038/ni.2714 · Cited by 660 · see citing works
Intermittent Hypoxemia and OSA
Dewan, N. A., Nieto, F. J., & Somers, V. K. (2015) · Chest · doi:10.1378/chest.14-0500 · Cited by 641 · see citing works
Digoxin and other cardiac glycosides inhibit HIF-1α synthesis and block tumor growth
Zhang, H., Qian, D. Z., Tan, Y. S., Lee, K., Gao, P., Ren, Y. R., Rey, S., Hammers, H., Chang, D., Pili, R., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0809763105 · Cited by 624 · see citing works
“HIF-1 overexpression in tumor biopsies is associated with increased patient mortality in human cancers of the bladder, brain, breast, cervix, endometrium, oropharynx, lung, skin, and stomach, which reflects the large battery of HIF-1 target genes encoding proteins that play important roles in many key aspects of cance…”
Toward Multi-Targeted Platinum and Ruthenium Drugs—A New Paradigm in Cancer Drug Treatment Regimens?
Kenny, R. G., & Marmion, C. J. (2019) · Chemical Reviews · doi:10.1021/acs.chemrev.8b00271 · Cited by 636 · see citing works
Hypoxia-inducible factor-1 in physiological and pathophysiological angiogenesis: applications and therapies
Zimna, A., & Kurpisz, M. (2015) · BioMed Research International · doi:10.1155/2015/549412 · Cited by 604 · see citing works
“However, notably, proangiogenic activity is directly linked with HIF-dependent VEGF activation, which results in an “angiogenic switch” in growing tumour masses [96].”
Background
An integrative genomics approach identifies Hypoxia Inducible Factor-1 (HIF-1)-target genes that form the core response to hypoxia
Benita, Y., Kikuchi, H., Smith, A. D., Zhang, M. Q., Chung, D. C., & Xavier, R. J. (2009) · Nucleic Acids Research · doi:10.1093/nar/gkp425 · Cited by 469 · see citing works
“In addition, cancer specificregulatory roles for HIF-2 have been demonstrated in an expanding list of cancers (13).”
Background
Tumor Microenvironment in Pancreatic Cancer Pathogenesis and Therapeutic Resistance
Sherman, M. H., & Beatty, G. L. (2022) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathmechdis-031621-024600 · Cited by 481 · see citing works
Oxidative stress and oxidative damage in chemical carcinogenesis
Klaunig, J. E., Wang, Z., Pu, X., & Zhou, S. (2011) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2009.11.028 · Cited by 475 · see citing works
“…HIF-1 expression has been shown to be correlated with poor outcome in patient with head and neck cancer, nasopharyngeal carcinoma, colorectal, pancreatic, breast, cervical, osteosarcoma, endometrial, ovarian, bladder, glioblastoma, and gastric carcinomas (for review, see Rankin and Giaccia, 2008).”
Background
Mechanisms of the Anti-Cancer and Anti-Inflammatory Actions of Vitamin D
Krishnan, A. V., & Feldman, D. (2011) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010510-100611 · Cited by 475 · see citing works
“Calcitriol inhibits VEGF-induced endothelial cell tube formation in vitro and decreases tumor vascularization in mice that bear xenografts of BCa cells overexpressing VEGF (157).”
BackgroundInfluential
SirT3 suppresses hypoxia inducible factor 1α and tumor growth by inhibiting mitochondrial ROS production
Bell, E. L., Emerling, B. M., Ricoult, S. J. H., & Guarente, L. (2011) · Oncogene · doi:10.1038/onc.2011.37 · Cited by 440 · see citing works
“Activation of HIF-1a will directly augment the transcription of genes involved in angiogenesis and metastasis, such as VEGF, MMP-9, lysyl oxidase and carbonic anhydrase IX (Rankin and Giaccia, 2008).”
Background
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
Stimuli‐Responsive Materials for Controlled Release of Theranostic Agents
Wang, Y., Shim, M. S., Levinson, N. S., Sung, H., & Younan Xia, A. (2014) · Advanced Functional Materials · doi:10.1002/adfm.201400279 · Cited by 379 · see citing works
Mechanisms of drug resistance in HCC
Ladd, A. D., Duarte, S. M., Şahin, İ., & Zarrinpar, A. (2023) · Hepatology · doi:10.1097/hep.0000000000000237 · Cited by 379 · see citing works
“[106,107] When HIF-1 α and HIF-2 α are upregulated in the HCC tumor microenvironment, they control processes regulating tumor progression and response to drug therapy.”
BackgroundInfluential
Lipid metabolism in cancer cells under metabolic stress
Munir, R., Lisec, J., Swinnen, J. V., & Zaidi, N. (2019) · British Journal of Cancer · doi:10.1038/s41416-019-0451-4 · Cited by 371 · see citing works
Familial Isolated Pituitary Adenomas (FIPA) and the Pituitary Adenoma Predisposition due to Mutations in the Aryl Hydrocarbon Receptor Interacting Protein (AIP) Gene
Beckers, A. M., Aaltonen, L. A., Daly, A., & Karhu, A. (2013) · Endocrine Reviews · doi:10.1210/er.2012-1013 · Cited by 356 · see citing works
HIF-1 regulation: not so easy come, easy go
Koh, M. Y., Spivak-Kroizman, T. R., & Powis, G. (2008) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2008.08.002 · Cited by 339 · see citing works
Drug repurposing in cancer
Sleire, L., Førde, H. E., Netland, I. A., Leiss, L., Skeie, B. S., & Enger, P. Ø. (2017) · Pharmacological Research · doi:10.1016/j.phrs.2017.07.013 · Cited by 329 · see citing works
“increased in tumors, and are associated with a worse prognosis (78).”
Background
Redox Homeostasis and Cellular Antioxidant Systems: Crucial Players in Cancer Growth and Therapy
Marengo, B., Nitti, M., Furfaro, A. L., Colla, R., Ciucis, C. D., Marinari, U. M., Pronzato, M. A., Traverso, N., & Domenicotti, C. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/6235641 · Cited by 319 · see citing works
Hypoxia-driven pathways in bone development, regeneration and disease
Maes, C., Carmeliet, G., & Schipani, E. (2012) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2012.36 · Cited by 300 · see citing works
D-2-hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function
Sasaki, M., Knobbe, C. B., Itsumi, M., Elia, A. J., Harris, I. S., Chio, I. I. C., Cairns, R. A., McCracken, S., Wakeham, A., Haight, J., et al. (2012) · Genes & Development · doi:10.1101/gad.198200.112 · Cited by 296 · see citing works
HIF1A Overexpression Is Associated with Poor Prognosis in a Cohort of 731 Colorectal Cancers
Baba, Y., Nosho, K., Shima, K., Irahara, N., Chan, A. T., Meyerhardt, J. A., Chung, D. C., Giovannucci, E. L., Fuchs, C. S., & Ogino, S. (2010) · American Journal Of Pathology · doi:10.2353/ajpath.2010.090972 · Cited by 284 · see citing works
“Thus, HIF1A may affect several key steps in colon tumorigenesis, including angiogenesis, metabolism, proliferation, and invasion.(49) Our observational results certainly support the “oncogenic” role of HIF1A in colorectal cancer.”
BackgroundResult
Hypoxia induced EMT: A review on the mechanism of tumor progression and metastasis in OSCC
Joseph, J. P., Harishankar, M. K., Pillai, A. A., & Devi, A. (2018) · Oral Oncology · doi:10.1016/j.oraloncology.2018.03.004 · Cited by 281 · see citing works
Targeting the Warburg effect: A revisited perspective from molecular mechanisms to traditional and innovative therapeutic strategies in cancer
Liao, M., Yao, D., Wu, L., Luo, C., Wang, Z., Zhang, J., & Liu, B. (2023) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2023.12.003 · Cited by 280 · see citing works
Chronic Autophagy Is a Cellular Adaptation to Tumor Acidic pH Microenvironments
Wojtkowiak, J. W., Rothberg, J. M., Kumar, V., Schramm, K. J., Haller, E. M., Proemsey, J. B., Lloyd, M. C., Sloane, B. F., & Gillies, R. J. (2012) · Cancer Research · doi:10.1158/0008-5472.can-11-3881 · Cited by 251 · see citing works
“Hypoxia-inducible factors (HIFs) are transcription factors that control the expression of numerous genes known to regulate glucose uptake, angiogenesis, cell proliferation, apoptosis, and autophagy (17).”
Background
Contextual Synthetic Lethality of Cancer Cell Kill Based on the Tumor Microenvironment
Chan, N. H. L., Pires, I. M., Bencokova, Z., Coackley, C. L., Luoto, K. R., Bhogal, N., Lakshman, M., Gottipati, P., Oliver, F. J., Helleday, T., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-2352 · Cited by 243 · see citing works
B cell regulation of the anti-tumor response and role in carcinogenesis
Schwartz, M. A., Zhang, Y. X., & Rosenblatt, J. D. (2016) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-016-0145-x · Cited by 244 · see citing works
Epithelial-mesenchymal transition: From molecular mechanisms, redox regulation to implications in human health and disease
Cannito, S., Novo, E., di Bonzo, L. V., Busletta, C., Colombatto, S., & Parola, M. (2010) · Antioxidants & Redox Signaling · doi:10.1089/ars.2009.2737 · Cited by 239 · see citing works
“Where the relationships between hypoxia, EMT and cancer are concerned, it is well known that hypoxia is a major and common feature of almost any clinically relevant human solid malignant tumor, including cancer of the breast, prostate, lung, pancreas, rectum, brain, uterine cervix, melanomas, liver, soft tissue sarcom…”
Influential
The oncofetal H19 RNA connection: Hypoxia, p53 and cancer
Matouk, I., Mezan, S., Mizrahi, A., Ohana, P., Abu-lail, R., Fellig, Y., de-Groot, N., Galun, E., & Hochberg, A. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2010.01.010 · Cited by 239 · see citing works
“Tumor tissue hypoxia enhances angiogenesis, tumor development, and metastasis, and in unison, could lead to a failure of response to current therapeutic modalities [1].”
Background
Tumor cell metabolism
Romero‐Garcia, S., López-González, J. S., ́ez-Viveros, J. L. B., Aguilar‐Cázares, D., & Prado-Garcı́a, H. (2011) · Cancer Biology & Therapy · doi:10.4161/cbt.12.11.18140 · Cited by 240 · see citing works
“Increasing evidence has associated HIF-1 function with metastatic characteristics, such as the epithelial to mesenchymal transition, cell detachment, invasion and tumor cell seeding;(28,30) HIF-1 overexpression and prevalence is also correlated with the severity of the cancer.(3,4,38,39) HIF-1 is a heterodimeric compl…”
Background
Hypoxia-Inducible Factor 3 Is an Oxygen-Dependent Transcription Activator and Regulates a Distinct Transcriptional Response to Hypoxia
Zhang, P., Yao, Q., Lu, L., Li, Y., Chen, P.-J., & Duan, C. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.02.011 · Cited by 232 · see citing works
“These HIF-1 and/or HIF-2 target genes participate in many biological processes, including erythropoiesis, angiogenesis, metabolic reprograming, cell-cycle regulation, and tumor progression (Gordan and Simon, 2007; Rankin and Giaccia, 2008).”
Background
Hif1α deletion reveals pro-neoplastic function of B cells in pancreatic neoplasia
Lee, K., Spata, M., Bayne, L., Buza, E., Durham, A., Allman, D., Vonderheide, R., & Simon, M. (2015) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-0822 · Cited by 203 · see citing works
“Once stabilized, HIF1α transactivates a wide range of genes involved in the regulation of metabolism, angiogenesis, cell survival, and inflammation (9, 10).”
Background
Hypoxia inducible factor as a therapeutic target for atherosclerosis
Jain, T., Nikolopoulou, E. A., Xu, Q., & Qu, A. (2017) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.09.003 · Cited by 214 · see citing works
“There is strong evidence to suggest that some variants have contrasting functions (Rankin and Giaccia, 2008).”
Background
The HIF-1 Hypoxia-Inducible Factor Modulates Lifespan in C. elegans
Zhang, Y., Shao, Z., Zhai, Z., Shen, C., & Powell-Coffman, J. A. (2009) · PLoS ONE · doi:10.1371/journal.pone.0006348 · Cited by 211 · see citing works
“There is also great interest in pharmaceuticals that can inhibit HIF and may be effective in combinatorial treatments for certain cancers [46].”
Background
Prognostic significance of hypoxia-inducible factor-1 , TWIST1 and Snail expression in resectable non-small cell lung cancer
Hung, J.-J., Yang, M.-H., Hsu, H.-S., Hsu, W.-H., Liu, J.-S., & Wu, K.-J. (2009) · Thorax · doi:10.1136/thx.2009.115691 · Cited by 207 · see citing works
“19 26 Increased HIF-1 a expression correlates with metastasis, poor prognosis and resistance to treatment in a variety of tumours including NSCLC. 9 27–29 HIF-1 a stabilisation was shown to induce the expression of certainEMT regulators.”
Background
The role of hypoxia-inducible factors in tumor angiogenesis and cell metabolism
Lv, X., Li, J., Chuhong, Z., Tian, H., Li, S., He, S., Yan, H., Tan, Y., Lei, M., Wen, M., et al. (2016) · Genes & Diseases · doi:10.1016/j.gendis.2016.11.003 · Cited by 209 · see citing works
“Accordingly, hypoxia-inducible factor (HIF) contributes to tumor progression in a positive feedback loop.(11,12)”
Background
Targeting CDK1 in cancer: mechanisms and implications
Wang, Q., Bode, A. M., & Zhang, T. (2023) · npj Precision Oncology · doi:10.1038/s41698-023-00407-7 · Cited by 209 · see citing works
Physiological and Genetic Adaptations to Diving in Sea Nomads
Ilardo, M. A., Moltke, I., Korneliussen, T. S., Cheng, J. Y., Stern, A. J., Racimo, F., Damgaard, P. D. B., Sikora, M., Seguin‐Orlando, A., Rasmussen, S., et al. (2018) · Cell · doi:10.1016/j.cell.2018.03.054 · Cited by 200 · see citing works
“, 1999), including intensive care treatment (McKenna and Martin, 2016) and tumorigenesis (Rankin and Giaccia, 2008).”
The Role of Vitamin D in Cancer Prevention and Treatment
Krishnan, A. V., Trump, D. L., Johnson, C. S., & Feldman, D. (2010) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2010.02.011 · Cited by 196 · see citing works
Development of Inhibitors Targeting Hypoxia-Inducible Factor 1 and 2 for Cancer Therapy
Yu, T., Tang, B., & Sun, X. (2017) · Yonsei Medical Journal · doi:10.3349/ymj.2017.58.3.489 · Cited by 192 · see citing works
“The discovery of hypoxia-inducible factors (HIFs) as master driving forces of the cellular adaption to hypoxia has provided a fundamental molecular link to the dilemma.(3) HIFs regulate a vast array of genes encoding proteins involved in cancer progression and treatment resistance.”
Hypoxic Induction of Vasorin Regulates Notch1 Turnover to Maintain Glioma Stem-like Cells
Man, J., Yu, X., Huang, H., Zhou, W., Xiang, C., Huang, H., Miele, L., Liu, Z.-G., Bebek, G., Bao, S., et al. (2017) · Cell stem cell · doi:10.1016/j.stem.2017.10.005 · Cited by 181 · see citing works
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Authors: Rankin, E. B., & Giaccia, A. J.
Affiliations: Stanford Medicine (US)
Corresponding author: Giaccia, A J
ORCID: Rankin, E B
Giaccia, A J
Venue: Cell Death & Differentiation
Publisher: Springer Science and Business Media LLC
Published: 2008-02-15
Volume: 15
Issue: 4
Pages: 678-685
ISSN: 1350-9047 (ISSN-L)
1476-5403
DOI: 10.1038/cdd.2008.21
PMC: PMC3050610
OpenAlex: W2014245338
Cited by: 806
References: 105
Citations by year: 2026: 18 · 2025: 24 · 2024: 30 · 2023: 34 · 2022: 43 · 2021: 42 · 2020: 39 · 2019: 38 · 2018: 33 · 2017: 44 · 2016: 45 · 2015: 48 · 2014: 56 · 2013: 51 · 2012: 46
FWCI: 5.10
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Cell Death and Differentiation (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Cancer Institute (P01CA067166, T32CA009151)
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, carcinogenesis, oxygen signaling, hypoxia-inducible factor alpha, angiogenesis, cancer metabolism, tumor growth, metastasis, radiation response, tumor differentiation, prognosis, apoptosis, cell proliferation
MeSH terms: Endothelial PAS Domain-Containing Protein 1, Adaptation, Physiological, Animals, Hypoxia, Cell Differentiation, Energy Metabolism, Humans, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplasms, Neovascularization, Pathologic, Oxygen, Signal Transduction, Cell Hypoxia, Cell Proliferation, Basic Helix-Loop-Helix Proteins, Hypoxia-Inducible Factor 1, alpha Subunit

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The role of hypoxia-inducible factors in tumorigenesis

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