HIFing the brakes: therapeutic opportunities for treatment of human malignancies.
The unfortunate ability of tumor cells to survive and expand in an uncontrolled manner has captivated the attention of clinicians and basic scientists alike. The molecular mechanisms that tumor cells use to grow are the very same pathways used in normal cell growth and differentiation. One important pathway conferring a growth advantage on tumor cells is the epidermal growth factor receptor (EGFR) pathway. Signaling through the EGFR leads to activation of the phosphatidylinositol 3-kinase and Akt pathway and to increased activity of multiple effectors, including hypoxia-inducible factors (HIFs), which are cellular transcription factors involved in environmental stress response. The target genes that HIF members stimulate that are relevant to tumor growth include transcriptional activators and repressors and cytokines and growth factors, as well as their receptors. In this Perspective, findings from several recent studies are discussed in terms of their effect on the signal transducers, target genes, and tumor properties that are ultimately affected during EGFR-stimulated HIF signaling in cancer cells.
Garcia
Joseph A
JA
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8573, USA. joseph.garcia@utsouthwestern.edu
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D051017:Apoptosis Regulatory Proteins; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000037:antagonists & inhibitors / Q000502:physiology*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000502:physiology; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D018450:Disease Progression; D015195:Drug Design; D066246:ErbB Receptors / Q000187:drug effects / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000502:physiology*; D016211:Transforming Growth Factor alpha / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000502:physiology; D006623:von Hippel-Lindau Disease / Q000235:genetics; D000099162:Endothelial PAS Domain-Containing Protein 1
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D066246:ErbB Receptors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D016211:Transforming Growth Factor alpha; D042461:Vascular Endothelial Growth Factor A; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497396:ARNT protein, human; C497442:HIF1A protein, human; C116973:HIF3A protein, human; C497443:Hif1a protein, mouse; C444643:Hif3a protein, mouse