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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.