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Educational Session: Hypoxia: Impact on Cancer Biology

Overexpression of hypoxia-inducible factor 1 in human cancers: Mechanisms and consequences.

Johns Hopkins University School of Medicine, Baltimore, MD

Abstract

In many human cancers, rapid cell proliferation in associated with the elaboration of tumor vasculature which is structurally and functionally abnormal, resulting in perfusion that is characterized by marked spatial and temporal heterogeneity. Studies of human cancers that are accessible to direct PO2 measurement by Eppendorf microelectrodes, such as cancers of the uterine cervix or head and neck, have led to two important findings. First, intratumoral oxygen concentrations are markedly reduced relative to surrounding normal tissue. Second, the risk that a tumor will invade surrounding tissue, metastasize to distant sites, fail ot respond to radiation and/or chemotherapy, and result in patient mortality is significantly increased in those tumors with the greatest degree of hypoxia (PO2 < 10 mm Hg).

Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes involved in critical aspects of cancer biology, including angiogenesis (vascular endothelial growth factor [VEGF], placental growth factor), cell proliferation and survival (insulin-like growth factor [IGF] 2, transforming growth factor [TGF] ), glucose metabolism (glucose transporter 1 and 3, hexokinase 1 and 2, lactate dehydrogenase A), and invasion (C-MET, matrix metalloproteinase 2, urokinase plasminogen activator receptor). HIF-1 is a heterodimer, consisting of a constitutively-expressed HIF-1ß subunit and a HIF-1 subunit, the expression of which is oxygen- and growth factor-regulated. A related protein, designated HIF-2, is also oxygen-regulated and can dimerize with HIF-1ß. Overexpression of HIF-1 in human colon or pancreatic cancer cells or transformed mouse embryo fibroblasts (MEFs) results in increased xenograft growth in nude mice. HIF-1 overexpression leads to increased tumor growth by at least two different mechanisms. HIF-1 overexpression in colon cancer cells induces increased tumor vascularization. In contrast, HIF-1 overexpression in pancreatic cancer cells results in increased glycolytic metabolism and protection against hypoxia-induced apoptosis. In transformed MEFs, loss of HIF-1 activity is associated with decreased resistance to oxygen deprivation, radiation, and chemotherapeutic agents that induce double-strand DNA breaks.

Immunohistochemical studies of human cancer biopsies have revealed that HIF-1 is overexpressed in the vast majority of human primary cancers and metastases. In cancers of the brain, breast, colon, endometrial, head and neck, lung, ovary, and pancreas, HIF-1 overexpression is associated with increased microvessel density and/or VEGF expression. Most importantly, HIF-1 overexpression is associated with increased risk of mortality in gastrointestinal stromal cell tumor of the stomach, oligodendroglioma, and cancers of the breast, cervix, endometrium, oropharynx, and ovary. HIF-2 overexpression is associated with increased risk of mortality in head and neck cancer and malignant melanoma. HIF-1 overexpression is also associated with resistance to photodynamic and radiation therapy in early-stage esophageal cancer and oropharyngeal squamous cell carcinoma. Analysis of oropharyngeal squamous cell carcinomas revealed two different patterns of HIF-1 overexpression. In approximately two-thirds of the tumor biopsy sections analyzed, HIF-1 was expressed at high levels in cells surrounding areas of necrosis, representing viable cells that were farthest removed from a blood vessel and subjected to the greatest degree of hypoxia. In the remaining cases, HIF-1 was expressed at high levels throughout the section, including cells immediately adjacent to a patent blood vessel, suggesting that a mechanism other than hypoxia was responsible.

In support of this hypothesis, increased HIF-1 expression has been shown to be associated with multiple genetic alterations in human cancer cells. Most dramatic is the effect in clear cell renal carcinoma (RCC) of loss-of-function mutations in the VHL gene, which encodes the von Hippel-Lindau tumor suppressor. VHL is the recognition subunit of an E3 ubiquitin-protein ligase that targets HIF-1 and HIF-2 for proteasomal degradation under non-hypoxic conditions. In the absence of VHL, HIF-1 and HIF-2 are constitutively expressed, resulting in dysregulated expression of HIF-1 target genes such as VEGF. As a result, RCC are among the most highly vascularized human tumors. Recent data indicate that dysregulated expression of the HIF-1 target gene TGF- in RCC cells, which express the epidermal growth factor receptor (EGFR), establishes an autocrine signaling loop. In addition, HIF-1-dependent activation of C-MET and CXCR4 may play critical roles in RCC invasion and metastasis. Thus, in RCC, dysregulated HIF-1 activity provides a molecular basis for at least three of the hallmarks of cancer: sustained angiogenesis, proliferation in the absence of exogenous growth factors, and tissue invasion/metastasis. Loss-of-function for other tumor suppressors, including p53, PTEN, and p14ARF, has been shown result in significant but more modest increases in HIF-1 expression. In addition, increased activity of the EGFR, IGF1R, HER2neu (ERBB2), SRC tyrosine kinases and/or the MAP kinase and phosphatidylinositol 3-kinase signal transduction pathways is associated with increased HIF-1 activity. Remarkably, whereas hypoxia increases HIF-1 stability, MAP kinase and phosphatidylinositol 3-kinase signaling have been shown to increase HIF-1 synthesis. Thus, oncogene gain-of-function may increase HIF-1 expression in a manner that is independent of and additive to that of hypoxia.

Taken together, the data presented suggest that increased HIF-1 activity may contribute to the increased risks of invasion, metastasis, treatment failure, and mortality that are associated with intratumoral hypoxia. Increased HIF-1 activity may contribute to the process by which oncogenic mutations are selected during the clonal evolution of human cancers. Anti-angiogenic effects of several novel signal transduction inhibitors appear to be due in part to their inhibition of HIF-1 activity. Efforts are currently underway to identify selective HIF-1 inhibitors as potential novel anti-cancer agents.