Adaptation of cancer cells to their microenvironment is an important driving force in the clonal selection that leads to invasive and metastatic disease. O2 concentrations are markedly reduced in many human cancers compared with normal tissue, and a major mechanism mediating adaptive responses to reduced O2 availability (hypoxia) is the regulation of transcription by hypoxia-inducible factor 1 (HIF-1). This review summarizes the current state of knowledge regarding the molecular mechanisms by which HIF-1 contributes to cancer progression, focusing on (1) clinical data associating increased HIF-1 levels with patient mortality; (2) preclinical data linking HIF-1 activity with tumor growth; (3) molecular data linking specific HIF-1 target gene products to critical aspects of cancer biology and (4) pharmacological data showing anticancer effects of HIF-1 inhibitors in mouse models of human cancer.

Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics

Hypoxia-Inducible Factor (HIF)-1 is a dimeric protein complex that plays an integral role in the body's response to low oxygen concentrations, or hypoxia. HIF-1 is among the primary genes involved in the homeostatic process, which can increase vascularization in hypoxic areas such as localized ischemia and tumors. It is a transcription factor for dozens of target genes; HIF-1 is also essential for immunological responses and is a crucial physiological regulator of homeostasis, vascularization, and anaerobic metabolism. Furthermore, HIF-1 is increasingly studied because of its perceived therapeutic potential. As it causes angiogenesis, enhancement of this gene within ischemic patients could promote the vessel proliferation needed for oxygenation. In contrast, as HIF-1 allows for survival and proliferation of cancerous cells due to its angiogenic properties, inhibition potentially could prevent the spread of cancer. With a growing understanding of the HIF-1 pathway, the inhibition and stimulation of its transcriptional activity via small molecules is now an attractive goal. Gene therapy to achieve both vessel proliferation and tumor regression has been demonstrated in animal studies but requires significant improvement and modification before becoming commercially available. This review focuses on the potential of the HIF-1 pathway in therapeutic intervention for the treatment of diseases such as cancer and ischemia.

Hypoxia-Inducible Factor (HIF)-1 regulatory pathway and its potential for therapeutic intervention in malignancy and ischemia.

Hypoxia-mediated drug resistance: novel insights on the functional interaction of HIFs and cell death pathways.

Hypoxia has been recognized as one of the fundamentally important features of solid tumors and plays a critical role in various cellular and physiologic events, including cell proliferation, survival, angiogenesis, immunosurveillance, metabolism, as well as tumor invasion and metastasis. These responses to hypoxia are at least partially orchestrated by activation of the hypoxia-inducible factors (HIFs). HIF-1 is a key regulator of the response of mammalian cells to oxygen deprivation and plays critical roles in the adaptation of tumor cells to a hypoxic microenvironment. Hypoxia and overexpression of HIF-1 have been associated with radiation therapy and chemotherapy resistance, an increased risk of invasion and metastasis, and a poor clinical prognosis of solid tumors. The discovery of HIF-1 signaling has led to a rapidly increasing understanding of the complex mechanisms involved in tumor hypoxia and has helped greatly in screening novel anticancer agents. In this review, we will first introduce the cellular responses to hypoxia and HIF-1 signaling pathway in hypoxia, and then summarize the multifaceted role of hypoxia in the hallmarks of human cancers.

Role of hypoxia in the hallmarks of human cancer.

Mitochondrial complex II is a tumor suppressor comprised of four subunits (SdhA, SdhB, SdhC, and SdhD). Mutations in any of these should disrupt complex II enzymatic activity, yet defects in SdhA produce bioenergetic deficiency while defects in SdhB, SdhC, or SdhD induce tumor formation. The mechanisms underlying these differences are not known. We show that the inhibition of distal subunits of complex II, either pharmacologically or via RNA interference of SdhB, increases normoxic reactive oxygen species (ROS) production, increases hypoxia-inducible factor alpha (HIF-alpha) stabilization in an ROS-dependent manner, and increases growth rates in vitro and in vivo without affecting hypoxia-mediated activation of HIF-alpha. Proximal pharmacologic inhibition or RNA interference of complex II at SdhA, however, does not increase normoxic ROS production or HIF-alpha stabilization and results in decreased growth rates in vitro and in vivo. Furthermore, the enhanced growth rates resulting from SdhB suppression are inhibited by the suppression of HIF-1alpha and/or HIF-2alpha, indicating that the mechanism of SdhB-induced tumor formation relies upon ROS production and subsequent HIF-alpha activation. Therefore, differences in ROS production, HIF proliferation, and cell proliferation contribute to the differences in tumor phenotype in cells lacking SdhB as opposed to those lacking SdhA.

Loss of the SdhB, but Not the SdhA, subunit of complex II triggers reactive oxygen species-dependent hypoxia-inducible factor activation and tumorigenesis.

OBJECTIVES The aim of the study was to observe the effect of antisense hypoxia-inducible factor 1alpha (HIF-1alpha) on progression, metastasis, and chemosensitivity of pancreatic cancer METHODS BxPc-3 cells transfected with antisense HIF-1alpha plasmid were exposed to 05% O2 for 4 hours Expressions of HIF-1alpha, survivin, and beta1 integrin were detected by reverse transcriptase -polymerase chain reaction and Western blotting Growth inhibition rates and apoptosis rates of BxPc-3 cells under different dosages of chemotherapy agents (5-fluorouracil, doxorubicin, and gemcitabine) were measured by MTT colorimetric assay and flow cytometry The migration of BxPc-3 cells was assayed using transwell cell culture chambers Subcutaneous transplantation of BxPc-3 cells in nude mice for 8 weeks was to assess progression and metastasis of pancreatic cancer RESULTS Expression of HIF-1alpha was obviously down-regulated, and at the same time, survivin and beta1-integrin expressions were markedly down-regulated in the experimental group (P < 005) Higher dosages (100, 200, and 400 mg/L of 5-fluorouracil; 005, 0075, and 01 mg/L of doxorubicin; and 10(-9), 10(-8), and 10(-7) mol/L of gemcitabine) caused a greater increase of inhibition in the experimental group than in control (P < 005) The number of migrated BxPc-3 cells in the experimental group was far less than in control (P < 005) In vivo, the tumor size and weight in the experimental group were significantly lower than those in control (P < 005) CONCLUSION Our data demonstrate that antisense HIF-1alpha inhibits expressions of survivin and beta1 integrin, enhancing apoptosis in human pancreatic cancer cells and restraining the progression and metastasis of pancreatic cancer Therefore, HIF-1alpha may play a very important role in progression, metastasis, and chemosensitivity of human pancreatic cancer Blocking HIF-1alpha in pancreatic cancer cells may offer an avenue for gene therapy

Effect of antisense hypoxia-inducible factor 1alpha on progression, metastasis, and chemosensitivity of pancreatic cancer.

Extracellular matrix (ECM) degradation is an essential step that allows tumor cells to penetrate a tissue barrier and become metastatic Heparanase (HPSE) is an endoglycosidase that specifically degrades heparin sulfate proteoglycans (HSPG), a chief component of ECM HPSE is not expressed in normal epithelial cells but can be detected in a variety of human carcinomas including pancreatic cancer In the present study, human pancreatic cancer cell line Panc-1 was transfected with HPSE antisense oligodeoxynucleotide (AS-ODN) in vitro, then the inhibitory effect of AS-ODN on HPSE gene expression and invasive ability of Panc-1 cells in vitro was examined The HPSE mRNA and protein expression of Panc-1 cells transfected with AS-ODN was significantly inhibited However, there were no marked inhibitory effects in Panc-1 cells treated with nonsense oligodeoxynucleotide (NS-ODN) Moreover, a modified Boyden chamber assay demonstrated that transfection with HPSE AS-ODN significantly inhibited invasive potential of Panc-1 cells in vitro after AS-ODN transfection This suggests that HPSE AS-ODN may contribute to the inhibition of HPSE mRNA and protein expression, and results in a decrease of the invasive ability of Panc-1 in vitro

Transfection of antisense oligodeoxynucleotide inhibits heparanase gene expression and invasive ability of human pancreatic cancer cell in vitro.

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Effect of antisense hypoxia-inducible factor 1alpha on progression, metastasis, and chemosensitivity of pancreatic cancer.

Transfection of antisense oligodeoxynucleotide inhibits heparanase gene expression and invasive ability of human pancreatic cancer cell in vitro.