ABSTRACT
Lack of oxygen (hypoxia) is a central hallmark of cancer and a pivotal driving force of malignant progression. Transcriptional activators of the hypoxia-inducible factor α (HIFα) family represent the principal molecular mediators of hypoxia under both physiological and pathophysiological conditions. While HIF-2α is expressed in a tissue- and cell-type-restricted manner, stabilization of HIF-1α was reported in tumours of widely different origin, and functional analyses led to the perception of HIF-1α as an oncoprotein. In this review, we aim to acknowledge HIFα's growing complexity by outlining its functional relevance for genomic integrity and tumour heterogeneity, two features of paramount importance for basic and clinical oncology. Pharmaceutical companies around the globe are ambitiously hunting for HIF-1α-inhibiting compounds, some of which are currently being evaluated in phase 1 trials. To avoid the rather disappointing clinical efficacy emblematic of most targeted therapeutics, potential resistance mechanisms of, as well as potential combination partners for, HIF-1α-inhibiting drugs should be evaluated. In this regard, the interrelation of HIF-1α with genomic integrity and tumour heterogeneity offers ample possibilities, potentially resulting in more efficient clinical translation of HIF-1α's pathobiology.
Subject(s)
DNA Repair , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Neoplasms/pathology , Animals , DNA Damage , Genomics , Humans , Molecular Targeted Therapy , Neoplasms/drug therapy , Neoplasms/genetics , Neoplasms/metabolismABSTRACT
Loss of the coxsackie and adenovirus receptor (CAR) has been found in various human cancers. Underlying mechanisms, however, are still poorly understood. Therefore, the objective of this study was to investigate the function of hypoxia, a ubiquitous phenomenon in carcinomas, in CAR regulation. In our approach, hypoxia and treatment with cobalt-(II)-chloride (CoCl(2)) induced a downregulation of CAR protein and mRNA expression, as well as a suppression of CAR gene promoter activity in AGS (gastric), SW480 (colon) and PC3 (prostate) cancer cells. In line with these findings we noted a decreased adenoviral uptake under hypoxic conditions. Aiming to further elucidate the molecular basis of this observation, a full-length hypoxia-inducible factor-1alpha (HIF-1alpha) cDNA was ectopically overexpressed in the AGS cell line diminishing CAR expression and CAR gene promoter activity. In line with these findings, exposure of HIF-1alpha-deficient AGS cells to hypoxia did not alter CAR mRNA expression level. On the basis of these data, it may be suggested that loss of CAR in human cancer cell lines under hypoxic conditions occurs in an HIF-1alpha-dependent manner.
Subject(s)
Cell Hypoxia/physiology , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Receptors, Virus/metabolism , Animals , Antimutagenic Agents/pharmacology , Blotting, Western , CHO Cells , Cell Line, Tumor , Cobalt/pharmacology , Coxsackie and Adenovirus Receptor-Like Membrane Protein , Cricetinae , Cricetulus , Gene Expression Regulation, Neoplastic/drug effects , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Promoter Regions, Genetic/genetics , Receptors, Virus/geneticsABSTRACT
Gastric adenocarcinoma is characterised by rapid emergence of systemic metastases, resulting in poor prognosis due to vanished curative treatment options. Better understanding of the molecular basis of gastric cancer spread is needed to design innovative treatments. The transcription factor HIF-1alpha (hypoxia-inducible factor 1alpha) is frequently overexpressed in human gastric cancer, and inhibition of HIF-1alpha has proven antitumour efficacy in rodent models, whereas the relevance of HIF-1alpha for the metastatic phenotype of gastric adenocarcinoma remains elusive. Therefore, we have conducted a comprehensive analysis of the role of HIF-1alpha for pivotal metastasis-associated processes of human gastric cancer. Immunhistochemistry for HIF-1alpha showed specific staining at the invading tumour edge in 90% of human gastric cancer samples, whereas normal gastric tissue was negative and only a minority of early gastric cancers (T1 tumours) showed specific staining. Hypoxia-inducible factor 1alpha-deficient cells showed a significant reduction of migratory, invasive and adhesive properties in vitro. Furthermore, the HIF-1alpha-inhibitor 2-methoxy-estradiol significantly reduced metastatic properties of gastric cancer cells. The accentuated expression at the invading edge together with the in vitro requirement of HIF-1alpha for migration, invasion and adherence argues for a pivotal role of HIF-1alpha in local invasion and, ultimately, systemic tumour spread. These results warrant the exploration of HIF-1alpha-inhibiting substances in clinical treatment studies of advanced gastric cancer.
