Is the hypoxia-inducible factor pathway important in gastric cancer?
Tumour hypoxia is well recognised in oncology to be a key factor resulting in treatment resistance and poor prognosis. Hypoxia leads to the expression of a number of gene products that are involved in tumour progression, invasion and metastasis formation. The most important of these proteins is thought to be hypoxia-inducible factor-1alpha (HIF-1alpha), which appears to be a master regulator of the cellular response to hypoxia. HIF-1alpha expression is associated with a poor prognosis and treatment response in a number of tumour sites. There is some evidence that the HIF-1alpha pathway might be involved in gastric carcinogenesis. Studies have shown reactive oxygen species from Helicobacter pylori, associated with the development of gastric cancer, stabilise HIF-1alpha. Non-steroidal anti-inflammatory drugs, shown to reduce the risk of gastric cancer, can decrease HIF-1alpha expression. Although a large study correlating HIF-1alpha expression with prognosis is lacking in gastric cancer, the immunohistochemical expression of HIF-1alpha target genes (Glut-1, VEGF, CA9, iNOS) is associated with a poor prognosis. In addition, the targeted inhibition of HIF-1alpha has been shown to inhibit the growth of gastric tumours in animals. Increased understanding of the importance of hypoxia and the HIF-1alpha pathways may therefore hold the key to prevention strategies, improved selection of patients for adjuvant therapy and new treatments for the disease.
Griffiths
E A
EA
Department of Gastrointestinal Surgery, South Manchester University Hospitals NHS Trust, Wythenshawe Hospital, South Moor Road, Wythenshawe, M23 9LT, UK.
Pritchard
S A
SA
Welch
I M
IM
Price
P M
PM
West
C M
CM
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D000951:Antigens, Neoplasm / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005544:Forecasting; D016147:Genes, Tumor Suppressor; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D016481:Helicobacter Infections / Q000150:complications; D016480:Helicobacter pylori; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D008833:Microcirculation; D009363:Neoplasm Proteins / Q000378:metabolism*; D011379:Prognosis; D013274:Stomach Neoplasms / Q000098:blood supply / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D051272:Glucose Transporter Type 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins; D042461:Vascular Endothelial Growth Factor A; D051546:Cyclooxygenase 2; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases