Just as low air pressure indicates bad weather is approaching, low oxygen tension in tumour tissue is bad news for cancer patients, as it indicates poor prognosis and an increased risk of developing metastases. So, although anti-angiogenic compounds effectively inhibit growth of solid tumours by reducing blood-vessel formation, hypoxia directly promotes tumour-cell invasiveness. But how is this possible? In the April issue of Cancer Cell, Pennacchietti and colleagues show that expression of the MET tyrosine kinase — the receptor for hepatocyte growth factor (HGF) encoded by the MET proto-oncogene — is induced by low oxygen tension, activating a programme of invasive growth.

Pennacchietti et al. found that MET mRNA expression increased in normal and tumour cell lines that were cultured under hypoxic conditions — 3% oxygen or 100 μM cobalt chloride — and this was followed by a similar increase in MET protein levels. Cobalt chloride is known to mimic hypoxia by stabilizing the hypoxia-inducible transcription factor HIF-1α. As multiple binding sites for HIF-1α are found within the MET promoter, the authors used luciferase reporter assays to show that hypoxia — and wild-type HIF-1α — activates transcription of MET. So, what effect does hypoxia have on MET expression in vivo? The authors identified hypoxic regions within tumour sections using HIF-1α-specific antibodies and found high levels of MET within these poorly vascularized areas. By contrast, regions expressing low levels of MET were highly vascularized and negative for HIF-1α expression.

It is clear that hypoxia induces MET expression in vitro and in vivo, but what is the biological significance of this? Immunoprecipitation assays using anti-MET and anti-phosphotyrosine antibodies showed that, although hypoxia had little effect on the phosphorylation of MET, it considerably increased MET activation in response to HGF signalling. Similarly, activation of GAB1 — a key signal transducer of MET — was also increased under hypoxic conditions, indicating that hypoxia amplifies the HGF signalling cascade. Activation of this pathway in cancer is known to give rise to metastases and the authors used a collagen invasion assay to show that, although hypoxia markedly amplifies the invasive effects of HGF, hypoxia alone was also sufficient to induce invasion.

So, there are two possible explanations — either hypoxia acts via a mechanism unrelated to MET, or hypoxia-induced MET overexpression sensitizes cells to extremely low levels of HGF present in the culture medium. Under normoxic conditions, overexpression of wild-type MET in cell lines closely reproduced the invasive effect of hypoxia in collagen invasion assays, whereas expression of a kinase-inactive form of MET completely prevented this, showing that activation of MET was, in fact, necessary for cellular invasion to occur. These results were confirmed using interference RNA experiments, in which inhibition of MET expression blocked cellular responses to HGF in normoxic and hypoxic conditions. Treating tumours with anti-angiogenic drugs might kill tumours, but at the same time cancer cells are being encouraged to escape. Combination therapy with MET inhibitors might help to overcome this problem.