Hypoxia-inducible factor-1 and oncogenic signalling.

An understanding of underlying mechanisms involved in the activation of HIF-1 in response to both hypoxic stress and oncogenic signals has important implications for how these processes may become deregulated in human cancer. Changes in microenvironmental stimuli such as hypoxia and growth factors in combination with genetic lesions, such as loss or inactivation of p53, PTEN or pVHL or oncogenic activation, can all lead to increased HIF-1 activity. This provides cancer cells with a distinct advantage for survival and proliferation, resulting in their ability to form vascular tumours, which are aggressive and metastatic. Accordingly, upregulation of HIF-1alpha, a key component of HIF-1, correlates with a poor treatment outcome using conventional therapies. A variety of mechanisms exist that regulate expression of HIF-1alpha. In recent years, it has become clear that an extensive network of signalling cascades converge on HIF-1alpha to regulate the transcriptional response. A better understanding of this regulation may provide a basis for the development of new cancer therapies. Copyright 2004 Wiley Periodicals, Inc.