Hypoxia response pathway in border cell migration.

Cell invasion and metastasis mark the most lethal phase of cancer, but little is known about the key molecular events that initiate this crucial turning point. Low oxygen, or hypoxia, is thought to be one trigger for metastasis. Hypoxic conditions within the tumor mass are thought to activate signaling pathways that stimulate invasiveness of cancer cells spreading the disease. However, the molecular basis of this process is not well understood. A recent study used Drosophila ovarian border cell migration to model the type of cell migration that occurs in tumors in response to oxygen deprivation through the activation of the hypoxia response pathway (Doronkin et al. Oncogene. 2009). This model organism approach revealed a highly sophisticated mechanism of control of cell migration that is regulated by multiple genetic inputs tied to the hypoxic response. Genetic manipulations with the components of the HIF-1 (hypoxia-inducible factor 1) pathway were able to either inhibit or block the migration of border cells or cause unprecedented acceleration of their migration. The HIF-1-mediated transcriptional cascade appears to be the major regulator of border cell locomotion. Based on the similarity of the fly and human HIF-1 pathways, this model organism study might lead to improvements in understanding hypoxia-induced metastasizing of human cancers. This article discusses new findings in the context of their relevance to cancer metastasis and speculates on the potential regulatory mechanisms and future research directions.