The incidence of distant metastases is higher in the tumours with low oxygen pressure than in those with high oxygen pressure. It is well known that hypoxia induces the transcription of various genes involved in angiogenesis and anaerobic metabolism necessary for the growth of tumour cells in vivo, suggesting that hypoxia may also induce the transcription of metastasis-associated genes. We sought to identify the metastasis-associated genes differentially expressed in tumour cells under hypoxic conditions with the use of a DNA microarray system. We found that hypoxia enhanced the expression of autocrine motility factor mRNA in various cancer cells and also enhanced the random motility of pancreatic cancer cells. Autocrine motility factor inhibitors abrogated the increase of motility under hypoxic conditions. In order to explore the roles of hypoxia-inducible factor-1a, we established hypoxia-inducible factor-1a-transfectants and dominant negative hypoxiainducible factor-1a-transfectants. Transfection with hypoxia-inducible factor-1a and dominant-negative hypoxia-inducible factor-1a enhanced and suppressed the expression of autocrine motility factor/phosphohexase isomerase/neuroleukin mRNA and the random motility, respectively. These results suggest that hypoxia may promote the metastatic potential of cancer cells through the enhanced autocrine motility factor/phosphohexase isomerase/neuroleukin mRNA expression and that the disruption of the hypoxia-inducible factor-1 pathway may be an effective treatment for metastasis. As metastasis is the major cause of death in cancer patients, control of metastasis is most important in the therapies for cancer patients. In order to control metastasis, we need to understand the details of metastatic process that is now thought to take multiple steps. Although a variety of factors have been documented to play important roles in the metastatic steps (Poste and Fidler, 1980;Liotta, 1986Liotta, , 1988Nicolson, 1988), many factors are yet to be elucidated. Several clinical investigations demonstrated that patients with hypoxic tumours had poor prognoses and that the incidence of distant metastases was higher in the tumours with low oxygen pressure than in those with high oxygen pressure (Gatenby et al, 1988;Brizel et al, 1996;Hockel et al, 1998;Rofstad, 2000). These studies suggest that the tumour cells exposed to hypoxia at the primary tumour sites acquire aggressive properties including metastatic potential more than the welloxygenated tumour cells do. In fact, recent reports have demonstrated that hypoxia enhances the expression of vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) in tumour cells, resulting in an increase of metastatic potential (Claffey and Robinson, 1996;Shi et al, 1999;Biroccio et al, 2000). However, it remains poorly understood how hypoxia promotes tumour cells' metastatic potential.When tumour cells are exposed to hypoxia, hypoxia-inducible factor-1 (HIF-1), which is a transcription factor composed of HIF-1a and HIF-1b subunits (Wang et al,...

Whereas mobilization to inflammatory sites is an important function of neutrophils, it remains to be determined whether granulocyte colony-stimulating factor (G-CSF) stimulates the mobilization of neutrophils to the inflammatory sites. This study compared the expression of more than 9000 genes in neutrophils treated with and without G-CSF with the use of a DNA microarray system to determine the effects of G-CSF on the function of neutrophils. It was found that messenger RNA expression of epithelial cell–derived neutrophil attractant-78 (ENA-78), which has been reported to be a chemotactic factor for neutrophils, was induced by G-CSF in neutrophils. The study demonstrated that the supernatant of G-CSF–treated neutrophils induced the chemotaxis of neutrophils and that anti–ENA-78 antibody and anti–CXCR-2 antibody inhibited the chemotaxis. These data suggest that G-CSF may enhance the mobilization of neutrophils and consequently augment the accumulation of neutrophils in the inflammatory sites through the secretion of ENA-78.