Hypoxia enhances the expression of autocrine motility factor and the motility of human pancreatic cancer cells

Abstract

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,...

Differential Responses of Myogenic C2C12 Cells to Hypoxia between Growth and Muscle-Induction Phases: Growth, Differentiation and Motility

“…We investigated the effect of hypoxia on the cell motility of C2C12 cells cultured in GM and IM, since hypoxia reportedly induces cell motility relating to metastatic capacity in neoplastic cells 29) . Cell motility was analyzed using Phagokinetic Tracks.…”

“…Myogenic cells show high motile activity once cells are activated in differentiation induction 28) , implying the important role of cell motility in muscle regeneration. In the hypoxic condition, cell motility is augmented, especially for cancer cells, resulting in the promotion of metastasis 29) . One of the key molecules responsible for hypoxia-induced motility stimulation is autocrine motility factor (AMF), a protein secreted by cancer cells, which stimulates the motility of not only cancer cells but also normal fibroblasts via an autocrine route [30][31][32][33] .…”

“…Furthermore, AMF/GPI is also identified as a neurotrophic factor, neuroleukin (NLK) 35,36) . This multi-functional molecule, a member of the ecto/exo-enzyme family, plays an important role in the enhancement of the motility induced by hypoxia 29) . So far, few reports have studied the effect of hypoxia on the motile properties of myogenic cells.…”

How to overcome (and exploit) tumor hypoxia for targeted gene therapy

“…1). To facilitate tumor cell detachment, migration and invasion, hypoxia can down-regulate cell adhesion molecules such as integrins (Hasan et al, 1998), and upregulate the urokinase-type plasminogen activator receptor (uPAR; Rofstad et al, 2002) and the autocrine motility factor (AMF; Niizeki et al, 2002). An association between primary tumor oxygenation and the likelihood of distant metastasis has been reported in clinical studies involving patients with high-grade soft tissue sarcoma (Brizel et al, 1996) and advanced squamous cell carcinoma of the uterine cervix (Sundfor et al, 1998;Pitson et al, 2001;Fyles et al, 2002).…”

Cellular differentiation determines the expression of the hypoxia-inducible protein NDRG1 in pancreatic cancer

“…Hypoxia can contribute significantly to an aggressive behaviour of pancreatic cancers through the hypoxia-induced expression of proangiogenic factors, such as vascular endothelial growth factor (VEGF) and interleukin-8 (Shi et al, 1999;Buchler et al, 2003;Hotz et al, 2005). Tumour hypoxia also has been shown to increase tumour growth and the metastatic potential of pancreatic cancer cells (Niizeki et al, 2002;Buchler et al, 2004). Additionally, pancreatic cancers highly express the hypoxiainducible transcription factor, hypoxia-inducible factor 1 (HIF-1) (Shibaji et al, 2003).…”