Autocrine motility factor signaling enhances pancreatic cancer metastasis

Purpose: Autocrine motility factor (AMF)/phosphoglucose isomerase (PGI) is a ubiquitous cytosolic enzyme that plays a key role in glycolysis. AMF/PGI is also a multifunctional protein that acts in the extracellular milieu as a potent mitogen/cytokine. Increased expression of AMF/PGI and its receptor has been found in a wide spectrum of malignancies and is associated with cancer progression and metastasis. Recent studies indicated that AMF is induced by hypoxia and enhances the random motility of pancreatic cancer cells. In the present study, the role and regulation of AMF in the growth and metastasis of pancreatic cancer cells were determined. Experimental Design: In this study, we assessed whether overexpression of AMF in human pancreatic cancer cells enhances the liver metastasis using an orthotopic mouse tumor model. We also investigated the intracellular signal transduction pathways of AMF in human pancreatic cancer cell lines. Results: Overexpression of AMF stimulated in vitro invasion of MIA PaCa-2 cells. In vivo, after orthotopic implantation into the pancreas of nude mice, parental and empty vector-transfected MIA PaCa-2 cells produced locally relatively small tumors with no evidence of liver metastasis, whereas AMF-transfected MIA PaCa-2 cells produced the large tumors and liver metastases. In addition, over-expression of AMF leads to down-regulation of E-cadherin expression associated with the up-regulation of the zinc-ringer transcription factor SNAIL expression. Conclusions: The data submitted here show that AMF expression significantly contributes to the aggressive phenotype of human pancreatic cancer and thus may provide a novel prognostic and therapeutic target.