oa Identification Of Genes Involved In The Growth Of Pancreatic Cancer Cells In The Rat Liver Of Nude Rats

Purpose: Owing to aggressiveness and chemo-resistance, pancreatic ductal adeno-carcinoma (PDAC) is characterised by a poor prognosis. At the advanced stage, which is characterised by metastasis into adjacent organs, especially the liver, all systemic treatment approaches have failed, so far. To address this disease spe¬cific dilemma we aimed to establish animal models, which mimic liver metastasis of PDAC and to identify the underlying genes. Methods: From a panel of sixteen pancreatic cancer cell lines, two human (Suit2-007 and Suit2-013) and a rat (ASML) cell line were selected for their property to grow in the liver of male RNU rats and mimic liver metastasis of PDAC. By serial transplantation the take rate was improved until they showed reliable and reproducible growth as orthotopic xenografts. For better monitoring of metastatic tumor growth in vivo, all three pancreatic cancer cell lines were stably transfected with eGFP and luciferase marker genes. In addition, the mRNA expression profile of 13 human PDAC cell lines was analyzed by BeadChip array analysis. Results: Three orthotopic xenograft models, which form liver metastasis of PDAC, were successfully established in male RNU rats following intra-portal implantation.The models vary in their aggressiveness and macroscopic growth. The Bead Chip array analysis showed that only 33 genes and 5 signalling pathways were identified as significantly associated with the ability of the cell lines to grow initially and/or consistently in rat liver. Only a minority of these genes (osteopontin, matrix metalloproteinase-1 and insulin-like growth factor 1) has been intensively studied and shown to be closely related to cancer progression. The function of the remaining 30 genes ranges from moderate to poorly investigated, and their function in cancer progression is still unclear. Conclusions: The ensuing three pancreatic cancer liver metastasis models vary in their aggressiveness and macroscopic growth. They will be used for preclinical evaluation of new therapeutic approaches aiming at the genes identified.