Background: Adenocarcinomas of the exocrine pancreas belong to the most aggressive malignancies with an overall 5-year survival rate of still less than 5%. The early development of distant metastases, such as peritoneal carcinomatosis, is a specific characteristic of this particular tumor entity, but their mechanisms are poorly understood. In a series of newly established orthotopic models for pancreatic carcinomas tumor growth, metastasis and their potential for mesothelial adhesion as one of the first steps of metastasis formation were investigated.
Methods: 16 cell lines of well- to undifferentiated pancreatic cancers from different tumor sites (primary or metastatic lesions) were used to implant subcutaneous donor tumors and subsequent orthotopic transplantation in nude mice. After 12 weeks primary tumor volume, local infiltration, and patterns of systemic metastases were assessed using a standardized dissemination score. This in vivo behaviour was compared with in vitro tumor cell adhesion to mesothelial cells. The data was tested for significant differences using Scheffé- and t-test (SPSS 13.0).
Results: In vivo experiments resulted in a tumor take rate of 100%. Differences regarding tumor size, infiltration and metastatic spread were found depending on differentiation and origin of the cell lines. Less differentiated cells of primary tumors and metastasis caused higher dissemination scores than better-differentiated cells (p<0.05). A significant increase (p<0.05) of tumor growth, infiltration and metastasis was also seen for cells originating from metastases compared to those from primary tumors. Adhesion assays revealed an adhesive potential at mesothelium of all cell lines (21-95%). Primary tumors with well-moderate differentiation presented significantly increased adhesion rates (mean 74-95%) compared to poorly-undifferentiated primary tumors (mean 31-55%) and well-moderately differentiated (mean 21-44%) or poorly-undifferentiated (mean 25-45%) metastases [p<0.05]. The maximum adhesion rates were found in average 76 min after addition of pancreatic cells to mesothelial monolayers (observation period 90min).
Conclusion: These experimental systems are an interesting tool for the investigation of mechanisms or pancreatic cancer progression and demonstrate that grade of differentiation and origins are relevant factors for tumor growth and metastatic spread. The correlation of pancreatic cells adhesion at the mesothelium with their origin and differentiation suggests that this adhesive potential is a required, but not rate-limiting step for the formation of peritoneal carcinomatosis in this tumor entity.