Loss of hepatocyte growth factor activator inhibitor type 1 participates in metastatic spreading of human pancreatic cancer cells in a mouse orthotopic transplantation model.
Bottom Line: Previously we reported that S2-CP8 cells, a metastatic variant of the SUIT-2 human pancreatic adenocarcinoma cell line, showed markedly decreased HAI-1 expression.In vitro migration and invasion assays revealed inhibitory effects of HAI-1 on S2-CP8 cell migration and invasion.These data indicate that HAI-1 loss contributes to invasion and dissemination of a highly metastatic subline of SUIT-2, suggesting crucial roles for the balance of pericellular serine proteases/inhibitors in pancreatic cancer progression.
Affiliation: Section of Oncopathology and Regenerative Biology, Department of Pathology, University of Miyazaki, Miyazaki, Japan; Clinical Research Center, The 2nd Affiliated Hospital School of Medicine, Zhejiang University, Hangzhou, China.Show MeSH
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Mentions: Finally, we examined the role of HAI-1 expression in metastatic spreading of S2-CP8 cells using a nude mouse orthotopic transplantation model. Dox was used instead of Tet to induce HAI-1 expression in this experiment. After implantation of S2-CP8_HAI-1tet#1 cells into the pancreas, mice were given drinking water that either did or did not contain 1 mg/mL Dox. The mice were killed and autopsied 26 days after cell implantation (Fig.5a). Dox treatment indeed induced significant expression of cell surface HAI-1. While the cells formed poorly differentiated tumors regardless of Dox treatment, intratumoral or peritumoral fibroblastic cells were more pronounced in the untreated tumors compared with those from Dox-treated mice (Fig.5b). Notably, mice treated with Dox to induce HAI-1 overexpression did not show metastasis to distant organs (n = 10) (Table1). In contrast, 50% of mice without Dox treatment (n = 9) showed metastases to lungs (44%, 4/9) and/or liver (22%, 2/9) (Table1 and Fig.5c). Dox treatment itself did not alter the metastatic capability of the cells, as pulmonary metastasis was equally observed after orthotopic implantation of parent S2-CP8 cells in both non-treated (67%, 2/3) and treated (75%, 3/4) groups. Interestingly, although induced HAI-1 expression enhanced cellular growth of S2-CP8_HAI-1tet#1 cells in vitro, in vivo tumor growth was significantly reduced by HAI-1 (Fig.5a).
Affiliation: Section of Oncopathology and Regenerative Biology, Department of Pathology, University of Miyazaki, Miyazaki, Japan; Clinical Research Center, The 2nd Affiliated Hospital School of Medicine, Zhejiang University, Hangzhou, China.