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Loss of hepatocyte growth factor activator inhibitor type 1 participates in metastatic spreading of human pancreatic cancer cells in a mouse orthotopic transplantation model.

Ye J, Kawaguchi M, Haruyama Y, Kanemaru A, Fukushima T, Yamamoto K, Lin CY, Kataoka H - Cancer Sci. (2013)

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.

View Article: PubMed Central - PubMed

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.

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Intra-pancreatic transplantation of S2-CP8_HAI-1tet#1 cells in nude mice. The treated mice were maintained with or without Dox administration and killed 26 days after injection. (a) Macroscopic findings of pancreatic tumors (arrows). Metastases and infarction in the liver are indicated by arrow heads and asterisks, respectively. Bar, 1 cm. Primary tumor volumes of parent S2-CP8 and S2-CP8_HAI-1tet#1 cells without or with Dox treatment are also shown (mean ± SEM). *P < 0.001 (Mann–Whitney U-tests). (b) Histology of pancreatic tumors (upper panel, H&E) and immunohistochemistry of HAI-1 (lower panel). Arrows indicate pancreatic acinar tissue. Bars, 50 μm. (c) Histology of metastatic lesions (liver and lungs) formed in the absence of Dox treatment. T, metastatic tumor. Bars, 50 μm.
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fig05: Intra-pancreatic transplantation of S2-CP8_HAI-1tet#1 cells in nude mice. The treated mice were maintained with or without Dox administration and killed 26 days after injection. (a) Macroscopic findings of pancreatic tumors (arrows). Metastases and infarction in the liver are indicated by arrow heads and asterisks, respectively. Bar, 1 cm. Primary tumor volumes of parent S2-CP8 and S2-CP8_HAI-1tet#1 cells without or with Dox treatment are also shown (mean ± SEM). *P < 0.001 (Mann–Whitney U-tests). (b) Histology of pancreatic tumors (upper panel, H&E) and immunohistochemistry of HAI-1 (lower panel). Arrows indicate pancreatic acinar tissue. Bars, 50 μm. (c) Histology of metastatic lesions (liver and lungs) formed in the absence of Dox treatment. T, metastatic tumor. Bars, 50 μm.

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).


Loss of hepatocyte growth factor activator inhibitor type 1 participates in metastatic spreading of human pancreatic cancer cells in a mouse orthotopic transplantation model.

Ye J, Kawaguchi M, Haruyama Y, Kanemaru A, Fukushima T, Yamamoto K, Lin CY, Kataoka H - Cancer Sci. (2013)

Intra-pancreatic transplantation of S2-CP8_HAI-1tet#1 cells in nude mice. The treated mice were maintained with or without Dox administration and killed 26 days after injection. (a) Macroscopic findings of pancreatic tumors (arrows). Metastases and infarction in the liver are indicated by arrow heads and asterisks, respectively. Bar, 1 cm. Primary tumor volumes of parent S2-CP8 and S2-CP8_HAI-1tet#1 cells without or with Dox treatment are also shown (mean ± SEM). *P < 0.001 (Mann–Whitney U-tests). (b) Histology of pancreatic tumors (upper panel, H&E) and immunohistochemistry of HAI-1 (lower panel). Arrows indicate pancreatic acinar tissue. Bars, 50 μm. (c) Histology of metastatic lesions (liver and lungs) formed in the absence of Dox treatment. T, metastatic tumor. Bars, 50 μm.
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fig05: Intra-pancreatic transplantation of S2-CP8_HAI-1tet#1 cells in nude mice. The treated mice were maintained with or without Dox administration and killed 26 days after injection. (a) Macroscopic findings of pancreatic tumors (arrows). Metastases and infarction in the liver are indicated by arrow heads and asterisks, respectively. Bar, 1 cm. Primary tumor volumes of parent S2-CP8 and S2-CP8_HAI-1tet#1 cells without or with Dox treatment are also shown (mean ± SEM). *P < 0.001 (Mann–Whitney U-tests). (b) Histology of pancreatic tumors (upper panel, H&E) and immunohistochemistry of HAI-1 (lower panel). Arrows indicate pancreatic acinar tissue. Bars, 50 μm. (c) Histology of metastatic lesions (liver and lungs) formed in the absence of Dox treatment. T, metastatic tumor. Bars, 50 μm.
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).

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.

View Article: PubMed Central - PubMed

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
Related in: MedlinePlus