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FGF10/FGFR2 signal induces cell migration and invasion in pancreatic cancer.

Nomura S, Yoshitomi H, Takano S, Shida T, Kobayashi S, Ohtsuka M, Kimura F, Shimizu H, Yoshidome H, Kato A, Miyazaki M - Br. J. Cancer (2008)

Bottom Line: Fibroblast growth factor 10 also induced expression of mRNA for membrane type 1-matrix metalloproteinase (MT1-MMP) and transforming growth factor (TGF)-beta1, and increased secretion of TGF-beta1 protein from these cell lines.These data indicate that stromal FGF10 induces migration and invasion in pancreatic cancer cells through interaction with FGFR2, resulting in a poor prognosis.This suggests that FGF10/FGFR2 signalling is a promising target for new molecular therapy against pancreatic cancer.

View Article: PubMed Central - PubMed

Affiliation: The Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba city, Chiba 260-8670, Japan.

ABSTRACT
Pancreatic cancer has one of the highest mortalities among all malignancies and there is an urgent need for new therapy. This might be achieved by resolving the detailed biological mechanism, and in this study we examined how pancreatic cancer cells develop aggressive properties by focusing on signalling through the fibroblast growth factor (FGF)10 and FGF receptor (FGFR)2, which play important roles in pancreatic organogenesis. Immunostaining of pancreatic cancer tissues showed that FGFR2 was expressed in cancer cells, whereas FGF10 was expressed in stromal cells surrounding the cancer cells. Patients with high FGFR2 expression in cancer cells had a shorter survival time compared to those with low FGFR2 expression. Fibroblast growth factor 10 induced cell migration and invasion of CFPAC-1 and AsPC-1 pancreatic cancer cells through interaction with FGFR2-IIIb, a specific isoform of FGFR2. Fibroblast growth factor 10 also induced expression of mRNA for membrane type 1-matrix metalloproteinase (MT1-MMP) and transforming growth factor (TGF)-beta1, and increased secretion of TGF-beta1 protein from these cell lines. These data indicate that stromal FGF10 induces migration and invasion in pancreatic cancer cells through interaction with FGFR2, resulting in a poor prognosis. This suggests that FGF10/FGFR2 signalling is a promising target for new molecular therapy against pancreatic cancer.

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Fibroblast growth factor 10 induces cell migration and invasion in pancreatic cell lines with FGFR2-IIIb expression. (A) RT–PCR analysis of FGF10 and FGFR2-IIIb in four pancreatic cell lines and cDNA obtained from normal lung tissue as a positive control. None of the cell lines express FGF10. MIA PaCa-2 and PanC-1 cells do not express FGFR2-IIIb, but CFPAC-1 and AsPC-1 do express this gene. (B) Representative results of cell migration (upper panels) and invasion (lower panels) for CFPAC-1 cells. Representative migrated and invaded cells are indicated with arrows. (C and D) Cell migration (C) and invasion (D) assay of all four cell lines cultured without (white column) or with (black column) FGF10 (100 ng ml−1). FGF10-induced cell migration and invasion in CFPAC-1 and AsPC-1 cells, but not in MIAPaCa-2 and PanC-1 cells. The numbers of migrated or invaded cells cultured with FGF10 are shown relative to a value of 100% for cell migration without ligand. (E and F) Inhibition of FGFR2-IIIb signalling by an FGFR2-IIIb/IgG chimera in CFPAC-1 cells. Migration (E) and invasion (F) assay. The numbers of migrated or invaded cells are shown relative to a value of 100% for cells cultured without FGF10 or chimera (control; white column). FGF10-induced migration and invasion in CFPAC-1 cells (black column). Addition of the FGFR2-IIIb/IgG chimera completely eliminated the effects of FGF10 (grey column), whereas the chimera itself did not affect cell migration and invasion of CFPAC-1 cells (striped column). *P<0.05.
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fig3: Fibroblast growth factor 10 induces cell migration and invasion in pancreatic cell lines with FGFR2-IIIb expression. (A) RT–PCR analysis of FGF10 and FGFR2-IIIb in four pancreatic cell lines and cDNA obtained from normal lung tissue as a positive control. None of the cell lines express FGF10. MIA PaCa-2 and PanC-1 cells do not express FGFR2-IIIb, but CFPAC-1 and AsPC-1 do express this gene. (B) Representative results of cell migration (upper panels) and invasion (lower panels) for CFPAC-1 cells. Representative migrated and invaded cells are indicated with arrows. (C and D) Cell migration (C) and invasion (D) assay of all four cell lines cultured without (white column) or with (black column) FGF10 (100 ng ml−1). FGF10-induced cell migration and invasion in CFPAC-1 and AsPC-1 cells, but not in MIAPaCa-2 and PanC-1 cells. The numbers of migrated or invaded cells cultured with FGF10 are shown relative to a value of 100% for cell migration without ligand. (E and F) Inhibition of FGFR2-IIIb signalling by an FGFR2-IIIb/IgG chimera in CFPAC-1 cells. Migration (E) and invasion (F) assay. The numbers of migrated or invaded cells are shown relative to a value of 100% for cells cultured without FGF10 or chimera (control; white column). FGF10-induced migration and invasion in CFPAC-1 cells (black column). Addition of the FGFR2-IIIb/IgG chimera completely eliminated the effects of FGF10 (grey column), whereas the chimera itself did not affect cell migration and invasion of CFPAC-1 cells (striped column). *P<0.05.

Mentions: First, we examined whether these cell lines expressed FGFR2 and FGF10. Reverse transcriptase–PCR analysis showed that all four cell lines did not express FGF10 mRNA, consistent with the results of immunostaining showing FGF10 expression in stromal cells, but not in cancer cells, in pancreatic cancer tissue (Figure 3A). Fibroblast growth factor 10 activity is dependent on its binding to the FGFR2-specific isoform, FGFR2-IIIb (Igarashi et al, 1998). Therefore, a primer set for FGFR2-IIIb was designed with a 5 primer for its specific exon in the FGFR2 gene. Reverse transcriptase–PCR analysis with this primer showed that CFPAC-1 and AsPC-1 cells expressed the FGFR2-IIIb isoform, whereas the other two cell lines did not do so (Figure 3A).


FGF10/FGFR2 signal induces cell migration and invasion in pancreatic cancer.

Nomura S, Yoshitomi H, Takano S, Shida T, Kobayashi S, Ohtsuka M, Kimura F, Shimizu H, Yoshidome H, Kato A, Miyazaki M - Br. J. Cancer (2008)

Fibroblast growth factor 10 induces cell migration and invasion in pancreatic cell lines with FGFR2-IIIb expression. (A) RT–PCR analysis of FGF10 and FGFR2-IIIb in four pancreatic cell lines and cDNA obtained from normal lung tissue as a positive control. None of the cell lines express FGF10. MIA PaCa-2 and PanC-1 cells do not express FGFR2-IIIb, but CFPAC-1 and AsPC-1 do express this gene. (B) Representative results of cell migration (upper panels) and invasion (lower panels) for CFPAC-1 cells. Representative migrated and invaded cells are indicated with arrows. (C and D) Cell migration (C) and invasion (D) assay of all four cell lines cultured without (white column) or with (black column) FGF10 (100 ng ml−1). FGF10-induced cell migration and invasion in CFPAC-1 and AsPC-1 cells, but not in MIAPaCa-2 and PanC-1 cells. The numbers of migrated or invaded cells cultured with FGF10 are shown relative to a value of 100% for cell migration without ligand. (E and F) Inhibition of FGFR2-IIIb signalling by an FGFR2-IIIb/IgG chimera in CFPAC-1 cells. Migration (E) and invasion (F) assay. The numbers of migrated or invaded cells are shown relative to a value of 100% for cells cultured without FGF10 or chimera (control; white column). FGF10-induced migration and invasion in CFPAC-1 cells (black column). Addition of the FGFR2-IIIb/IgG chimera completely eliminated the effects of FGF10 (grey column), whereas the chimera itself did not affect cell migration and invasion of CFPAC-1 cells (striped column). *P<0.05.
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Related In: Results  -  Collection

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fig3: Fibroblast growth factor 10 induces cell migration and invasion in pancreatic cell lines with FGFR2-IIIb expression. (A) RT–PCR analysis of FGF10 and FGFR2-IIIb in four pancreatic cell lines and cDNA obtained from normal lung tissue as a positive control. None of the cell lines express FGF10. MIA PaCa-2 and PanC-1 cells do not express FGFR2-IIIb, but CFPAC-1 and AsPC-1 do express this gene. (B) Representative results of cell migration (upper panels) and invasion (lower panels) for CFPAC-1 cells. Representative migrated and invaded cells are indicated with arrows. (C and D) Cell migration (C) and invasion (D) assay of all four cell lines cultured without (white column) or with (black column) FGF10 (100 ng ml−1). FGF10-induced cell migration and invasion in CFPAC-1 and AsPC-1 cells, but not in MIAPaCa-2 and PanC-1 cells. The numbers of migrated or invaded cells cultured with FGF10 are shown relative to a value of 100% for cell migration without ligand. (E and F) Inhibition of FGFR2-IIIb signalling by an FGFR2-IIIb/IgG chimera in CFPAC-1 cells. Migration (E) and invasion (F) assay. The numbers of migrated or invaded cells are shown relative to a value of 100% for cells cultured without FGF10 or chimera (control; white column). FGF10-induced migration and invasion in CFPAC-1 cells (black column). Addition of the FGFR2-IIIb/IgG chimera completely eliminated the effects of FGF10 (grey column), whereas the chimera itself did not affect cell migration and invasion of CFPAC-1 cells (striped column). *P<0.05.
Mentions: First, we examined whether these cell lines expressed FGFR2 and FGF10. Reverse transcriptase–PCR analysis showed that all four cell lines did not express FGF10 mRNA, consistent with the results of immunostaining showing FGF10 expression in stromal cells, but not in cancer cells, in pancreatic cancer tissue (Figure 3A). Fibroblast growth factor 10 activity is dependent on its binding to the FGFR2-specific isoform, FGFR2-IIIb (Igarashi et al, 1998). Therefore, a primer set for FGFR2-IIIb was designed with a 5 primer for its specific exon in the FGFR2 gene. Reverse transcriptase–PCR analysis with this primer showed that CFPAC-1 and AsPC-1 cells expressed the FGFR2-IIIb isoform, whereas the other two cell lines did not do so (Figure 3A).

Bottom Line: Fibroblast growth factor 10 also induced expression of mRNA for membrane type 1-matrix metalloproteinase (MT1-MMP) and transforming growth factor (TGF)-beta1, and increased secretion of TGF-beta1 protein from these cell lines.These data indicate that stromal FGF10 induces migration and invasion in pancreatic cancer cells through interaction with FGFR2, resulting in a poor prognosis.This suggests that FGF10/FGFR2 signalling is a promising target for new molecular therapy against pancreatic cancer.

View Article: PubMed Central - PubMed

Affiliation: The Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba city, Chiba 260-8670, Japan.

ABSTRACT
Pancreatic cancer has one of the highest mortalities among all malignancies and there is an urgent need for new therapy. This might be achieved by resolving the detailed biological mechanism, and in this study we examined how pancreatic cancer cells develop aggressive properties by focusing on signalling through the fibroblast growth factor (FGF)10 and FGF receptor (FGFR)2, which play important roles in pancreatic organogenesis. Immunostaining of pancreatic cancer tissues showed that FGFR2 was expressed in cancer cells, whereas FGF10 was expressed in stromal cells surrounding the cancer cells. Patients with high FGFR2 expression in cancer cells had a shorter survival time compared to those with low FGFR2 expression. Fibroblast growth factor 10 induced cell migration and invasion of CFPAC-1 and AsPC-1 pancreatic cancer cells through interaction with FGFR2-IIIb, a specific isoform of FGFR2. Fibroblast growth factor 10 also induced expression of mRNA for membrane type 1-matrix metalloproteinase (MT1-MMP) and transforming growth factor (TGF)-beta1, and increased secretion of TGF-beta1 protein from these cell lines. These data indicate that stromal FGF10 induces migration and invasion in pancreatic cancer cells through interaction with FGFR2, resulting in a poor prognosis. This suggests that FGF10/FGFR2 signalling is a promising target for new molecular therapy against pancreatic cancer.

Show MeSH
Related in: MedlinePlus