Bone morphogenetic protein 2 exerts diverse effects on cell growth in vitro and is expressed in human pancreatic cancer in vivo

J. Kleeff, H. Maruyama, T. Ishiwata, H. Sawhney, H. Friess, M. W. Buchler, Murray Korc

Research output: Contribution to journalArticle

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Abstract

Background and Aims: Bone morphogenetic proteins (BMPs) belong to the transforming growth factor β superfamily of signaling molecules. We characterized the expression of BMP-2 and its receptors in human pancreatic tissues and pancreatic cancer cell lines and examined the effects of BMP-2 on mitogenesis. Methods: Expression of BMP-2 and its receptors was determined by Northern blot analysis using specific complementary DNA probes. Distribution of BMP-2 in pancreatic cancers was examined by immunohistochemistry and in situ hybridization. Effects of BMP-2 on mitogenesis were assessed by monitoring cell proliferation and activation of mitogen-activated protein kinase (MAPK). Results: Compared with the normal pancreas, pancreatic cancers showed a 12.5-fold (P <0.01), 2-fold (P <0.01), and 8-fold (P <0.01) increase of BMP-2, BMP receptor (R)-1A, and BMPR-II messenger RNA levels, respectively. By immunohistochemistry and in situ hybridization, BMP-2 was expressed in the cancer cells within the tumor mass. There was a significant correlation between the presence of BMP-2 immunostaining in the tumors and shorter postoperative survival. Pancreatic cancer cell lines expressed variable levels of messenger RNA encoding BMP-2 and its receptors. BMP-2 stimulated the growth of two pancreatic cancer cell lines (ASPC-1 and CAPAN- 1). This mitogenic effect was associated with MAPK activation and blocked by the MAPK inhibitor PD98059 in CAPAN-1 but not in ASPC-1 cells. In both cell lines, expression of wild-type Smad4 abolished the BMP-2-mediated growth stimulation. BMP-2 inhibited the growth of COLO-357 cells, an effect that was blocked by expressing a dominant negative Smad4. BMP-2 had no effect in three cell lines that underexpressed either the BMP receptors or Smad1. Conclusions: These findings indicate that BMP-2 has the capacity to act as a mitogen when Smad4 is mutated and suggest that it might play a role in the pathobiology of human pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)1202-1216
Number of pages15
JournalGastroenterology
Volume116
Issue number5
DOIs
StatePublished - 1999
Externally publishedYes

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Bone Morphogenetic Protein 2
Pancreatic Neoplasms
Growth
Cell Line
Mitogen-Activated Protein Kinases
Bone Morphogenetic Protein Receptors
In Vitro Techniques
In Situ Hybridization
Immunohistochemistry
Neoplasms
Messenger RNA
Bone Morphogenetic Proteins
DNA Probes
Transforming Growth Factors
Protein Kinase Inhibitors
Mitogens
Northern Blotting

ASJC Scopus subject areas

  • Gastroenterology

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Bone morphogenetic protein 2 exerts diverse effects on cell growth in vitro and is expressed in human pancreatic cancer in vivo. / Kleeff, J.; Maruyama, H.; Ishiwata, T.; Sawhney, H.; Friess, H.; Buchler, M. W.; Korc, Murray.

In: Gastroenterology, Vol. 116, No. 5, 1999, p. 1202-1216.

Research output: Contribution to journalArticle

Kleeff, J, Maruyama, H, Ishiwata, T, Sawhney, H, Friess, H, Buchler, MW & Korc, M 1999, 'Bone morphogenetic protein 2 exerts diverse effects on cell growth in vitro and is expressed in human pancreatic cancer in vivo', Gastroenterology, vol. 116, no. 5, pp. 1202-1216. https://doi.org/10.1016/S0016-5085(99)70024-7
Kleeff, J. ; Maruyama, H. ; Ishiwata, T. ; Sawhney, H. ; Friess, H. ; Buchler, M. W. ; Korc, Murray. / Bone morphogenetic protein 2 exerts diverse effects on cell growth in vitro and is expressed in human pancreatic cancer in vivo. In: Gastroenterology. 1999 ; Vol. 116, No. 5. pp. 1202-1216.
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abstract = "Background and Aims: Bone morphogenetic proteins (BMPs) belong to the transforming growth factor β superfamily of signaling molecules. We characterized the expression of BMP-2 and its receptors in human pancreatic tissues and pancreatic cancer cell lines and examined the effects of BMP-2 on mitogenesis. Methods: Expression of BMP-2 and its receptors was determined by Northern blot analysis using specific complementary DNA probes. Distribution of BMP-2 in pancreatic cancers was examined by immunohistochemistry and in situ hybridization. Effects of BMP-2 on mitogenesis were assessed by monitoring cell proliferation and activation of mitogen-activated protein kinase (MAPK). Results: Compared with the normal pancreas, pancreatic cancers showed a 12.5-fold (P <0.01), 2-fold (P <0.01), and 8-fold (P <0.01) increase of BMP-2, BMP receptor (R)-1A, and BMPR-II messenger RNA levels, respectively. By immunohistochemistry and in situ hybridization, BMP-2 was expressed in the cancer cells within the tumor mass. There was a significant correlation between the presence of BMP-2 immunostaining in the tumors and shorter postoperative survival. Pancreatic cancer cell lines expressed variable levels of messenger RNA encoding BMP-2 and its receptors. BMP-2 stimulated the growth of two pancreatic cancer cell lines (ASPC-1 and CAPAN- 1). This mitogenic effect was associated with MAPK activation and blocked by the MAPK inhibitor PD98059 in CAPAN-1 but not in ASPC-1 cells. In both cell lines, expression of wild-type Smad4 abolished the BMP-2-mediated growth stimulation. BMP-2 inhibited the growth of COLO-357 cells, an effect that was blocked by expressing a dominant negative Smad4. BMP-2 had no effect in three cell lines that underexpressed either the BMP receptors or Smad1. Conclusions: These findings indicate that BMP-2 has the capacity to act as a mitogen when Smad4 is mutated and suggest that it might play a role in the pathobiology of human pancreatic cancer.",
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T1 - Bone morphogenetic protein 2 exerts diverse effects on cell growth in vitro and is expressed in human pancreatic cancer in vivo

AU - Kleeff, J.

AU - Maruyama, H.

AU - Ishiwata, T.

AU - Sawhney, H.

AU - Friess, H.

AU - Buchler, M. W.

AU - Korc, Murray

PY - 1999

Y1 - 1999

N2 - Background and Aims: Bone morphogenetic proteins (BMPs) belong to the transforming growth factor β superfamily of signaling molecules. We characterized the expression of BMP-2 and its receptors in human pancreatic tissues and pancreatic cancer cell lines and examined the effects of BMP-2 on mitogenesis. Methods: Expression of BMP-2 and its receptors was determined by Northern blot analysis using specific complementary DNA probes. Distribution of BMP-2 in pancreatic cancers was examined by immunohistochemistry and in situ hybridization. Effects of BMP-2 on mitogenesis were assessed by monitoring cell proliferation and activation of mitogen-activated protein kinase (MAPK). Results: Compared with the normal pancreas, pancreatic cancers showed a 12.5-fold (P <0.01), 2-fold (P <0.01), and 8-fold (P <0.01) increase of BMP-2, BMP receptor (R)-1A, and BMPR-II messenger RNA levels, respectively. By immunohistochemistry and in situ hybridization, BMP-2 was expressed in the cancer cells within the tumor mass. There was a significant correlation between the presence of BMP-2 immunostaining in the tumors and shorter postoperative survival. Pancreatic cancer cell lines expressed variable levels of messenger RNA encoding BMP-2 and its receptors. BMP-2 stimulated the growth of two pancreatic cancer cell lines (ASPC-1 and CAPAN- 1). This mitogenic effect was associated with MAPK activation and blocked by the MAPK inhibitor PD98059 in CAPAN-1 but not in ASPC-1 cells. In both cell lines, expression of wild-type Smad4 abolished the BMP-2-mediated growth stimulation. BMP-2 inhibited the growth of COLO-357 cells, an effect that was blocked by expressing a dominant negative Smad4. BMP-2 had no effect in three cell lines that underexpressed either the BMP receptors or Smad1. Conclusions: These findings indicate that BMP-2 has the capacity to act as a mitogen when Smad4 is mutated and suggest that it might play a role in the pathobiology of human pancreatic cancer.

AB - Background and Aims: Bone morphogenetic proteins (BMPs) belong to the transforming growth factor β superfamily of signaling molecules. We characterized the expression of BMP-2 and its receptors in human pancreatic tissues and pancreatic cancer cell lines and examined the effects of BMP-2 on mitogenesis. Methods: Expression of BMP-2 and its receptors was determined by Northern blot analysis using specific complementary DNA probes. Distribution of BMP-2 in pancreatic cancers was examined by immunohistochemistry and in situ hybridization. Effects of BMP-2 on mitogenesis were assessed by monitoring cell proliferation and activation of mitogen-activated protein kinase (MAPK). Results: Compared with the normal pancreas, pancreatic cancers showed a 12.5-fold (P <0.01), 2-fold (P <0.01), and 8-fold (P <0.01) increase of BMP-2, BMP receptor (R)-1A, and BMPR-II messenger RNA levels, respectively. By immunohistochemistry and in situ hybridization, BMP-2 was expressed in the cancer cells within the tumor mass. There was a significant correlation between the presence of BMP-2 immunostaining in the tumors and shorter postoperative survival. Pancreatic cancer cell lines expressed variable levels of messenger RNA encoding BMP-2 and its receptors. BMP-2 stimulated the growth of two pancreatic cancer cell lines (ASPC-1 and CAPAN- 1). This mitogenic effect was associated with MAPK activation and blocked by the MAPK inhibitor PD98059 in CAPAN-1 but not in ASPC-1 cells. In both cell lines, expression of wild-type Smad4 abolished the BMP-2-mediated growth stimulation. BMP-2 inhibited the growth of COLO-357 cells, an effect that was blocked by expressing a dominant negative Smad4. BMP-2 had no effect in three cell lines that underexpressed either the BMP receptors or Smad1. Conclusions: These findings indicate that BMP-2 has the capacity to act as a mitogen when Smad4 is mutated and suggest that it might play a role in the pathobiology of human pancreatic cancer.

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