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

Gastroenterology. 1999 May;116(5):1202-16. doi: 10.1016/s0016-5085(99)70024-7.

Abstract

Background & aims: Bone morphogenetic proteins (BMPs) belong to the transforming growth factor beta 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)-IA, 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Protein Receptors, Type I
  • Bone Morphogenetic Protein Receptors, Type II
  • Bone Morphogenetic Proteins / biosynthesis*
  • Bone Morphogenetic Proteins / pharmacology*
  • Cell Division / drug effects
  • Cricetinae
  • DNA-Binding Proteins / biosynthesis
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization
  • Male
  • Middle Aged
  • Pancreas / metabolism
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / mortality
  • Pancreatic Neoplasms / pathology*
  • Protein-Serine-Threonine Kinases / biosynthesis
  • Receptors, Growth Factor / biosynthesis
  • Smad Proteins
  • Smad1 Protein
  • Survival Rate
  • Trans-Activators / biosynthesis
  • Transforming Growth Factor beta*
  • Tumor Cells, Cultured

Substances

  • BMP2 protein, human
  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Proteins
  • DNA-Binding Proteins
  • Receptors, Growth Factor
  • SMAD1 protein, human
  • Smad Proteins
  • Smad1 Protein
  • Trans-Activators
  • Transforming Growth Factor beta
  • Protein-Serine-Threonine Kinases
  • BMPR2 protein, human
  • Bone Morphogenetic Protein Receptors, Type I
  • Bone Morphogenetic Protein Receptors, Type II