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Carcinogenesis Advance Access published online on December 4, 2008
Carcinogenesis, doi:10.1093/carcin/bgn274
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Bone Morphogenetic Proteins Induce Pancreatic Cancer Cell Invasiveness through a Smad1-dependent Mechanism that Involves Matrix Metalloproteinase Protein-2

Kelly J. Gordon1,2, Kellye C. Kirkbride1,2, Tam How3 and Gerard C. Blobe2,3,4

2 Department of Pharmacology and Cancer Biology
3 Department of Medicine, Duke University, Durham, North Carolina

4 Corresponding author: Box 91004, B354 LSRC Research Drive, Durham, NC 27708, Tel: (919) 668-1352, Fax: (919) 681-6906, Email: blobe001{at}mc.duke.edu

Bone morphogenetic proteins (BMPs) have an emerging role in human cancers. Here we demonstrate that the BMP signaling pathway is intact and functional in human pancreatic cancer cells, with several BMP signaling components and transcriptional targets upregulated in human pancreatic cancer specimens compared to normal pancreatic tissue. Functionally, multiple BMP family members, including BMP-2, BMP-4 and BMP-7, induce an epithelial to mesenchymal transition (EMT) in the human pancreatic cancer cell line Panc-1, as demonstrated by morphological alterations and loss of E-cadherin expression. BMP-mediated EMT results in an increase in invasiveness of Panc-1 cells, in part through increased expression and activity of matrix metalloproteinase-2 (MMP-2), a known mediator of pancreatic cancer cell invasiveness. Accompanying EMT, BMP reduces expression of the TGF-β superfamily receptor, TGF-β type III receptor (TβRIII), for which we have previously demonstrated loss of expression during pancreatic cancer progression. Maintaining TβRIII expression inhibits BMP-mediated invasion and suppresses Smad1 activation. Further, Smad1 is required for BMP-induced invasiveness and partially responsible for BMP-mediated increases in MMP-2 activity. These data suggest that BMP signaling, through Smad1 induction and upregulation of MMP-2, is an important mediator of pancreatic cancer invasiveness and a potential therapeutic target for treating this deadly disease.

Key Words: BMP • epithelial to mesenchymal transition (EMT) • MMP-2 • Smad1 • TGF-β type III receptor (TβRIII) • cell invasion • pancreatic cancer

1 Authors contributed equally

Received July 11, 2008; revised November 15, 2008; accepted November 29, 2008.


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