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Carcinogenesis Advance Access published online on November 13, 2007
Carcinogenesis, doi:10.1093/carcin/bgm249
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Loss of Type III Transforming Growth Factor ß Receptor Expression Increases Motility and Invasiveness associated with Epithelial to Mesenchymal Transition during Pancreatic Cancer Progression

Kelly J. Gordon1, Mei Dong2, Elizabeth M. Chislock1, Timothy A. Fields3 and Gerard C. Blobe1,2,4

1 Duke University Medical Center, Department of Pharmacology and Cancer Biology, Durham, NC 27710
2 Duke University Medical Center, Department of Medicine, Durham, NC 27710
3 Duke University Medical Center, Department of Pathology, Durham, NC 27710

4 Corresponding author: 221B MSRB Research Drive, Box 2631 DUMC, Durham, NC 27710, Tel: (919) 668-1352, Fax: (919) 668-2458, Email: blobe001{at}mc.duke.edu

Epithelial to mesenchymal transitions (EMTs) contribute to increases in cellular motility and invasiveness during embryonic development and tumorigenesis. The transforming growth factor ß (TGF-ß) signaling pathway is a key regulator of EMT. The TGF-ß superfamily co-receptor, the type III TGF-ß receptor (TßRIII, or betaglycan), is required for EMT during embryonic heart development and palate fusion. Here we establish that in a pancreatic cancer model of EMT, TßRIII expression is specifically lost during EMT at the mRNA and protein levels, while levels of the TGF-ß type I and type II receptors are maintained at the mRNA level. Loss of TßRIII expression at the protein level precedes the loss of E-cadherin and cytoskeletal reorganization during early stages of EMT. However, maintaining TßRIII expression does not block these aspects of EMT, but instead suppresses the increased motility and invasiveness associated with EMT. Reciprocally, shRNA-mediated knockdown of endogenous TßRIII increases cellular motility without affecting Snail or E-cadherin levels. The ability of TßRIII to suppress motility and invasiveness does not depend on its cytoplasmic domain or its co-receptor function. Instead, this suppression of invasion is partially mediated by ectodomain shedding of TßRIII, generating soluble TßRIII. In human pancreatic cancer specimens TßRIII expression decreases at both the mRNA and protein levels, with the degree of loss correlating with worsening tumor grade. Taken together these studies support a role for loss of TßRIII expression during the EMT of pancreatic cancer progression, with a specific role for soluble TßRIII in suppressing EMT associated increases in motility and invasion.

Key Words: tumor suppressor • TGF-ß signaling • pancreatic cancer • invasion • EMT

Received July 30, 2007; revised October 30, 2007; accepted November 3, 2007.


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