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Targeting Endogenous Transforming Growth Factor ß Receptor Signaling in SMAD4-Deficient Human Pancreatic Carcinoma Cells Inhibits Their Invasive Phenotype¹

Departments of ¹ Internal Medicine (Medical Oncology) and ² Surgery (Surgical Oncology), The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, New Brunswick, New Jersey, and ³ Scios, Inc., Fremont, California

Transforming growth factor-ß (TGF-ß) suppresses tumor formation by blocking cell cycle progression and maintaining tissue homeostasis. In pancreatic carcinomas, this tumor suppressive activity is often lost by inactivation of the TGF-ß-signaling mediator, Smad4. We found that human pancreatic carcinoma cell lines that have undergone deletion of MADH4 constitutively expressed high endogenous levels of phosphorylated receptor-associated Smad proteins (pR-Smad2 and pR-Smad3), whereas Smad4-positive lines did not. These elevated pR-Smad levels could not be attributed to a decreased dephosphorylation rate nor to increased expression of TGF-ß type I (TßR-I) or type II (TßR-II) receptors. Although minimal amounts of free bioactive TGF-ß1 and TGF-ß2 were detected in conditioned medium, treatment with a pan-specific (but not a TGF-ß3 specific) TGF-ß-neutralizing antibody and with anti-_Vß₆ integrin antibody decreased steady-state pSmad2 levels and activation of a TGF-ß-inducible reporter gene in neighboring cells, respectively. Thus, activation of TGF-ß at the cell surface was responsible for the increased autocrine endogenous and paracrine signaling. Blocking TßR-I activity using a selective kinase inhibitor (SD-093) strongly decreased the in vitro motility and invasiveness of the pancreatic carcinoma cells without affecting their growth characteristics, morphology, or the subcellular distribution of E-cadherin and F-actin. Moreover, exogenous TGF-ß strongly stimulated in vitro invasiveness of BxPC-3 cells, an effect that could also be blocked by SD-093. Thus, the motile and invasive properties of Smad4-deficient pancreatic cancer cells are at least partly driven by activation of endogenous TGF-ß signaling. Therefore, targeting the TßR-I kinase represents a potentially powerful novel therapeutic approach for the treatment of this disease.

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