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2HS-glycoprotein, an Antagonist of Transforming Growth Factor ß In vivo, Inhibits Intestinal Tumor Progression

¹ Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; ² Departments of Molecular and Medical Genetics and Surgery, University of Toronto, Toronto, Ontario, Canada; and ³ Interdisziplinären Zentrums für Klinische Forschung BIOMAT, Klinikum der Rheinisch-Westfälischen Technischen Hoschschule, Aachen, Aachen, Germany

Transforming growth factor (TGF)-ß1 is associated with tumor progression and resistance to chemotherapy in established cancers, as well as host immune suppression. Here, we show that the serum glycoprotein 2-HS-glycoprotein (AHSG) blocks TGF-ß1 binding to cell surface receptors, suppresses TGF-ß signal transduction, and inhibits TGF-ß-induced epithelial-mesenchymal transition, suggesting that AHSG may play a role in tumor progression. In 66 consecutive sporadic human colorectal cancer specimens, we observed a 3-fold depletion of ASHG in tumor compared with normal tissue, whereas levels of other abundant plasma proteins, albumin and transferrin, were equivalent. Using the Multiple intestinal neoplasia/+ (Min/+) mouse model of intestinal tumorigenesis, we found twice as many intestinal polyps overall, twice as many large polyps (>3 mm diameter), and more progression to invasive adenocarcinoma in Min/+ Ahsg^–/– mice than in littermates expressing Ahsg. Phosphorylated Smad2 was more abundant in the intestinal mucosa and tumors of Min/+ mice lacking Ahsg, demonstrating increased TGF-ß signaling in vivo. Furthermore, TGF-ß-mediated suppression of immune cell function was exaggerated in Ahsg^–/– animals, as shown by inhibition of macrophage activation and reduction in 12-O-tetradecanoylphorbol 13-acetate–induced cutaneous inflammation. Reconstitution of Ahsg^–/– mice with bovine Ahsg suppressed endogenous TGF-ß-dependent signaling to wild-type levels, suggesting that therapeutic enhancement of AHSG levels may benefit patients whose tumors are driven by TGF-ß.

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