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α2HS-glycoprotein, an Antagonist of Transforming Growth Factor β In vivo , Inhibits Intestinal Tumor Progression

2004; American Association for Cancer Research; Volume: 64; Issue: 18 Linguagem: Inglês

10.1158/0008-5472.can-04-1117

1538-7445

Carol J. Swallow, Emily A. Partridge, Jennifer Macmillan, Tania Tajirian, Gianni M. DiGuglielmo, Kazy Hay, Melanie Szweras, Willi Jahnen‐Dechent, Jeffrey L. Wrana, Mark Redston, Steven Gallinger, James W. Dennis,

Pancreatic and Hepatic Oncology Research

Abstract Transforming growth factor (TGF)-β1 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 α2-HS-glycoprotein (AHSG) blocks TGF-β1 binding to cell surface receptors, suppresses TGF-β signal transduction, and inhibits TGF-β-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-β signaling in vivo. Furthermore, TGF-β-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-β-dependent signaling to wild-type levels, suggesting that therapeutic enhancement of AHSG levels may benefit patients whose tumors are driven by TGF-β.