alpha2HS-glycoprotein, an antagonist of transforming growth factor beta in vivo, inhibits intestinal tumor progression.
Transforming growth factor (TGF)-beta1 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 alpha2-HS-glycoprotein (AHSG) blocks TGF-beta1 binding to cell surface receptors, suppresses TGF-beta signal transduction, and inhibits TGF-beta-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-beta signaling in vivo. Furthermore, TGF-beta-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-beta-dependent signaling to wild-type levels, suggesting that therapeutic enhancement of AHSG levels may benefit patients whose tumors are driven by TGF-beta.
Swallow
Carol J
CJ
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. cswallow@mtsinai.on.ca
Partridge
Emily A
EA
Macmillan
Jennifer C
JC
Tajirian
Tania
T
DiGuglielmo
Gianni M
GM
Hay
Kazy
K
Szweras
Melanie
M
Jahnen-Dechent
Willi
W
Wrana
Jeff L
JL
Redston
Mark
M
Gallinger
Steven
S
Dennis
James W
JW
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001667:Binding, Competitive; D001798:Blood Proteins / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D002417:Cattle; D015179:Colorectal Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D008262:Macrophage Activation / Q000502:physiology; D017737:Macrophages, Peritoneal / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D053773:Transforming Growth Factor beta1; D060749:alpha-2-HS-Glycoprotein
C556354:AHSG protein, human; C556357:Ahsg protein, mouse; D001798:Blood Proteins; D018125:Receptors, Transforming Growth Factor beta; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D060749:alpha-2-HS-Glycoprotein; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II