A secreted form of ADAM9 promotes carcinoma invasion through tumor-stromal interactions.
Tumor cell invasion is a process regulated by integrins, matrix-degrading enzymes, and interactions with host tissue stromal cells. The ADAM family of proteins plays an important role in modulating various cellular responses. Here, we show that an alternatively spliced variant of ADAM9 is secreted by hepatic stellate cells and promotes carcinoma invasion. ADAM9-S induced a highly invasive phenotype in several human tumor cell lines in Matrigel assays, and the protease activity of ADAM9-S was required for invasion. ADAM9-S binds directly to alpha6beta4 and alpha2beta1 integrins on the surface of colon carcinoma cells through the disintegrin domain. ADAM9-S was also able to cleave laminin and promote invasion. Analysis of human liver metastases revealed that ADAM9 is expressed by stromal liver myofibroblasts, particularly those that are localized within the tumor stroma at the invasive front. These results emphasize the importance of tumor-stromal interactions in invasion and suggest that ADAM9-S can be an important determinant in the ability of cancer cells to invade and colonize the liver.
Mazzocca
Antonio
A
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Coppari
Roberto
R
De Franco
Raffaella
R
Cho
Je-Yoel
JY
Libermann
Towia A
TA
Pinzani
Massimo
M
Toker
Alex
A
D051722:ADAM Proteins; D000595:Amino Acid Sequence; D000818:Animals; D002450:Cell Communication / Q000502:physiology*; D045744:Cell Line, Tumor; D003094:Collagen; D003110:Colonic Neoplasms / Q000473:pathology*; D019483:Disintegrins / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D004338:Drug Combinations; D006801:Humans; D038982:Integrin alpha2beta1 / Q000378:metabolism; D039161:Integrin alpha6beta4 / Q000378:metabolism; D007797:Laminin; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008114:Liver Neoplasms, Experimental / Q000378:metabolism / Q000556:secondary*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D008666:Metalloendopeptidases / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D011509:Proteoglycans; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology
D019483:Disintegrins; D004338:Drug Combinations; D038982:Integrin alpha2beta1; D039161:Integrin alpha6beta4; D007797:Laminin; D008565:Membrane Proteins; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen; D051722:ADAM Proteins; C098339:ADAM9 protein, human; C498316:Adam9 protein, mouse; D008666:Metalloendopeptidases