Mazzocca Antonio, Coppari Roberto, De Franco Raffaella, Cho Je-Yoel, Libermann Towia A, Pinzani Massimo, Toker Alex
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Cancer Res. 2005 Jun 1;65(11):4728-38. doi: 10.1158/0008-5472.CAN-04-4449.
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.
肿瘤细胞侵袭是一个由整合素、基质降解酶以及与宿主组织基质细胞的相互作用所调控的过程。ADAM蛋白家族在调节各种细胞反应中起重要作用。在此，我们表明肝星状细胞分泌一种ADAM9的可变剪接变体，并促进癌侵袭。在基质胶实验中，ADAM9-S在几种人类肿瘤细胞系中诱导出高度侵袭性表型，且ADAM9-S的蛋白酶活性是侵袭所必需的。ADAM9-S通过去整合素结构域直接结合结肠癌细胞表面的α6β4和α2β1整合素。ADAM9-S还能够切割层粘连蛋白并促进侵袭。对人肝转移灶的分析显示，ADAM9由肝基质肌成纤维细胞表达，尤其是那些位于侵袭前沿肿瘤基质内的细胞。这些结果强调了肿瘤-基质相互作用在侵袭中的重要性，并表明ADAM9-S可能是癌细胞侵袭和在肝脏中定植能力的一个重要决定因素。
