Rosso Ombretta, Piazza Tiziana, Bongarzone Italia, Rossello Armando, Mezzanzanica Delia, Canevari Silvana, Orengo Anna Maria, Puppo Andrea, Ferrini Silvano, Fabbi Marina
Department of Translational Oncology, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
Mol Cancer Res. 2007 Dec;5(12):1246-53. doi: 10.1158/1541-7786.MCR-07-0060.
Previous findings indicated that the activated leukocyte cell adhesion molecule (ALCAM) is expressed by tumors and plays a role in tumor biology. In this study, we show that ALCAM is shed from epithelial ovarian cancer (EOC) cells in vitro, leading to the generation of a soluble ALCAM (sALCAM), consisting of most of the extracellular domain. A similar sALCAM molecule was also found in the ascitic fluids and sera from EOC patients, suggesting that this process also occurs in vivo. sALCAM is constitutively produced by EOC cells, and this process can be enhanced by cell treatment with pervanadate, phorbol 12-myristate 13-acetate (PMA), or epidermal growth factor (EGF), a known growth factor for EOC. Pharmacologic inhibitors of matrix metalloproteinases (MMP) and of a disintegrin and metalloproteases (ADAM), and the tissue inhibitor of metalloproteinase-3, significantly inhibited sALCAM release by EOC cells. The ADAM17/TACE molecule was expressed in EOC cell lines and ADAM17/TACE silencing by specific small interfering RNA-reduced ALCAM shedding. In addition, inhibitors of ADAM function blocked EOC cell motility in a wound-healing assay. Conversely, a recombinant antibody blocking ALCAM adhesive functions and inducing ALCAM internalization enhanced EOC cell motility. Altogether, our data suggest that the disruption of ALCAM-mediated adhesion is a relevant step in EOC motility, and ADAM17/TACE takes part in this process, which may be relevant to EOC invasive potential.
先前的研究结果表明，活化白细胞细胞黏附分子（ALCAM）在肿瘤中表达，并在肿瘤生物学中发挥作用。在本研究中，我们发现体外培养的上皮性卵巢癌细胞（EOC）可释放ALCAM，从而产生可溶性ALCAM（sALCAM），其由大部分细胞外结构域组成。在EOC患者的腹水和血清中也发现了类似的sALCAM分子，这表明该过程在体内也会发生。EOC细胞可组成性产生sALCAM，用过氧钒酸盐、佛波酯12 - 肉豆蔻酸酯13 - 乙酸酯（PMA）或表皮生长因子（EGF，一种已知的EOC生长因子）处理细胞可增强这一过程。基质金属蛋白酶（MMP）和去整合素金属蛋白酶（ADAM）的药理抑制剂以及金属蛋白酶组织抑制剂 - 3可显著抑制EOC细胞释放sALCAM。ADAM17/TACE分子在EOC细胞系中表达，通过特异性小干扰RNA沉默ADAM17/TACE可减少ALCAM的释放。此外，在伤口愈合试验中，ADAM功能抑制剂可阻断EOC细胞的迁移。相反，一种阻断ALCAM黏附功能并诱导ALCAM内化的重组抗体可增强EOC细胞的迁移。总之，我们的数据表明，ALCAM介导的黏附破坏是EOC迁移的一个相关步骤，ADAM17/TACE参与了这一过程，这可能与EOC的侵袭潜能有关。
