Department of Integrated Oncological Therapies, IRCCS AOU San Martino-IST, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
Int J Cancer. 2013 Jun 1;132(11):2597-605. doi: 10.1002/ijc.27948. Epub 2012 Dec 13.
Activated leukocyte cell adhesion molecule (ALCAM) is involved in cell-cell interactions in cancer. Shedding of its ectodomain by the metalloprotease ADAM17/TACE generates a soluble form (sALCAM). Here, we show that serum sALCAM levels were significantly higher in epithelial ovarian cancer (EOC) (p < 0.005) than in controls. The performance of sALCAM as classifier, tested by receiver operating characteristic curve, resulted in an area under the curve (AUC) of 0.8067. Serum sALCAM levels showed direct correlation with Carbohydrate Antigen-125 (CA125/MUC16). Moreover, significantly higher levels were found in type II tumors, even in stage I/II, suggesting that elevated sALCAM is an early feature of aggressive EOC. In addition, sALCAM levels were higher in ascites than in sera, suggesting local processing of ALCAM in the peritoneal cavity. In immunodeficient mice, intraperitoneally implanted with a human EOC cell line, human sALCAM progressively increased in serum and was even higher in the ascites. The biochemical characterization of the sALCAM in EOC sera and ascites, showed two predominant forms of approximately 95 and 65 kDa but no EOC-specific isoform. In addition, full-length transmembrane ALCAM but no soluble form was detected in tumor-derived exosomes found in ascites. Finally, in vitro invasion assays showed that inhibition of ADAM17/TACE activity decreased EOC invasive properties, while opposite effects were mediated by a sALCAM-Fc chimera and by an antibody interfering with ALCAM/ALCAM interactions. Altogether these data suggest that sALCAM is a marker of EOC, which correlates with more aggressive type II tumors, and that ADAM17/TACE activity and sALCAM itself mediate enhanced invasiveness.
激活白细胞细胞黏附分子（ALCAM）参与癌症中的细胞-细胞相互作用。金属蛋白酶 ADAM17/TACE 对其细胞外结构域的脱落会产生可溶性形式（sALCAM）。在这里，我们发现上皮性卵巢癌（EOC）患者的血清 sALCAM 水平明显高于对照组（p<0.005）。通过接收者操作特征曲线测试，sALCAM 作为分类器的性能得出曲线下面积（AUC）为 0.8067。血清 sALCAM 水平与碳水化合物抗原 125（CA125/MUC16）呈直接相关。此外，在 II 型肿瘤中发现了更高的水平，甚至在 I/II 期，这表明升高的 sALCAM 是侵袭性 EOC 的早期特征。此外，sALCAM 水平在腹水高于血清，这表明 ALCAM 在腹腔内的局部处理。在免疫缺陷小鼠中，用人卵巢癌细胞系进行腹腔内植入，血清中的人 sALCAM 逐渐增加，腹水甚至更高。EOC 血清和腹水 sALCAM 的生化特征表明存在两种主要形式，约为 95 和 65 kDa，但没有 EOC 特异性同工型。此外，在腹水来源的肿瘤衍生外泌体中检测到全长跨膜 ALCAM，但没有可溶性形式。最后，体外侵袭实验表明，抑制 ADAM17/TACE 活性降低了 EOC 的侵袭性，而 sALCAM-Fc 嵌合体和干扰 ALCAM/ALCAM 相互作用的抗体则产生相反的作用。总之，这些数据表明 sALCAM 是 EOC 的标志物，与更具侵袭性的 II 型肿瘤相关，ADAM17/TACE 活性和 sALCAM 本身介导增强的侵袭性。
