Distinct selectin ligands on colon carcinoma mucins can mediate pathological interactions among platelets, leukocytes, and endothelium
Distinct selectin ligands on colon carcinoma mucins can mediate pathological interactions among platelets, leukocytes, and endothelium
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DOI：
10.1016/s0002-9440(10)65142-5
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发表时间：
1999-08-01
影响因子：
6
通讯作者：
Varki, A
中科院分区：
文献类型：
--
作者：
Kim, YJ;Borsig, L;Varki, A
选择素是介导白细胞、血小板和内皮细胞之间钙依赖性细胞 - 细胞相互作用的黏附分子。选择素的天然血管配体大多是粘蛋白型糖蛋白。已知粘蛋白表达增加和糖基化改变是癌症进展的显著特征。我们先前已经表明，所有三种选择素都以钙依赖的方式与结肠癌细胞系结合，并且在P - 选择素缺陷小鼠中癌症生长和转移形成减弱。在此我们表明，三种重组可溶性选择素识别原发性结肠癌组织样本内的配体。亲和层析显示，所有三种选择素的配体都是对O - 唾液酸糖蛋白酶敏感的粘蛋白，它们以钙和唾液酸依赖的方式被识别。此外，粘蛋白上每种选择素都有单独的结合位点，允许单个粘蛋白分子被一种以上选择素交叉结合。我们还表明，纯化的癌性粘蛋白上的选择素配体能够介导血小板、白细胞和内皮细胞之间至少四种不同的病理相互作用。这些发现可以解释据报道发生在白细胞、血小板和内皮细胞之间的血源性肿瘤细胞的一些黏附事件，这些事件被认为在调节肿瘤转移的一些早期事件中起作用。
Selectins are adhesion molecules that mediate calcium-dependent cell-cell interactions among leukocytes, platelets, and endothelial cells, The naturally occurring vascular ligands for the selectins are mostly mucin-type glycoproteins. Increased expression and altered glycosylation of mucins are known to be prominent features of carcinoma progression. We have previously shown that all three selectins bind to colon carcinoma cell Lines in a calcium-dependent fashion and that carcinoma growth and metastasis formation are attenuated in P-selectin-deficient mice. Here we show that the three recombinant soluble selectins recognize ligands within, primary colon carcinoma tissue samples. Affinity chromatography showed that the ligands for all three selectins are O-sialoglycoprotease-sensitive mucins that are recognized in a calcium and sialic acid-dependent manner. Furthermore, there are separate binding sites on the mucins for each selectin, allowing cross-binding of a single mucin molecule by more than one selectin, We also show that the selectin ligands on purified carcinoma mucins can mediate at least four different pathological interactions among platelets, leukocytes, and endothelial cells. These findings could explain some of the adhesive events of blood-borne tumor cells reported to occur with leukocytes, platelets, and endothelial cells, which are believed to play a part in modulating some early events in tumor metastases.