Cooperative role of E-cadherin and sialyl-Lewis X/A-deficient MUC1 in the passive dissemination of tumor emboli in inflammatory breast carcinoma
Cooperative role of E-cadherin and sialyl-Lewis X/A-deficient MUC1 in the passive dissemination of tumor emboli in inflammatory breast carcinoma
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DOI：
10.1038/sj.onc.1205389
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发表时间：
2002-05-16
期刊：
影响因子：
8
通讯作者：
Barsky, SH
中科院分区：
文献类型：
--
作者：
Alpaugh, ML;Tomlinson, JS;Barsky, SH
炎症性乳腺癌（IBC）的特征是淋巴血管间隙内的华丽肿瘤栓塞，称为淋巴血管浸润（LVI）。使用IBC的人类scid模型（MARY-X），我们已经证明使用逆转录病毒介导的显性阴性E-cadherin突变方法（H-2K(d)-E-cad），肿瘤细胞栓子（IBC球体）是在完整和过表达的E-cadherin/ α， β -catenin轴的基础上形成的，该轴介导肿瘤细胞-肿瘤细胞粘附，类似于胚胎囊胚，并解释了栓子的致密性。相比之下，肿瘤细胞栓塞（IBC球形）在体外和体内都不能结合周围的血管内皮细胞，因为其过表达的MUC1上的sialyl-Lewis X/A碳水化合物配体结合表位明显减少，而MUC1是结合内皮细胞e -选择素所必需的。这种对肿瘤细胞内皮细胞的厌恶进一步促进了IBC球体的致密性及其在转移传播中的被动性。这种被动表现为原发肿瘤触诊后转移性肺栓塞的急剧增加。为了评估这种转移传播的被动性，我们比较了触诊对MARY-X的影响与触诊对衍生的显性阴性E-cadherin突变体（H-2K(d)-E-cad）的影响，以及其他已知的人类肿瘤异种移植物的影响，这些移植物没有（MCF-7, T47D），低（MDA-MB-231, MDA-MB-468）或高（C8161, M24(met)）水平的自发转移，但没有LVI。触诊异种移植物同样使瘤内压力增加200% (10- 30mmhg)，但显著增加肺转移灶的数量和大小10-100倍(P
Inflammatory breast carcinoma (IBC) is characterized by florid tumor emboli within lymphovascular spaces termed lymphovascular invasion (LVI). Using a human-scid model of IBC (MARY-X), we have demonstrated using retrovirally-mediated dominant-negative E-cadherin mutant approaches (H-2K(d)-E-cad), that the tumor cell embolus (IBC spheroid) forms on the basis of an intact and overexpressed E-cadherin/alpha, beta-catenin axis which mediates tumor cell-tumor cell adhesion analogous to the embryonic blastocyst and accounts for the compactness of the embolus. The tumor cell embolus (IBC spheroid), in contrast, fails to bind the surrounding vascular endothelial cells both in vitro and in vivo because of markedly decreased sialyl-Lewis X/A carbohydrate ligand-binding epitopes on its overexpressed MUC1 which are necessary for binding endothelial cell E-selectin. This tumor cell-endothelial cell aversion further contributes to the compactness of the IBC spheroid and its passivity in metastasis dissemination. This passivity is manifested by a dramatic increase in metastatic pulmonary emboli following palpation of the primary tumor. In assessing this passivity of metastatic dissemination, we compared the effects of palpation on MARY-X with the effects of palpation on a derived dominant-negative E-cadherin mutant (H-2K(d)-E-cad), as well as other well known human tumoral xenografts exhibiting no (MCF-7, T47D), low (MDA-MB-231, MDA-MB-468) or high (C8161, M24(met)) levels of spontaneous metastasis but no LVI. Palpation of each xenograft similarly increased intratumoral pressure by 200% (10-->30 mmHg) but dramatically increased the numbers and sizes of pulmonary metastases 10-100-fold (P