CD44 Cross-linking induces integrin-mediated adhesion, and transendothelial migration in breast cancer cell line by up-regulation of LFA-1 (αLβ2) and VLA-4 (α4β1)
CD44 Cross-linking induces integrin-mediated adhesion, and transendothelial migration in breast cancer cell line by up-regulation of LFA-1 (αLβ2) and VLA-4 (α4β1)
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DOI：
10.1016/j.yexcr.2004.10.015
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发表时间：
2005-03-10
影响因子：
3.7
通讯作者：
Hsu, HW
中科院分区：
文献类型：
--
作者：
Wang, HS;Hung, Y;Hsu, HW
CD44是一种广泛表达的细胞表面糖蛋白，在细胞-细胞粘附、细胞-底物相互作用、淋巴细胞归巢和肿瘤转移中起重要作用。肿瘤要通过血管和淋巴管途径发生转移，肿瘤细胞必须首先附着在内皮细胞上。最近的研究表明，CD44在某些类型肿瘤中的高表达与癌细胞的血源性扩散有关。然而，CD44与肿瘤细胞转移的功能相关性尚不清楚。本研究以MDA-MB-435S乳腺癌细胞系为研究对象，探讨了CD44交联诱导肿瘤细胞粘附和跨内皮迁移的机制。发现乳腺癌细胞表达高水平的CD44。通过流式细胞分析和免疫荧光染色，我们证明了CD44交联导致淋巴细胞功能相关抗原-1 （LFA-1）和极迟抗原-4 （vla4）通过胞吐作用显著诱导表达。在Hs578T乳腺癌细胞系中也观察到这些结果。此外，还研究了LFA-1-和vla -4介导的粘附和跨内皮癌细胞迁移。Anti-LFA-1 mAb或anti- vla4 mAb单独对粘附或跨内皮癌细胞迁移没有影响，但当加在一起时能够抑制这两种功能。这表明CD44交联诱导MDA-MB-435S细胞中LFA-1和VLA-4的表达，增加整合素介导的对内皮细胞的粘附，导致乳腺癌细胞的跨内皮迁移。这些观察结果为CD44在MDA-MB-435S细胞中通过胞吐作用诱导lfa - 1和vla4表达的新功能提供了直接证据。由于这些诱导整合素促进肿瘤细胞向靶组织的迁移，因此可能通过药物手段抑制肿瘤细胞向靶组织的迁移，从而潜在地降低肿瘤的侵袭能力和转移。(C) 2004爱思唯尔公司版权所有。
CD44, a widely expressed cell surface glycoprotein, plays a major role in cell-cell adhesion, cell-substrate interaction, lymphocyte homing, and tumor metastasis. For tumor metastasis to occur through the blood vessel and lymphatic vessel pathway, the tumor cells must first adhere to endothelial cells. Recent studies have shown that high expression of CD44 in certain types of tumors is associated with the hematogenic spread of cancer cells. However, the functional relevance of CD44 to tumor cell metastasis remains unknown. In this study, we investigated the mechanisms of CD44 cross-linking-induced adhesion and transendothelial migration of tumor cells using MDA-MB-435S breast cancer cell line. Breast cancer cells were found to express high levels of CD44. Using flow cytometric analysis and immunofluorescence staining, we demonstrated that cross-linking of CD44 resulted in a marked induction of the expression of lymphocyte function-associated antigen-1 (LFA-1) and very late antigen-4 (VLA-4) by exocytosis. These results were also observed with the Hs578T breast cancer cell line. Furthermore, LFA-1- and VLA-4-mediated adhesion and transendothelial cancer cell migration were also studied. Anti-LFA-1 mAb or anti-VLA-4 mAb alone had no effect on adhesion or transendothelial cancer cell migration, but were able to inhibit both of these functions when added together. This shows that CD44 cross-linking induces LFA-1 and VLA-4 expression in MDA-MB-435S cells and increases integrin-mediated adhesion to endothelial cells, resulting in the transendothelial migration of breast cancer cells. These observations provide direct evidence of a new function for CD44 that is involved in the induction of LFA-I and VLA-4 expression by exocytosis in MDA-MB-435S cells. Because these induced integrins promote tumor cell migration into the target tissue, it may be possible to suppress this by pharmacological means, and thus potentially cause a reduction in invasive capability and metastasis. (C) 2004 Elsevier Inc. All rights reserved.