Wang Hwai-Shi, Hung Ying, Su Cheng-Hsi, Peng Shu-Ting, Guo Yi-Jhih, Lai Mei-Chun, Liu Ching-Yi, Hsu Jia-Wei
Institute of Anatomy and Cell Biology, School of Medicine, Yang Ming University, 155, Sec. 2, Lih-Nong Street, Shih-Pai, 112, Peitou, Taipei 112, Taiwan, ROC.
Exp Cell Res. 2005 Mar 10;304(1):116-26. doi: 10.1016/j.yexcr.2004.10.015. Epub 2004 Nov 26.
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-1 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.
CD44是一种广泛表达的细胞表面糖蛋白，在细胞间黏附、细胞与基质相互作用、淋巴细胞归巢及肿瘤转移中起主要作用。肿瘤细胞要通过血管和淋巴管途径发生转移，必须首先黏附于内皮细胞。最近的研究表明，某些类型肿瘤中CD44的高表达与癌细胞的血行播散有关。然而，CD44与肿瘤细胞转移的功能相关性仍不清楚。在本研究中，我们使用MDA-MB-435S乳腺癌细胞系研究了CD44交联诱导肿瘤细胞黏附及跨内皮迁移的机制。发现乳腺癌细胞高表达CD44。通过流式细胞术分析和免疫荧光染色，我们证明CD44交联通过胞吐作用显著诱导淋巴细胞功能相关抗原-1（LFA-1）和极迟抗原-4（VLA-4）的表达。在Hs578T乳腺癌细胞系中也观察到了这些结果。此外，还研究了LFA-1和VLA-4介导的黏附及跨内皮癌细胞迁移。单独的抗LFA-1单克隆抗体或抗VLA-4单克隆抗体对黏附或跨内皮癌细胞迁移均无影响，但两者共同添加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，并增加整合素介导的对内皮细胞的黏附，从而导致乳腺癌细胞的跨内皮迁移。这些观察结果为CD44的新功能提供了直接证据，即CD44通过胞吐作用参与MDA-MB-435S细胞中LFA-1和VLA-4表达的诱导。由于这些诱导的整合素促进肿瘤细胞迁移到靶组织中，有可能通过药理学手段抑制这一过程，从而可能降低侵袭能力和转移。
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