Exogenous expression of N-cadherin in breast cancer cells induces cell migration, invasion, and metastasis.
Exogenous expression of N-cadherin in breast cancer cells induces cell migration, invasion, and metastasis.
复制标题
N-钙粘着蛋白在乳腺癌细胞中的外源表达会诱导细胞迁移，侵袭和转移。
DOI：
10.1083/jcb.148.4.779
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发表时间：
2000-02-21
影响因子：
7.8
通讯作者：
Aaronson, S A
中科院分区：
文献类型：
--
作者：
Hazan, R B;Phillips, G R;Qiao, R F;Norton, L;Aaronson, S A
E-钙粘蛋白和n -钙粘蛋白是钙依赖性的细胞粘附分子，它们介导细胞间的粘附，也调节细胞迁移和肿瘤侵袭。e -钙粘蛋白介导的黏附缺失已被证明在上皮肿瘤从良性向侵袭性转变过程中发挥重要作用。然而，最近的证据表明，cadherin家族的另一成员N-cadherin在缺乏E-cadherin表达的高侵袭性肿瘤细胞系中表达。这些发现提出了n -钙粘蛋白导致侵袭性表型的可能性。为了确定N-cadherin是否促进了侵袭和转移，我们用N-cadherin转染了弱转移且表达e -cadherin的乳腺癌细胞株MCF-7，并分析了N-cadherin对细胞迁移、侵袭和转移的影响。转染后的细胞同时表达E-和n -钙粘蛋白，并表现出两种分子的同型细胞粘附。在体外，表达n -cadherin的细胞更有效地迁移，对基质的侵袭增加，并更有效地粘附在内皮细胞单层上。所有细胞均产生低水平的基质金属蛋白酶MMP-9，仅在表达n -钙粘蛋白的细胞中，FGF-2处理可显著上调基质金属蛋白酶MMP-9。该处理也大大增强了基质的迁移和入侵。将表达n -cadherin的细胞（而非控制MCF-7的细胞）注射到裸鼠乳腺脂肪垫后，广泛转移到肝脏、胰腺、唾液腺、大网膜、肺、淋巴结和腰脊髓肌。E-和N-cadherin在原发肿瘤和转移灶中均保持表达。这些结果表明，即使在正常抑制e -钙粘蛋白存在的情况下，n -钙粘蛋白也能促进运动、侵袭和转移。表达n -cadherin的细胞对生长因子的反应增加了MMP-9的产生，这可能使它们具有更强的穿透基质蛋白屏障的能力，而它们对内皮粘附的增加可能提高了它们进入和退出血管系统的能力，这两个特性可能是表达n -cadherin的细胞转移的原因。
E- and N-cadherin are calcium-dependent cell adhesion molecules that mediate cell–cell adhesion and also modulate cell migration and tumor invasiveness. The loss of E-cadherin–mediated adhesion has been shown to play an important role in the transition of epithelial tumors from a benign to an invasive state. However, recent evidence indicates that another member of the cadherin family, N-cadherin, is expressed in highly invasive tumor cell lines that lacked E-cadherin expression. These findings have raised the possibility that N-cadherin contributes to the invasive phenotype. To determine whether N-cadherin promotes invasion and metastasis, we transfected a weakly metastatic and E-cadherin–expressing breast cancer cell line, MCF-7, with N-cadherin and analyzed the effects on cell migration, invasion, and metastasis. Transfected cells expressed both E- and N-cadherin and exhibited homotypic cell adhesion from both molecules. In vitro, N-cadherin–expressing cells migrated more efficiently, showed an increased invasion of Matrigel, and adhered more efficiently to monolayers of endothelial cells. All cells produced low levels of the matrix metalloproteinase MMP-9, which was dramatically upregulated by treatment with FGF-2 only in N-cadherin–expressing cells. Migration and invasion of Matrigel were also greatly enhanced by this treatment. When injected into the mammary fat pad of nude mice, N-cadherin–expressing cells, but not control MCF-7 cells, metastasized widely to the liver, pancreas, salivary gland, omentum, lung, lymph nodes, and lumbar spinal muscle. The expression of both E- and N-cadherin was maintained both in the primary tumors and metastatic lesions. These results demonstrate that N-cadherin promotes motility, invasion, and metastasis even in the presence of the normally suppressive E-cadherin. The increase in MMP-9 production by N-cadherin–expressing cells in response to a growth factor may endow them with a greater ability to penetrate matrix protein barriers, while the increase in their adherence to endothelium may improve their ability to enter and exit the vasculature, two properties that may be responsible for metastasis of N-cadherin–expressing cells.