Hazan R B, Phillips G R, Qiao R F, Norton L, Aaronson S A
The Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine of New York University, New York, New York 10029, USA.
J Cell Biol. 2000 Feb 21;148(4):779-90. doi: 10.1083/jcb.148.4.779.
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.
E-钙黏蛋白和N-钙黏蛋白是钙依赖性细胞黏附分子，它们介导细胞间黏附，还能调节细胞迁移和肿瘤侵袭性。E-钙黏蛋白介导的黏附丧失已被证明在上皮肿瘤从良性向侵袭性状态的转变中起重要作用。然而，最近的证据表明，钙黏蛋白家族的另一个成员N-钙黏蛋白在缺乏E-钙黏蛋白表达的高侵袭性肿瘤细胞系中表达。这些发现增加了N-钙黏蛋白促成侵袭表型的可能性。为了确定N-钙黏蛋白是否促进侵袭和转移，我们用N-钙黏蛋白转染了低转移性且表达E-钙黏蛋白的乳腺癌细胞系MCF-7，并分析了对细胞迁移、侵袭和转移的影响。转染细胞同时表达E-钙黏蛋白和N-钙黏蛋白，并表现出来自这两种分子的同型细胞黏附。在体外，表达N-钙黏蛋白的细胞迁移更有效，对基质胶的侵袭增加，并且更有效地黏附于内皮细胞单层。所有细胞产生低水平的基质金属蛋白酶MMP-9，仅在表达N-钙黏蛋白的细胞中，用FGF-2处理可使其显著上调。这种处理也极大地增强了对基质胶的迁移和侵袭。当注射到裸鼠的乳腺脂肪垫中时，表达N-钙黏蛋白的细胞而非对照MCF-7细胞广泛转移至肝脏胰腺、唾液腺、网膜、肺、淋巴结和腰脊肌。E-钙黏蛋白和N-钙黏蛋白的表达在原发性肿瘤和转移灶中均得以维持。这些结果表明，即使存在通常具有抑制作用的E-钙黏蛋白，N-钙黏蛋白也能促进运动性、侵袭和转移。表达N-钙黏蛋白的细胞对生长因子反应而导致的MMP-9产生增加，可能使其具有更强的穿透基质蛋白屏障的能力，而它们对内皮细胞黏附的增加可能改善其进出脉管系统的能力，这两种特性可能是表达N-钙黏蛋白的细胞发生转移的原因。
