Sema3E-Plexin D1 signaling drives human cancer cell invasiveness and metastatic spreading in mice
Sema3E-Plexin D1 signaling drives human cancer cell invasiveness and metastatic spreading in mice
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DOI：
10.1172/jci42118
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发表时间：
2010-08-01
影响因子：
15.9
通讯作者：
Tamagnone, Luca
中科院分区：
文献类型：
--
作者：
Casazza, Andrea;Finisguerra, Veronica;Tamagnone, Luca
信号素3E(Semaphorin 3E，Sema3E)是一种分泌型分子，参与轴突的寻路和抑制发育及再生后的血管生成。Sema3E在转移性癌细胞中也高表达，但其在肿瘤进展中的机制尚不清楚。在这里，我们发现Sema3E及其受体网络蛋白D1的表达与人类肿瘤的转移进展有关。与临床数据一致的是，在人转移癌细胞中下调Sema3E或Plexin D1的内源性表达，抑制了其注射到小鼠体内的转移潜能，而对肿瘤生长没有明显影响。相反，外源Sema3E在癌细胞中的过表达增加了它们的侵袭力、跨内皮细胞迁移和转移扩散，尽管它抑制了肿瘤血管的形成，导致小鼠肿瘤生长减少。Sema3E在肿瘤细胞中的侵袭和转移活性依赖于Plexin D1相关的ErbB2/Neu癌基因激酶的反式激活。总之，癌细胞中的Sema3E-Plexin D1信号与其转移行为密切相关，因此可能成为阻断肿瘤转移策略的一个有前途的靶点。
Semaphorin 3E (Sema3E) is a secreted molecule implicated in axonal path finding and inhibition of developmental and postischentic angiogenesis. Sema3E is also highly expressed in metastatic cancer cells, but its mechanistic role in tumor progression was not understood. Here we show that expression of Sema3E and its receptor Plexin D1 correlates with the metastatic progression of human tumors. Consistent with the clinical data, knocking down endogenous expression of either Sema3E or Plexin D1 in human metastatic carcinoma cells hampered their metastatic potential when injected into mice, while tumor growth was not markedly affected. Conversely, overexpression of exogenous Sema3E in cancer cells increased their invasiveness, transendothelial migration, and metastatic spreading, although it inhibited tumor vessel formation, resulting in reduced tumor growth in mice. The proinvasive and metastatic activity of Sema3E in tumor cells was dependent on transactivation of the Plexin D1-associated ErbB2/Neu oncogenic kinase. In sum, Sema3E-Plexin D1 signaling in cancer cells is crucially implicated in their metastatic behavior and may therefore be a promising target for strategies aimed at blocking tumor metastasis.