Netrin-1 expression confers a selective advantage for tumor cell survival in metastatic breast cancer
Netrin-1 expression confers a selective advantage for tumor cell survival in metastatic breast cancer
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DOI：
10.1073/pnas.0709810105
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发表时间：
2008-03-25
影响因子：
11.1
通讯作者：
Mehlen, Patrick
中科院分区：
文献类型：
--
作者：
Fitamant, Julien;Guenebeaud, Celine;Mehlen, Patrick
Netrin-1是一种轴突导航因子，它通过调节细胞凋亡在结直肠肿瘤的发生发展中发挥重要作用。netrin-1受体DCC和UNC 5 H被证明属于依赖性受体家族，其在不存在其配体的情况下具有诱导细胞凋亡的能力。这种特性赋予这些受体肿瘤抑制活性。这些依赖性受体之一在肿瘤细胞表面的表达确实被推测为使该细胞依赖于其存活的配体可用性，从而抑制不受控制的细胞增殖或转移。因此，对于肿瘤细胞来说，失去这种依赖性受体活性是一种选择性优势，如先前在人类癌症中DCC和UNC 5 H表达的丧失所述。然而，该模型预测，通过获得配体的自分泌表达可以获得类似的优势。我们在这里描述，与人类非转移性乳腺肿瘤不同，大部分转移性乳腺癌过表达netrin-1。此外，我们表明，netrin-1表达乳腺转移性肿瘤细胞系进行细胞凋亡时netrin-1的表达实验性降低，或当诱饵可溶性受体胞外域加入。此类治疗可以预防乳腺癌细胞系肺定殖的同基因小鼠模型和异种移植人乳腺肿瘤自发肺转移模型中转移的形成。因此，netrin-1的表达中观察到的大部分人转移性乳腺肿瘤赋予肿瘤细胞存活的选择性优势，并可能代表一个有前途的替代抗癌治疗策略的目标。
Netrin-1, an axon navigation cue was proposed to play a crucial role during colorectal tumorigenesis by regulating apoptosis. The netrin-1 receptors DCC and UNC5H were shown to belong to the family of dependence receptors that share the ability to induce apoptosis in the absence of their ligands. Such a trait confers on these receptors a tumor suppressor activity. Expression of one of these dependence receptors at the surface of a tumor cell is indeed speculated to render this cell dependent on ligand availability for its survival, hence inhibiting uncontrolled cell proliferation or metastasis. Consequently, it is a selective advantage for a tumor cell to lose this dependence receptor activity, as previously described with losses of DCC and UNC5H expression in human cancers. However, the model predicts that a similar advantage may be obtained by gaining autocrine expression of the ligand. We describe here that, unlike human nonmetastatic breast tumors, a large fraction of metastatic breast cancers overexpress netrin-1. Moreover, we show that netrin-1-expressing mammary metastatic tumor cell lines undergo apoptosis when netrin-1 expression is experimentally decreased or when decoy soluble receptor ectodomains are added. Such treatments prevent metastasis formation both in a syngenic mouse model of lung colonization of a mammary cancer cell line and in a model of spontaneous lung metastasis of xenografted human breast tumor. Thus, netrin-1 expression observed in a large fraction of human metastatic breast tumors confers a selective advantage for tumor cell survival and potentially represents a promising target for alternative anticancer therapeutic strategies.