SIX1 induces lymphangiogenesis and metastasis via upregulation of VEGF-C in mouse models of breast cancer
SIX1 induces lymphangiogenesis and metastasis via upregulation of VEGF-C in mouse models of breast cancer
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DOI：
10.1172/jci59858
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发表时间：
2012-05-01
影响因子：
15.9
通讯作者：
Ford, Heide L.
中科院分区：
文献类型：
--
作者：
Wang, Chu-An;Jedlicka, Paul;Ford, Heide L.
乳腺癌淋巴结转移与预后不良之间的关系在几十年前就被观察到了。然而，肿瘤细胞浸润淋巴系统的机制尚未完全了解。最近，已经提出淋巴系统在转移性播散中具有积极作用，并且肿瘤分泌的生长因子刺激淋巴管生成。因此，我们研究是否SIX 1，一个同源结构域的转录因子先前与乳腺癌淋巴结阳性，参与淋巴管生成和淋巴转移。在将人乳腺癌细胞注射到免疫缺陷小鼠中的模型中，我们发现SIX 1表达促进了乳腺癌细胞的瘤周和瘤内淋巴管生成、淋巴侵袭和远处转移。SIX 1诱导前淋巴管生成因子VEGF-C的转录，这是淋巴管生成和淋巴转移所必需的。使用小鼠乳腺癌模型，我们发现VEGF-C不足以介导SIX 1的所有转移效应，表明SIX 1通过额外的VEGF-C非依赖性途径起作用。最后，我们通过证实SIX 1和VEGF-C在人乳腺癌中的共表达，验证了这种促转移SIX 1/VEGF-C轴的临床意义。这些数据定义了SIX 1在乳腺癌细胞淋巴扩散中的关键作用，为乳腺癌中VEGF-C表达如何上调、导致淋巴管生成和转移提供了直接的机制解释。
An association between lymph node metastasis and poor prognosis in breast cancer was observed decades ago. However, the mechanisms by which tumor cells infiltrate the lymphatic system are not completely understood. Recently, it has been proposed that the lymphatic system has an active role in metastatic dissemination and that tumor-secreted growth factors stimulate lymphangiogenesis. We therefore investigated whether SIX1, a homeodomain-containing transcription factor previously associated in breast cancer with lymph node positivity, was involved in lymphangiogenesis and lymphatic metastasis. In a model in which human breast cancer cells were injected into immune-compromised mice, we found that SIX1 expression promoted peritumoral and intratumoral lymphangiogenesis, lymphatic invasion, and distant metastasis of breast cancer cells. SIX1 induced transcription of the prolymphangiogenic factor VEGF-C, and this was required for lymphangiogenesis and lymphatic metastasis. Using a mouse mammary carcinoma model, we found that VEGF-C was not sufficient to mediate all the metastatic effects of SIX1, indicating that SIX1 acts through additional, VEGF-C-independent pathways. Finally, we verified the clinical significance of this prometastatic SIX1/VEGF-C axis by demonstrating coexpression of SIX1 and VEGF-C in human breast cancer. These data define a critical role for SIX1 in lymphatic dissemination of breast cancer cells, providing a direct mechanistic explanation for how VEGF-C expression is upregulated in breast cancer, resulting in lymphangiogenesis and metastasis.