Axl is an essential epithelial-to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival
Axl is an essential epithelial-to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival
复制标题
DOI：
10.1073/pnas.0909333107
复制
发表时间：
2010-01-19
影响因子：
11.1
通讯作者：
Lorens, James B.
中科院分区：
文献类型：
--
作者：
Gjerdrum, Christine;Tiron, Crina;Lorens, James B.
转移是大多数癌症相关死亡的根本原因。因此，进一步了解肿瘤细胞扩散的分子机制是一个至关重要的健康问题。上皮到间充质转化（EMTs）赋予癌细胞增强的迁移和生存特性，促进恶性进展。表征EMT效应物可能产生新的见解转移和新的治疗途径。我们发现，原发性乳腺癌中酪氨酸激酶受体Axl的存在可以独立预测患者总体生存率的降低，并且与患者转移灶相匹配的患者Axl表达增强。我们证明了Axl在永生化乳腺上皮细胞中被EMT强烈诱导，并与其配体Gas6建立自分泌信号回路。转移性乳腺癌细胞的外显子RNA干扰分析描绘了Axl表达在体外间充质样细胞侵袭和体内外源和组织工程微环境中肿瘤形成的明显阈值。重要的是，在两种不同的基于光学成像的实验性乳腺癌模型中，Axl敲除完全阻止了高转移性乳腺癌细胞从乳腺向淋巴结和几个主要器官的扩散，并提高了总生存率。这些发现表明，Axl代表了肿瘤细胞EMT的下游效应，这是乳腺癌转移所必需的。因此，检测和靶向治疗表达axl的肿瘤是乳腺癌治疗的重要新策略。
Metastasis underlies the majority of cancer-related deaths. Thus, furthering our understanding of the molecular mechanisms that enable tumor cell dissemination is a vital health issue. Epithelial-to-mesenchymal transitions (EMTs) endow carcinoma cells with enhanced migratory and survival attributes that facilitate malignant progression. Characterization of EMT effectors is likely to yield new insights into metastasis and novel avenues for treatment. We show that the presence of the receptor tyrosine kinase Axl in primary breast cancers independently predicts strongly reduced overall patient survival, and that matched patient metastatic lesions show enhanced Axl expression. We demonstrate that Axl is strongly induced by EMT in immortalized mammary epithelial cells that establishes an autocrine signaling loop with its ligand, Gas6. Epiallelic RNA interference analysis in metastatic breast cancer cells delineated a distinct threshold of Axl expression for mesenchymal-like in vitro cell invasiveness and formation of tumors in foreign and tissue-engineered microenvironments in vivo. Importantly, in two different optical imaging based experimental breast cancer models, Axl knockdown completely prevented the spread of highly metastatic breast carcinoma cells from the mammary gland to lymph nodes and several major organs and increased overall survival. These findings suggest that Axl represents a downstream effector of the tumor cell EMT that is required for breast cancer metastasis. Thus, the detection and targeted treatment of Axl-expressing tumors represents an important new therapeutic strategy for breast cancer.