The chemokine CXCL12 has been shown to regulate breast tumor growth, however, its mechanism in initiating distant metastasis is not well understood. Here, we generated a novel conditional allele of Cxcl12 in mice and used a fibroblast-specific Cre transgene along with various mammary tumor models to evaluate CXCL12 function in the breast cancer metastasis. Ablation of CXCL12 in stromal fibroblasts of mice significantly delayed the time to tumor onset and inhibited distant metastasis in different mouse models. Elucidation of mechanisms using in vitro and in vivo model systems revealed that CXCL12 enhances tumor cell intravasation by increasing vascular permeability and expansion of a leaky tumor vasculature. Furthermore, our studies revealed CXCL12 enhances permeability by recruiting endothelial precursor cells and decreasing endothelial tight junction and adherence junction proteins. High expression of stromal CXCL12 in large cohort of breast cancer patients was directly correlated to blood vessel density and inversely correlated to recurrence and overall patient survival. In addition, our analysis revealed that stromal CXCL12 levels in combination with number of CD31+ blood vessels confers poorer patient survival compared to individual protein level. However, no correlation was observed between epithelial CXCL12 and patient survival or blood vessel density. Our findings describe the novel interactions between fibroblasts-derived CXCL12 and endothelial cells in facilitating tumor cell intrvasation, leading to distant metastasis. Overall, our studies indicate that cross-talk between fibroblast-derived CXCL12 and endothelial cells could be used as novel biomarker and strategy for developing tumor microenvironment based therapies against aggressive and metastatic breast cancer.

中文翻译：

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成纤维细胞衍生的CXCL12通过促进肿瘤细胞的浸润促进乳腺癌的转移。

趋化因子CXCL12已被证明可调节乳腺肿瘤的生长，但是，其启动远处转移的机制尚不清楚。在这里，我们在小鼠中生成了Cxcl12的新型条件性等位基因，并使用了成纤维细胞特异性Cre转基因以及各种乳腺肿瘤模型来评估CXCL12在乳腺癌转移中的功能。小鼠基质成纤维细胞中CXCL12的消融显着延迟了肿瘤发作的时间，并在不同的小鼠模型中抑制了远处转移。对使用体外和体内模型系统的机制的阐明表明，CXCL12通过增加血管通透性和扩大渗漏的肿瘤脉管系统来增强肿瘤细胞的血管内介入。此外，我们的研究表明CXCL12通过募集内皮前体细胞并减少内皮紧密连接和粘附连接蛋白来增强通透性。大量乳腺癌患者中基质CXCL12的高表达与血管密度直接相关，与复发和患者总体生存率呈负相关。此外，我们的分析显示基质CXCL12水平与CD31 +血管数目相结合，与个体蛋白水平相比，赋予患者较差的生存率。然而，在上皮CXCL12与患者存活率或血管密度之间未观察到相关性。我们的发现描述了成纤维细胞衍生的CXCL12与内皮细胞之间的新型相互作用，促进肿瘤细胞的浸润，导致远处转移。全面的，