Fibroblast-derived CXCL12 promotes breast cancer metastasis by facilitating tumor cell intravasation.
Fibroblast-derived CXCL12 promotes breast cancer metastasis by facilitating tumor cell intravasation.
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成纤维细胞来源的CXCL12通过促进肿瘤细胞内渗来推动乳腺癌转移。
DOI：
10.1038/s41388-018-0263-7
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发表时间：
2018-08
期刊：
影响因子：
8
通讯作者：
Ganju RK
中科院分区：
文献类型：
--
作者：
Ahirwar DK;Nasser MW;Ouseph MM;Elbaz M;Cuitiño MC;Kladney RD;Varikuti S;Kaul K;Satoskar AR;Ramaswamy B;Zhang X;Ostrowski MC;Leone G;Ganju RK
趋化因子CXCL12已被证明可以调节乳腺肿瘤的生长，然而，其引发远处转移的机制还不清楚。在此，我们在小鼠中产生了Cxcl12的新的条件等位基因，并使用成纤维细胞特异性Cre转基因沿着各种乳腺肿瘤模型来评估CXCL12在乳腺癌转移中的功能。在不同的小鼠模型中，在小鼠基质成纤维细胞中消融CXCL12显著延迟肿瘤发作的时间并抑制远处转移。使用体外和体内模型系统阐明的机制表明，CXCL12通过增加血管通透性和扩张渗漏的肿瘤血管系统来增强肿瘤细胞的内渗。此外，我们的研究表明，CXCL12通过招募内皮前体细胞和减少内皮紧密连接和粘附连接蛋白来增强通透性。在大的乳腺癌患者队列中，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负相关。此外，我们的分析显示，与单个蛋白水平相比，基质CXCL12水平与CD31+血管数量的组合具有较差的患者存活率。然而，上皮CXCL12和患者的生存率或血管密度之间没有相关性。我们的研究结果描述了成纤维细胞衍生的CXCL12和内皮细胞之间的新的相互作用，以促进肿瘤细胞浸润，导致远处转移。总的来说，我们的研究表明，成纤维细胞衍生的CXCL12和内皮细胞之间的串扰可以用作开发针对侵袭性和转移性乳腺癌的基于肿瘤微环境的疗法的新生物标志物和策略。
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 co-related to blood vessel density and inversely co-related to recurrence and overall patient survival. In addition, our analysis revealed that stromal CXCL12 levels in combination with number of CD31+ blood vessels have poorer patient survival compared to individual protein level. However, no co-relation 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 for 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.
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影响因子：
56.9
作者：
Asahara, T;Murohara, T;Isner, JM
通讯作者：
Isner, JM
影响因子：
50.3
作者：
Hanahan, Douglas;Coussens, Lisa M.
通讯作者：
Coussens, Lisa M.
DOI：
10.1073/pnas.1320318110
发表时间：
2013-12-10
影响因子：
11.1
作者：
Feig, Christine;Jones, James O.;Fearon, Douglas T.
通讯作者：
Fearon, Douglas T.
影响因子：
11.2
作者：
Nasser MW;Qamri Z;Deol YS;Ravi J;Powell CA;Trikha P;Schwendener RA;Bai XF;Shilo K;Zou X;Leone G;Wolf R;Yuspa SH;Ganju RK
通讯作者：
Ganju RK
影响因子：
5
作者：
Smolkova B;Mego M;Horvathova Kajabova V;Cierna Z;Danihel L;Sedlackova T;Minarik G;Zmetakova I;Krivulcik T;Gronesova P;Karaba M;Benca J;Pindak D;Mardiak J;Reuben JM;Fridrichova I
通讯作者：
Fridrichova I