Importance of CCL2-CCR2A/2B signaling for monocyte migration into spheroids of breast cancer-derived fibroblasts
Importance of CCL2-CCR2A/2B signaling for monocyte migration into spheroids of breast cancer-derived fibroblasts
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DOI：
10.1016/j.imbio.2010.05.019
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发表时间：
2010-09-01
期刊：
影响因子：
2.8
通讯作者：
Kunz-Schughart, Leoni A.
中科院分区：
文献类型：
--
作者：
Ksiazkiewicz, Magdalena;Gottfried, Eva;Kunz-Schughart, Leoni A.
相当一部分的肿瘤相关巨噬细胞（TAM）位于促纤维增生性乳腺癌的富含成纤维细胞的间质室中。我们分析了血单核细胞（MO），TAM的前体细胞，进入3-D培养的癌细胞和乳腺肿瘤来源的成纤维细胞的迁移活动。MO迁移到乳腺肿瘤球状体中是高度可变的：Hs 578 T球状体显示出高MO浸润率，T47 D培养物是中等的，而BT549、BT474和MCF-7球状体浸润较差。肿瘤来源的成纤维细胞球体中MO浸润也很高;然而，通过CD 14/CD 16表达谱未鉴定出具有特异性浸润潜力的MO亚群。百日咳毒素和霍乱毒素可抑制MO的浸润，但只有阻断G（i）蛋白功能的百日咳毒素才能完全抑制MO的迁移。G（i）偶联的CCL 2受体CCR 2A/2B在大致所有MO上表达。此外，高度浸润的肿瘤来源的成纤维细胞和Hs 578 T球状体分泌大量的CCL 2。与此一致，通过添加重组CCL 2以干扰CCL 2梯度或通过用CCR 2A/2B阻断抗体预孵育MO来抑制MO向成纤维细胞球状体中的浸润。然而，MO浸润的Hs 578 T球体，不能被CCL 2受体阻断剂抑制。我们的研究清楚地表明，CCL 2-CCR 2A/2B途径是至关重要的招聘血液MO到肿瘤成纤维细胞的地区，而其他因素可能是相关的MO迁移到肿瘤细胞的网站。(C)2010年Elsevier GmbH。All rights reserved.
A considerable fraction of tumor-associated macrophages (TAM) is located in the fibroblast-rich stromal compartment of desmoplastic breast carcinoma. We analyzed the migratory activity of blood monocytes (MO), the precursor cells of TAM, into 3-D cultures of carcinoma cells and fibroblasts from breast tumor origin. MO migration into breast tumor spheroids was highly variable: Hs578T spheroids showed high MO infiltration rates, T47D cultures were intermediate, whereas BT549, BT474 and MCF-7 spheroids were poorly infiltrated. MO infiltration was also high in tumor-derived fibroblast spheroids; however, no MO subpopulation with specific infiltrative potential was identified by CD14/CD16 expression profile. The infiltration of MO could be inhibited by pre-exposure to pertussis and cholera toxins, but only pertussis toxin, which blocks G(i) protein function, entirely inhibited MO migration. The G(i) coupled CCL2 receptor CCR2A/2B was expressed on roughly all MO. Furthermore, highly infiltrated tumor-derived fibroblast and Hs578T spheroids secreted considerable amounts of CCL2. In line with this, the infiltration of MO into fibroblast spheroids was suppressed by either addition of recombinant CCL2 to disturb the CCL2 gradient or by pre-incubation of MO with a CCR2A/2B blocking antibody. MO infiltration of Hs578T spheroids, however, could not be inhibited by CCL2 receptor blockade. Our study clearly shows that the CCL2-CCR2A/2B pathway is crucial for the recruitment of blood MO into tumor fibroblastic areas, whereas additional factors may be relevant for the migration of MO into tumor cell sites. (C) 2010 Elsevier GmbH. All rights reserved.