Connexin-43 upregulation in micrometastases and tumor vasculature and its role in tumor cell attachment to pulmonary endothelium.
Connexin-43 upregulation in micrometastases and tumor vasculature and its role in tumor cell attachment to pulmonary endothelium.
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DOI：
10.1186/1741-7015-6-20
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发表时间：
2008-07-22
期刊：
影响因子：
9.3
通讯作者：
Al-Mehdi AB
中科院分区：
文献类型：
--
作者：
Elzarrad MK;Haroon A;Willecke K;Dobrowolski R;Gillespie MN;Al-Mehdi AB
在肿瘤发生和转移过程中，肿瘤细胞之间以及肿瘤与血管内皮细胞之间的间隙连接通讯的调节是复杂的。在肿瘤发生和转移过程中缺失间隙连接细胞间通讯的概念一直存在争议。虽然肿瘤发生和转移的某些阶段，如不受控制的细胞分裂和细胞脱离，可能需要失去细胞间连接，但其他阶段，如内渗、内皮附着和血管形成，可能需要增加细胞间的接触。我们假设，在这个多阶段方案中，连接蛋白43作为细胞粘附分子介导转移性肿瘤附着于肺内皮的中枢参与。我们研究了肿瘤细胞对肺血管的附着、肿瘤生长和连接蛋白43的表达，将转移性肺肿瘤切片注射到同基因乳腺癌细胞系的裸鼠尾静脉中，过度表达野生型连接蛋白43或显性负突变的连接蛋白43。使用connexin-43单克隆抗体进行高分辨率免疫荧光显微镜和Western blot分析。采用钙黄素橙红AM染料转移荧光成像评价间隙连接功能。过表达connexin-43的乳腺癌细胞对肺内皮的粘附增强，而表达阴性connexin-43的乳腺癌细胞对肺内皮的粘附明显减弱。在体外和体内的肿瘤细胞内皮细胞接触区、肿瘤内血管区和微转移灶中，均观察到连接蛋白-43的上调。Connexin-43通过增加癌细胞对肺内皮细胞的粘附，促进转移性“归巢”。连接蛋白43在肿瘤细胞-内皮细胞接触区域的显著上调，无论是在先前存在的“归巢”血管中还是在新形成的肿瘤血管中，都表明连接蛋白43可以作为微转移和肿瘤血管系统的潜在标记物，并且它可能在内皮细胞早期并入小肿瘤中发挥作用，作为血管发生的种子。
The modulation of gap junctional communication between tumor cells and between tumor and vascular endothelial cells during tumorigenesis and metastasis is complex. The notion of a role for loss of gap junctional intercellular communication in tumorigenesis and metastasis has been controversial. While some of the stages of tumorigenesis and metastasis, such as uncontrolled cell division and cellular detachment, would necessitate the loss of intercellular junctions, other stages, such as intravasation, endothelial attachment, and vascularization, likely require increased cell-cell contact. We hypothesized that, in this multi-stage scheme, connexin-43 is centrally involved as a cell adhesion molecule mediating metastatic tumor attachment to the pulmonary endothelium. Tumor cell attachment to pulmonary vasculature, tumor growth, and connexin-43 expression was studied in metastatic lung tumor sections obtained after tail-vein injection into nude mice of syngeneic breast cancer cell lines, overexpressing wild type connexin-43 or dominant-negatively mutated connexin-43 proteins. High-resolution immunofluorescence microscopy and Western blot analysis was performed using a connexin-43 monoclonal antibody. Calcein Orange Red AM dye transfer by fluorescence imaging was used to evaluate the gap junction function. Adhesion of breast cancer cells to the pulmonary endothelium increased with cancer cells overexpressing connexin-43 and markedly decreased with cells expressing dominant-negative connexin-43. Upregulation of connexin-43 was observed in tumor cell-endothelial cell contact areas in vitro and in vivo, and in areas of intratumor blood vessels and in micrometastatic foci. Connexin-43 facilitates metastatic 'homing' by increasing adhesion of cancer cells to the lung endothelial cells. The marked upregulation of connexin-43 in tumor cell-endothelial cell contact areas, whether in preexisting 'homing' vessels or in newly formed tumor vessels, suggests that connexin-43 can serve as a potential marker of micrometastases and tumor vasculature and that it may play a role in the early incorporation of endothelial cells into small tumors as seeds for vasculogenesis.
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胞质内连接蛋白的病理意义：对肿瘤进展的影响
影响因子：
2.4
作者：
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影响因子：
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