Reciprocal Interactions between Tumor-Associated Macrophages and CD44-Positive Cancer Cells via Osteopontin/CD44 Promote Tumorigenicity in Colorectal Cancer
Reciprocal Interactions between Tumor-Associated Macrophages and CD44-Positive Cancer Cells via Osteopontin/CD44 Promote Tumorigenicity in Colorectal Cancer
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肿瘤相关巨噬细胞和 CD44 阳性癌细胞之间通过骨桥蛋白/CD44 的相互作用促进结直肠癌的致瘤性
DOI：
10.1158/1078-0432.ccr-12-2788
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发表时间：
2013-02-15
影响因子：
11.5
通讯作者：
Chen, Quan
中科院分区：
文献类型：
--
作者：
Rao, Guanhua;Wang, Hongyi;Chen, Quan
目的：CD 44在结直肠癌的肿瘤发生和进展中具有重要的功能，但是这种分子如何使癌细胞从肿瘤微环境中受益，特别是肿瘤相关巨噬细胞（TAM），仍然不清楚。实验设计：进行体内致瘤性测定以评估鼠TAM在人结肠直肠癌细胞的肿瘤发生中的作用。通过免疫组化、定量PCR和Western印迹法检测TAMs体外和体内骨桥蛋白（OPN）的表达水平。软琼脂集落形成试验用于评估接受不同治疗的结直肠癌细胞的集落形成性。采用组织芯片技术分析OPN、CD 44 v6、CD 68表达水平与临床预后的关系。结果如下：我们发现，当巨噬细胞与CD 44阳性结直肠癌细胞共注射或共培养时，能够产生更高水平的OPN，从而促进结直肠癌细胞的致瘤性和克隆形成。CD 44的敲低或用CD 44的阻断抗体处理减弱了OPN分泌。OPN通过与其受体CD 44结合，激活c-jun-NH 2-kinase信号通路，促进大肠癌细胞的克隆形成。此外，组织微阵列数据显示，OPN表达与CD 44 v6结合，与结直肠癌患者生存率呈负相关。结论：这些结果表明，OPN-CD 44相互作用对于结直肠癌的进展是重要的，并且可以作为治疗结直肠癌的潜在治疗靶点。临床癌症研究; 19（4）; 785-97。©2012 AACR。
Purpose: CD44 is of functional importance for tumor initiation and progression in colorectal cancer, but how this molecule benefits cancer cells from the tumor microenvironment, especially tumor-associated macrophages (TAM), remains poorly defined. Experimental Design: In vivo tumorigenic assays were conducted to assess the role of murine TAMs in the tumorigenesis of human colorectal cancer cells. Both in vitro and in vivo osteopontin (OPN) expression levels in TAMs were examined by immunohistochemistry, quantitative PCR, and Western blotting. Soft agar colony formation assays were used to estimate the clonogenicity of colorectal cancer cells that had received different treatments. The relationships between the expression levels of OPN, CD44v6, and CD68 and clinical prognosis were evaluated by tissue microarray analysis. Results: We found that macrophages, when coinjected or cocultured with CD44-positive colorectal cancer cells, were able to produce higher levels of OPN, which in turn facilitated the tumorigenicity and clonogenicity of the colorectal cancer cells. The knockdown of CD44 or treatment with blocking antibodies to CD44 attenuated OPN secretion. OPN, through binding to its receptor CD44, activated c-jun-NH2-kinase signaling and promoted the clonogenicity of colorectal cancer cells. Moreover, tissue microarray data have shown that OPN expression, in combination with CD44v6, has a negative correlation with colorectal cancer patient survival. Conclusions: These results suggest that the OPN–CD44 interaction is important for colorectal cancer progression and could serve as a potential therapeutic target for the treatment of colorectal cancer. Clin Cancer Res; 19(4); 785–97. ©2012 AACR.