Interleukin 7-expressing fibroblasts promote breast cancer growth through sustenance of tumor cell stemness.
Interleukin 7-expressing fibroblasts promote breast cancer growth through sustenance of tumor cell stemness.
复制标题
表达白细胞介素7的成纤维细胞通过维持肿瘤细胞的干细胞性来促进乳腺癌的生长。
DOI：
10.1080/2162402x.2017.1414129
复制
发表时间：
2018
期刊：
影响因子：
7.2
通讯作者：
Ludewig B
中科院分区：
文献类型：
--
作者：
Boesch M;Onder L;Cheng HW;Novkovic M;Mörbe U;Sopper S;Gastl G;Jochum W;Ruhstaller T;Knauer M;Ludewig B
肿瘤微环境中含有与癌症相关的成纤维细胞，它们是癌症进展的主要调节剂。在这里，我们评估了不同癌症相关的成纤维细胞亚群对原位小鼠模型中乳腺癌生长和癌细胞干细胞的影响程度。我们发现，在白细胞介素7启动子的控制下，表达Cre重组酶的成纤维细胞主要占据肿瘤边缘，在那里它们与肿瘤细胞物理相互作用。瘤内消融表达白细胞介素7的成纤维细胞会损害乳腺肿瘤的生长并降低癌细胞的克隆潜能。此外，cDNA表达谱显示产生白细胞介素7的成纤维细胞具有明显的致癌特征。特别是，Cxcl12在产生白细胞介素7的成纤维细胞中表达强烈增强，细胞类型特异性基因消融和全身药物抑制表明Cxcl12 /CXCR4轴影响乳腺肿瘤细胞的干细胞性。原发性人乳腺癌相关成纤维细胞中CXCL12和其他干细胞因子的表达升高表明，某些成纤维细胞群体支持肿瘤细胞的干细胞性，从而促进乳腺癌的生长。
The tumor microenvironment harbors cancer-associated fibroblasts that function as major modulators of cancer progression. Here, we assessed to which extent distinct cancer-associated fibroblast subsets impact mammary carcinoma growth and cancer cell stemness in an orthotopic murine model. We found that fibroblasts expressing the Cre recombinase under the control of the interleukin 7 promoter occupied mainly the tumor margin where they physically interacted with tumor cells. Intratumoral ablation of interleukin 7-expressing fibroblasts impaired breast tumor growth and reduced the clonogenic potential of cancer cells. Moreover, cDNA expression profiling revealed a distinct oncogenic signature of interleukin 7-producing fibroblasts. In particular, Cxcl12 expression was strongly enhanced in interleukin 7-producing fibroblasts and cell type-specific genetic ablation and systemic pharmacological inhibition revealed that the CXCL12/CXCR4 axis impacts breast tumor cell stemness. Elevated expression of CXCL12 and other stem cell factors in primary human breast cancer-associated fibroblasts indicates that certain fibroblast populations support tumor cell stemness and thereby promote breast cancer growth.