Boesch Maximilian, Onder Lucas, Cheng Hung-Wei, Novkovic Mario, Mörbe Urs, Sopper Sieghart, Gastl Guenther, Jochum Wolfram, Ruhstaller Thomas, Knauer Michael, Ludewig Burkhard
Institute of Immunobiology, Kantonsspital St. Gallen, Rorschacherstrasse 95, St. Gallen, Switzerland.
Internal Medicine V, Medical University of Innsbruck, Anichstrasse 35, Innsbruck, Austria.
Oncoimmunology. 2018 Jan 3;7(4):e1414129. doi: 10.1080/2162402X.2017.1414129. eCollection 2018.
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, 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 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.
肿瘤微环境中存在癌症相关成纤维细胞，它们是癌症进展的主要调节因子。在此，我们评估了不同的癌症相关成纤维细胞亚群在原位小鼠模型中对乳腺癌生长和癌细胞干性的影响程度。我们发现，在白细胞介素7启动子控制下表达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发生物理相互作用。肿瘤内对白介素7表达成纤维细胞的消融损害了乳腺肿瘤生长并降低了癌细胞的克隆形成潜力。此外，cDNA表达谱揭示了产生白介素7的成纤维细胞独特的致癌特征。特别是， 在产生白介素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理学抑制表明CXCL12/CXCR4轴影响乳腺肿瘤细胞干性。原发性人乳腺癌相关成纤维细胞中 及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干性，从而促进乳腺癌生长。
