Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Mail Code 8852, Dallas, TX 75390-8852, USA.
Mol Cancer Ther. 2012 Nov;11(11):2473-82. doi: 10.1158/1535-7163.MCT-12-0431. Epub 2012 Aug 28.
In lung cancer, platelet-derived growth factor receptor α (PDGFRα) is expressed frequently by tumor-associated stromal cells and by cancer cells in a subset of tumors. We sought to determine the effect of targeting stromal PDGFRα in preclinical lung tumor xenograft models (human tumor, mouse stroma). Effects of anti-human (IMC-3G3) and anti-mouse (1E10) PDGFRα monoclonal antibodies (mAb) on proliferation and PDGFRα signaling were evaluated in lung cancer cell lines and mouse fibroblasts. Therapy studies were conducted using established PDGFRα-positive H1703 cells and PDGFRα-negative Calu-6, H1993, and A549 subcutaneous tumors in immunocompromised mice treated with vehicle, anti-PDGFRα mAbs, chemotherapy, or combination therapy. Tumors were analyzed for growth and levels of growth factors. IMC-3G3 inhibited PDGFRα activation and the growth of H1703 cells in vitro and tumor growth in vivo, but had no effect on PDGFRα-negative cell lines or mouse fibroblasts. 1E10 inhibited growth and PDGFRα activation of mouse fibroblasts, but had no effect on human cancer cell lines in vitro. In vivo, 1E10-targeted inhibition of murine PDGFRα reduced tumor growth as single-agent therapy in Calu-6 cells and enhanced the effect of chemotherapy in xenografts derived from A549 cells. We also identified that low expression cancer cell expression of VEGF-A and elevated expression of PDGF-AA were associated with response to stromal PDGFRα targeting. We conclude that stromal PDGFRα inhibition represents a means for enhancing control of lung cancer growth in some cases, independent of tumor cell PDGFRα expression.
在肺癌中，血小板衍生生长因子受体α（PDGFRα）经常由肿瘤相关的基质细胞和肿瘤细胞在肿瘤的亚群中表达。我们试图确定靶向基质 PDGFRα 在临床前肺肿瘤异种移植模型（人肿瘤，鼠基质）中的作用。评估了抗人（IMC-3G3）和抗鼠（1E10）PDGFRα 单克隆抗体（mAb）对肺癌细胞系和小鼠成纤维细胞增殖和 PDGFRα 信号的影响。使用已建立的 PDGFRα 阳性 H1703 细胞和 PDGFRα 阴性 Calu-6、H1993 和 A549 皮下肿瘤，在免疫缺陷小鼠中进行了治疗研究，这些小鼠接受了载体、抗 PDGFRα mAb、化疗或联合治疗。分析了肿瘤的生长和生长因子水平。IMC-3G3 抑制 PDGFRα 激活和 H1703 细胞在体外的生长以及体内肿瘤的生长，但对 PDGFRα 阴性细胞系或小鼠成纤维细胞没有影响。1E10 抑制生长和 PDGFRα 激活小鼠成纤维细胞，但在体外对人癌细胞系没有影响。在体内，1E10 靶向抑制小鼠 PDGFRα 作为单一疗法可减少 Calu-6 细胞的肿瘤生长，并增强源自 A549 细胞的异种移植物中的化疗效果。我们还发现，VEGF-A 的癌细胞表达水平低和 PDGF-AA 的表达水平高与对基质 PDGFRα 靶向的反应相关。我们的结论是，抑制基质 PDGFRα 代表了增强某些情况下控制肺癌生长的一种手段，而与肿瘤细胞 PDGFRα 表达无关。
