Department of Targeted Therapeutics, MIRA Institute of Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands.
Mol Cancer Ther. 2012 Nov;11(11):2419-28. doi: 10.1158/1535-7163.MCT-11-0758. Epub 2012 Aug 29.
New approaches to block the function of tumor stromal cells such as cancer-associated fibroblasts and pericytes is an emerging field in cancer therapeutics as these cells play a crucial role in promoting angiogenesis and tumor growth via paracrine signals. Because of immunomodulatory and other antitumor activities, IFNγ, a pleiotropic cytokine, has been used as an anticancer agent in clinical trials. Unfortunately only modest beneficial effects, but severe side effects, were seen. In this study, we delivered IFNγ to stromal fibroblasts and pericytes, considering its direct antifibrotic activity, using our platelet-derived growth factor-beta receptor (PDGFβR)-binding carrier (pPB-HSA), as these cells abundantly express PDGFβR. We chemically conjugated IFNγ to pPB-HSA using a heterobifunctional PEG linker. In vitro in NIH3T3 fibroblasts, pPB-HSA-IFNγ conjugate activated IFNγ-signaling (pSTAT1α) and inhibited their activation and migration. Furthermore, pPB-HSA-IFNγ inhibited fibroblasts-induced tube formation of H5V endothelial cells. In vivo in B16 tumor-bearing mice, pPB-HSA-IFNγ rapidly accumulated in tumor stroma and pericytes and significantly inhibited the tumor growth while untargeted IFNγ and pPB-HSA carrier were ineffective. These antitumor effects of pPB-HSA-IFNγ were attributed to the inhibition of tumor vascularization, as shown with α-SMA and CD-31 staining. Moreover, pPB-HSA-IFNγ induced MHC-II expression specifically in tumors compared with untargeted IFNγ, indicating the specificity of this approach. This study thus shows the impact of drug targeting to tumor stromal cells in cancer therapy as well as provides new opportunities to use cytokines for therapeutic application.
针对肿瘤基质细胞（如癌相关成纤维细胞和周细胞）功能的新方法是癌症治疗学中的一个新兴领域，因为这些细胞通过旁分泌信号在促进血管生成和肿瘤生长中起着至关重要的作用。由于免疫调节和其他抗肿瘤活性，IFNγ 作为一种多效细胞因子，已在临床试验中被用作抗癌药物。不幸的是，只看到了适度的有益效果，但却出现了严重的副作用。在这项研究中，我们使用血小板衍生生长因子-β受体（PDGFβR）结合载体（pPB-HSA）将 IFNγ 递送给基质成纤维细胞和周细胞，考虑到其直接的抗纤维化活性，因为这些细胞大量表达 PDGFβR。我们使用杂双功能 PEG 接头将 IFNγ 化学偶联到 pPB-HSA 上。在体外 NIH3T3 成纤维细胞中，pPB-HSA-IFNγ 缀合物激活 IFNγ 信号（pSTAT1α）并抑制其激活和迁移。此外，pPB-HSA-IFNγ 抑制了成纤维细胞诱导的 H5V 内皮细胞管形成。在 B16 荷瘤小鼠体内，pPB-HSA-IFNγ 迅速在肿瘤基质和周细胞中积累，并显著抑制肿瘤生长，而未靶向的 IFNγ 和 pPB-HSA 载体则无效。pPB-HSA-IFNγ 的这些抗肿瘤作用归因于肿瘤血管生成的抑制，如α-SMA 和 CD-31 染色所示。此外，与未靶向的 IFNγ 相比，pPB-HSA-IFNγ 特异性诱导肿瘤中 MHC-II 的表达，表明这种方法具有特异性。因此，这项研究表明了药物靶向肿瘤基质细胞在癌症治疗中的影响，并为细胞因子的治疗应用提供了新的机会。
