title: Versican silencing improves the antitumor efficacy of endostatin by alleviating its induced inflammatory and immunosuppressive changes in the tumor microenvironment.
abstract: The systematic application of antiangiogenic therapy remains an issue of concern, mainly due to the hypoxic and inflammatory changes in the tumor microenvironment elicited by antiangiogenic therapy. Versican, a 'bridge' connecting inflammation with tumor progression as well as playing a central role in the generation of an inflammatory tumor microenvironment is a promising candidate for the intervention of inflammatory changes in the tumor microenvironment elicited by antiangiogenic therapy. To examine this hypothesis, a short-hairpin RNA targeting versican (shVCAN) was designed and shVCAN stable-transfected B16F1 and Lewis lung carcinoma (LLC) cell lines were established. Simultaneously, the established B16F1 and LLC tumor models were used to investigate the effect of versican silencing on the tumor burden of mice. The results showed that, versican silencing exerted an inhibitory effect on the proliferative and migratory ability of B16F1 cells, but did not affect LLC cells. Endostatin exhibited modest inhibition of tumor growth in tumor-bearing mice. Versican silencing alone effectively suppressed orthotopic tumor growth and significantly prolonged survival time of mice more effectively when combined with endostatin. Endostatin elicited inflammatory and immunosuppressive changes in the tumor microenvironment, including an accumulation of myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs) and inflammatory cytokines. In addition, NF-κB and HIF-1α were overexpressed in the tumor. Versican silencing improved the antitumor efficacy of endostatin by alleviating its induced changes in the tumor microenvironment. Thus, versican silencing in the tumor microenvironment offers a promising approach to reverse the tumor refractoriness to antiangiogenic therapies.
authors: Department of Medical Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 61004, P.R. China.
authors: Zi
authors: Z
authors: Wang
authors: Department of Medical Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 61004, P.R. China.
authors: Zhixi
authors: Z
authors: Li
authors: Department of Medical Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 61004, P.R. China.
authors: Yuyi
authors: Y
authors: Wang
authors: Department of Medical Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 61004, P.R. China.
authors: Dan
authors: D
authors: Cao
authors: Department of Medical Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 61004, P.R. China.
authors: Xia
authors: X
authors: Wang
authors: Department of Medical Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 61004, P.R. China.
authors: Ming
authors: M
authors: Jiang
authors: Department of Medical Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 61004, P.R. China.
authors: Mei
authors: M
authors: Li
authors: Department of Medical Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 61004, P.R. China.
authors: Xi
authors: X
authors: Yan
authors: Department of Medical Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 61004, P.R. China.
authors: Yan
authors: Y
authors: Li
authors: Department of Medical Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 61004, P.R. China.
authors: Yanyang
authors: Y
authors: Liu
authors: Department of Medical Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan 61004, P.R. China.
authors: Feng
authors: F
authors: Luo
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D043169:Endostatins / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000096:biosynthesis; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D059016:Tumor Microenvironment / Q000187:drug effects; D053675:Versicans / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D020533:Angiogenesis Inhibitors; D043169:Endostatins; D016328:NF-kappa B; D034741:RNA, Small Interfering; C508322:VCAN protein, human; D053675:Versicans