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Fusion with human lung cancer cells elongates the life span of human umbilical endothelial cells and enhances the anti-tumor immunity

  • Original Article – Cancer Research
  • Published:
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Abstract

Purpose

Human umbilical endothelial cells (HUVECs) have been proved as an effective whole-cell vaccine inhibiting tumor angiogenesis. However, HUVECs divide a very limited number of passages before entering replicative senescence, which limits its application for clinical situation. Here, we fused HUVECs with human pulmonary adenocarcinoma cell line A549s and investigated the anti-tumor immunity of the hybrids against mice Lewis lung cancer.

Methods

HUVECs were fused with A549s using polyethylene glycol and were sorted by flow cytometry. The fusion cells (HUVEC–A549s) were confirmed by testing the expression of telomerase and VE-cadherin, the senescence-associated β-galactosidase activity, and tube formation ability. HUVEC–A549s were then irradiated and injected into the C57BL/6 mice of protective, therapeutic, and metastatic models. The mechanism of the anti-tumor immunity was explored by analyzing mice sera, spleen T lymphocytes, tumor microenvironment, and histological changes.

Results

HUVEC–A549s coexpressed tumor and endothelial markers and maintained the vascular function of tube forming at passage 30 without showing signs of senescence. HUVEC–A549s could induce protective and therapeutic anti-tumor activity for LL2 model and presented stronger activity against metastasis than HUVECs. Both humoral and cellular immunity were participated in the anti-angiogenic activity, as HUVECs-neutralizing IgG and HUVECs-toxic lymphocytes were increased. Angiogenic mediators (VEGF and TGF-β) and tumor microenvironment cells MDSCs and Tregs were also diminished.

Conclusions

Our findings might provide a novel strategy for HUVECs-related immunotherapy, and this vaccine requires lower culture condition than primary HUVECs while enhancing the anti-tumor immunity.

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Acknowledgments

This work was supported by National Natural Science Foundation of China (Nos. 81372246 and 81123003), National High Technology Research and Development Program of China (Nos. 2014AA020708 and 2015AA020309), China Postdoctoral Science Foundation (Grants 20120181110029), National Science and Technology Major Projects for “Major New Drugs Innovation and Development” (No. 2009zx09503-020) and the National Basic Research Program of China (No. 2010CB529900).

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Authors and Affiliations

  1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital and Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, 610041, Sichuan, People’s Republic of China

    Xiyan Mu, Chunju Fang, Jing Zhou, Yufeng Xi, Li Zhang, Yuquan Wei & Yang Wu

  2. Department of Gynecology and Obstetrics, West China Second Hospital, Sichuan University, Chengdu, 610041, Sichuan, People’s Republic of China

    Xiyan Mu, Tao Yi & Xia Zhao

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  1. Xiyan Mu
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  2. Chunju Fang
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  4. Yufeng Xi
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  5. Li Zhang
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  7. Tao Yi
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  8. Yang Wu
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  9. Xia Zhao
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Correspondence to Yang Wu or Xia Zhao.

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Mu, X., Fang, C., Zhou, J. et al. Fusion with human lung cancer cells elongates the life span of human umbilical endothelial cells and enhances the anti-tumor immunity. J Cancer Res Clin Oncol 142, 111–123 (2016). https://doi.org/10.1007/s00432-015-2002-6

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  • DOI: https://doi.org/10.1007/s00432-015-2002-6

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