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Apelin receptor antagonist boosts dendritic cell vaccine efficacy in controlling angiogenic, metastatic and apoptotic-related factors in 4T1 breast tumor-bearing mice

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Abstract

Apelin/APJ axis plays a critical role in cancer progression, thus its targeting inhibits tumor growth. However, blocking of Apelin/APJ axis in combination with immunotherapeutic approaches may be more effective. This study aimed to investigate the effects of APJ antagonist ML221 in combination with a DC vaccine on angiogenic, metastatic and apoptotic-related factors in a breast cancer (BC) model. Four groups of female BALB/c mice with 4T1-induced BC were treated with PBS, APJ antagonist ML221, DC vaccine, and “ML221 + DC vaccine”. After completion of the treatment, the mice were sacrificed and the serum levels of IL-9 and IL-35 as well as the mRNA expression of angiogenesis (including VEGF, FGF-2, and TGF-β), metastasis (including MMP-2, MMP-9, CXCR4) and apoptosis-related markers (Bcl-2, Bax, Caspase-3) in tumor tissues were determined using ELISA and real-time PCR, respectively. Angiogenesis was also evaluated by co-immunostaining of tumor tissues with CD31 and DAPI. Primary tumor metastasis to the liver was analyzed using hematoxylin–eosin staining. The efficiency of combination therapy with “ML221 + DC vaccine” was remarkably higher than single therapies in preventing liver metastasis compared to the control group. In comparison with the control group, combination therapy could significantly reduce the expression of MMP-2, MMP-9, CXCR4, VEGF, FGF-2, and TGF-β in tumor tissues (P < 0.05). It also decreased the serum level of IL-9 and IL-35 compared with the control group (P < 0.0001). Moreover, vascular density and vessel diameter were significantly reduced in the combination therapy group compared with the control group (P < 0.0001). Overall, our findings demonstrate that combination therapy using a blocker of the apelin/APJ axis and DC vaccine can be considered a promising therapeutic program in cancers.

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Funding

This study was financially supported by a Grant (No. 97408) from Rafsanjan University of Medical Sciences, Rafsanjan, Iran.

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Author notes

  1. Pedram Basirjafar, Tayyebeh Tavakoli and Raziyeh Zandvakili have contributed equally to this study.

Authors and Affiliations

  1. Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran

    Javad Masoumi, Pedram Basirjafar, Tayyebeh Tavakoli, Raziyeh Zandvakili, Mohammad-Taghi Rezayati, Hossein Khorramdelazad & Abdollah Jafarzadeh

  2. Molecular Medicine Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran

    Javad Masoumi, Pedram Basirjafar, Tayyebeh Tavakoli, Raziyeh Zandvakili, Mohammad-Taghi Rezayati, Hossein Khorramdelazad & Abdollah Jafarzadeh

  3. Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Javad Masoumi

  4. Immunology of Infectious Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran

    Nahid Zainodini & Mahnaz Ramezani

  5. Department of Immunology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran

    Maryam Nemati & Abdollah Jafarzadeh

  6. Occupational Safety and Health Research Center, NICICO, World Safety Organization and Rafsanjan University of Medical Sciences, Rafsanjan, Iran

    Fatemeh Ayoobi

  7. Department of Pathology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran

    Morteza Khademalhosseini

  8. Department of Medical Biology, Faculty of Medicine, University of EGE, Izmir, Turkey

    Rostamlou Arman

Authors
  1. Javad Masoumi
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  2. Nahid Zainodini
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  13. Abdollah Jafarzadeh
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Correspondence to Abdollah Jafarzadeh.

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Masoumi, J., Zainodini, N., Basirjafar, P. et al. Apelin receptor antagonist boosts dendritic cell vaccine efficacy in controlling angiogenic, metastatic and apoptotic-related factors in 4T1 breast tumor-bearing mice. Med Oncol 40, 179 (2023). https://doi.org/10.1007/s12032-023-02030-9

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  • DOI: https://doi.org/10.1007/s12032-023-02030-9

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