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

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.

• Authors: Javad Masoumi, Nahid Zainodini, Pedram Basirjafar, Tayyebeh Tavakoli, Raziyeh Zandvakili, Maryam Nemati, Mahnaz Ramezani, Mohammad-Taghi Rezayati, Fatemeh Ayoobi, Morteza Khademalhosseini, Hossein Khorramdelazad, Rostamlou Arman, Abdollah Jafarzadeh
• Journal: Medical oncology (Northwood, London, England) (Med Oncol) Vol. 40 Issue 6 Pg. 179 (May 15 2023) ISSN: 1559-131X [Electronic] United States
• PMID: 37188900 (Publication Type: Journal Article)
• Copyright: © 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Chemical References

• 4-oxo-6-((pyrimidin-2-ylthio)methyl)-4H-pyran-3-yl 4-nitrobenzoate
• Apelin
• Apelin Receptors
• Fibroblast Growth Factor 2
• Interleukin-9
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 9
• Transforming Growth Factor beta
• Vascular Endothelial Growth Factor A

Topics

• Animals
• Female
• Mice
• Apelin (genetics, metabolism)
• Apelin Receptors (genetics, metabolism)
• Breast Neoplasms (therapy)
• Dendritic Cells (metabolism)
• Fibroblast Growth Factor 2
• Interleukin-9
• Liver Neoplasms
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 9
• Transforming Growth Factor beta
• Vaccine Efficacy
• Vascular Endothelial Growth Factor A (genetics, metabolism)