Apelin 受体拮抗剂增强树突状细胞疫苗在控制 4T1 乳腺癌荷瘤小鼠血管生成、转移和凋亡相关因子方面的疗效

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.