Relaxin combined with transarterial chemoembolization achieved synergistic effect and inhibited metastases of liver cancer in rabbit VX2 model

Abstract

Abstract Objective To explore the effect and mechanism of relaxin (RLX) in the growth and metastasis of liver cancer after combination treatment with transarterial chemoembolization (TACE). Materials and methods HCCLM3 cells and Huh-7 cells were adopted to evaluate the effect of tumor proliferation, migration, and invasion after RLX administration in vitro. The rabbit VX2 model was used to evaluate the biosafety, doxorubicin penetration, local tumor response, synergistic effect and survival benefit of RLX combined with TACE treatment. The effect of RLX combined with TACE on tumor metastasis was also evaluated. Results RLX had not alternated the proliferation, migration, and invasion of HCCLM3 cells and Huh-7 cells, and the expression of E-cadherin and HIF-1α also remained unchanged but only upregulated the MMP-9 protein in vitro. In the rabbit VX2 model, compared to the received normal saline group (NS) and received TACE mono-therapy group (TACE), the group that received TACE combined with RLX (TACE+RLX) showed improved local tumor response and survival benefit. Furthermore, TACE combined with RLX was found to reduce tumor metastasis. This combination therapy reduced the fibrotic extracellular matrix in the tumor microenvironment, allowing for better penetration of doxorubicin and improved infiltration of CD8+ T cells. Additionally, RLX combined with TACE was able to decrease the expression of HIF-1α. The biosafety of TACE combined with RLX was also confirmed. Conclusion RLX synergized with TACE by mitigating fibrotic extracellular matrix and tumor hypoxic microenvironment, improving therapeutic effect and inhibiting metastases for the treatment of liver cancer.