[Effect of sorafenib on lymphangiogenesis in subcutaneously transplanted human cholangiocarcinoma in nude mice].

Objective: To study the effects of sorafenib on lymphangiogenesis in transplanted human cholangiocarcinoma in nude mice.

Methods: The model of transplanted human cholangiocarcinoma in nude mice was established by subcutaneous inoculation of cholangiocarcinoma cell line QBC 939 cells. Thirty-six nude mice were randomly divided into 3 groups after tumor formation: control group, sorafenib 30 mg × kg⁻¹ × d⁻¹ group and sorafenib 60 mg × kg⁻¹ × d⁻¹ group (n = 12 each), and then treated by gavage for 6 weeks. The tumor growth of the dose groups and control group was measured with calipers. Using immunohistochemical staining, the lymphatic microvessels at tumor edge were marked by LYVE-1 and counted. The expression of VEGFR-3 mRNA in paracancerous tissues was evaluated by RT-PCR.

Results: Sorafenib significantly depressed the growth of cholangiocarcinoma. The inhibitory rate in the sorafenib 30 mg × kg⁻¹ × d⁻¹ group and 60 mg × kg⁻¹ × d⁻¹ group was 55.1% and 67.9%, respectively. The LMVDs of the control group, sorafenib 30 mg × kg⁻¹ × d⁻¹ group and 60 mg × kg⁻¹ × d⁻¹ group were 11.75 ± 3.19, 6.84 ± 2.18 and 5.03 ± 1.91, respectively. The LMVD of the control group was significantly higher than that in the dose groups (P < 0.01). The relative expressions of VEGFR-3 mRNA in the control group, sorafenib 30 mg × kg⁻¹ × d⁻¹ group and 60 mg × kg⁻¹ × d⁻¹ group were 2.158 ± 0.312, 1.027 ± 0.144 and 0.736 ± 0.149, respectively. The relative expression of VEGFR-3 mRNA in the control group was significantly higher than that in the dose groups (P < 0.05). No occurrence of lymph node metastasis was found in all groups.

Conclusion: Sorafenib can significantly inhibit the growth of xenograft cholangiocarcinoma in nude mice. Sorafenib may reduce LMVD by down-regulation of the expression of VEGF-C/D and VEGFR-3 signaling axis.