OBJECTIVETo study the effects of sorafenib on lymphangiogenesis in transplanted human cholangiocarcinoma in nude mice.

METHODSThe 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.

RESULTSSorafenib 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.

CONCLUSIONSorafenib 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.