| Objective: High-intensity focused ultrasound (HIFU) is a widely appliedto treatment for unresectable hepatocellular carcinoma. However,insufficient HIFU can result in rapid progression of the residual tumor. Themechanism of such rapid growth of the residual tumor after HIFU ablationis poorly understood. The aim of this study was to investigate the dynamicangiogenesis of residual tumor, and the temporal effect and mechanism ofthe HIF-1,2α in the residual tumor angiogenesis.Methods: Xenograft tumors of HepG2cells were created bysubcutaneously inoculating nude mice (athymic BALB/c nu/nu mice) withhepatoma cells. About thirty days after inoculation, all mice (except controlgroup) were treated by HIFU and assigned randomly to7groups accordingto various time intervals (1st,3rd,5th day (d) and1st,2nd,3rd,4th week(w)). The residual tumor tissues were obtained from the experimentalgroups at various time points. Protein levels of HIF-1α, HIF-2α, VEGF-A, and EphA2were quantified by immunohistochemistry analysis andWestern Blot assays, and mRNA levels measured by Q-PCR.Microvascular density was calculated with counting of CD31positivevascular endothelial cells by immunohistochemical staining.Results: Compared with the control group, protein and mRNA levels ofHIF-1α reached their highest levels on the3rd day (P<0.01), thendecreased (P<0.05). HIF-2α expression reached its highest level on the2ndweek compared with control group (P<0.01), then decreased (2w-4w)(P<0.05). The protein and mRNA levels of VEGF-A and EphA2in theresidual tumor tissues group that received HIFU were significantlydecreased until1week compared with the control group (P<0.01).However, the levels increased compared to controls in2-4weeks(P<0.05). Similar results were obtained for MVD expression (P<0.05).Conclusion: Insufficient HIFU ablation promotes the angiogenesis inresidual carcinoma tissue over time. The data indicate that the HIF-1,2α/VEGFA/EphA2pathway is probably involved. |
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