Antiangiogenic therapy enhances the efficacy of transcatheter arterial embolization for hepatocellular carcinomas.
Transcatheter arterial embolization (TAE) is a well-established technique for unresectable hepatic malignancies. However, TAE can temporally halt the growth of hepatic tumors by blocking their arterial supply, but often tumors rapidly develop collateral blood vessels via angiogenesis. We have previously demonstrated that intraportal delivery of adeno-associated viral particles expressing angiostatin leads to long-term expression of angiostatin capable of inhibiting angiogenesis and suppressing the outgrowth of tumors in the liver. Thus, we hypothesize that adeno-associated virus (AAV)-mediated antiangiogenic therapy could enhance the efficacy of TAE to combat liver cancers. To achieve this objective, we engineered a recombinant AAV vector encoding rat angiostatin. Intraportal delivery of this vector led to long term and stable transgenic expression of angiostatin locally in rat hepatocytes and suppressed the growth of CBRH7919 hepatocellular carcinomas established in rat livers by inhibiting formation of neovessels. Although TAE therapy led to necrosis of liver tumors and suppressed their growth, the neovessels of tumors were rapidly reformed 3 weeks after TAE. However, intraportal injection of AAV-angiostatin inhibited the angiogenesis stimulated by TAE, synergized with TAE in suppressing growth of tumors established in livers and prolonged the survival of rats. In conclusion, these encouraging results warrant future investigation of the use of antiangiogenic therapy for enhancing the therapeutic efficacy of TAE to treat unresectable liver cancers.
Jiang
Hongchi
H
The Hepatosplenic Surgery Center, Department of General Surgery, The First Clinical Medical School of Harbin Medical University, Harbin, China.
Meng
Qinghui
Q
Tan
Hongtao
H
Pan
Shangha
S
Sun
Bei
B
Xu
Ruian
R
Sun
Xueying
X
D043168:Angiostatins / Q000097:blood / Q000235:genetics / Q000502:physiology; D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D016461:Chemoembolization, Therapeutic / Q000379:methods*; D003131:Combined Modality Therapy; D000229:Dependovirus / Q000235:genetics; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D008099:Liver / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic / Q000628:therapy*; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome
D043168:Angiostatins