Transient increased expression of VEGF and MMP-1 in a rat liver tumor model after hepatic arterial occlusion.
OBJECTIVE
This study investigates the influence of hepatic arterial occlusion (HAO) on blood perfusion of transplanted cancer in rat's liver, and the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-1 (MMP-1) and explores the mechanisms involved in transcatheter arterial embolization (TAE)-induced metastasis of liver cancer preliminarily.


METHODS
Walker 256 carcinosarcoma was transplanted into rat's liver to create the liver cancer model. Hepatic arterial ligation (HAL) was used to block the hepatic arterial blood supply and simulate TAE. Rats bearing tumor were divided into three groups: control, laparotomy control, and HAL groups. Blood perfusion of tumor was analyzed by a Hoechst 33342 labeling assay. The level of serum VEGF was assayed by ELISA; and the expression of VEGF and MMP-1 mRNA was detected by in situ hybridization.


RESULTS
Two days after HAL, the number of Hoechst 33342 labeled cells which represent the blood perfusion of the tumor directly and hypoxia of tumor indirectly in the HAL group decreased significantly compared with that in the control group (329.1+/-29.3 vs. 383.6+/-19.2, P<0.01). The level of serum VEGF in the HAL group increased significantly compared with that of the control group (92.5+/-43.9 pg/mL vs. 54.9+/-19.3 pg/mL, P<0.05). The expression of VEGF and MMP-1 mRNA in the tumor tissue of the HAL group increased significantly compared with that of the control and the laparotomy control groups (P<0.05). The blood perfusion data of the tumor, represented by number of Hoechst 33342 labeled cells, showed an inverse correlation with the expression of VEGF mRNA in tumor tissue (P<0.05). While 6 days after HAL, the blood perfusion of tumor in HAL group decreased and the expression of VEGF and MMP-1 increased only slightly, not significantly, compared with that in the control group.


CONCLUSIONS
In conclusion, blockage of hepatic arterial blood supply results in transient decreased blood perfusion and increased expression of metastasis-associated genes VEGF and MMP-1 of transplanted liver cancer in rats. Decreased blood perfusion and hypoxia may be the major reason for up-regulated expression of VEGF. Better understanding of the mechanisms involved with TAE-induced metastasis may lead to the enhancement of the long-term effects of TAE for liver cancer.
Guo
Wei-Jian
WJ
Department of Oncology, Xinhua Hospital of Shanghai Second Medical University, Shanghai, China 200092. guoweijian1@sohu.com
Li
Jie
J
Chen
Zhen
Z
Zhuang
Jun-Yan
JY
Gu
Wen-Hua
WH
Zhang
Li
L
Pang
Jiong
J
Lu
Chang-Hong
CH
Zhang
Wen Zhu
WZ
Cheng
Yu Fan
YF
D000818:Animals; D002279:Carcinoma 256, Walker / Q000098:blood supply / Q000378:metabolism* / Q000556:secondary / Q000628:therapy*; D004621:Embolization, Therapeutic / Q000009:adverse effects*; D006499:Hepatic Artery / Q000601:surgery; D017403:In Situ Hybridization; D008026:Ligation; D008114:Liver Neoplasms, Experimental / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D011919:Rats, Inbred Strains; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D042461:Vascular Endothelial Growth Factor A; D020781:Matrix Metalloproteinase 1