Herbal compound "Songyou Yin" reinforced the ability of interferon-alfa to inhibit the enhanced metastatic potential induced by palliative resection of hepatocellular carcinoma in nude mice.
BACKGROUND
Liver resection is a widely accepted treatment for hepatocellular carcinoma (HCC). Our previous clinical study showed that the rate of palliative resection was 34.0% (1958-2008, 2754 of 8107). However, the influence of palliative resection on tumor metastasis remains controversial. The present study was conducted to evaluate the effect of palliative resection on residual HCC and to explore interventional approaches.


METHODS
Palliative resection was done in an orthotopic nude mice model of HCC (MHCC97H) with high metastatic potential. Tumor growth, invasion, metastasis, lifespan, and some molecular alterations were examined in vivo and in vitro. Mice that underwent palliative resection were treated with the Chinese herbal compound "Songyou Yin," interferon-alfa-1b (IFN-α), or their combination to assess their effects.


RESULTS
In the palliative resection group, the number of lung metastatic nodules increased markedly as compared to the sham operation group (14.3 ± 4.7 versus 8.7 ± 3.6, P < 0.05); tumor matrix metalloproteinase 2 (MMP2) activity was elevated by 1.4-fold, with up-regulation of vascular endothelial growth factor (VEGF) and down-regulation of tissue inhibitor of metalloproteinase 2 (TIMP2). The sera of mice undergoing palliative resection significantly enhanced cell invasiveness by 1.3-fold. After treatment, tumor volume was 1205.2 ± 581.3 mm3, 724.9 ± 337.6 mm3, 507.6 ± 367.0 mm3, and 245.3 ± 181.2 mm3 in the control, "Songyou Yin," IFN-α, and combination groups, respectively. The combined therapy noticeably decreased the MMP2/TIMP2 ratio and prolonged the lifespan by 42.2%. Moreover, a significant (P < 0.001) reduction of microvessel density was found: 43.6 ± 8.5, 34.5 ± 5.9, 23.5 ± 5.6, and 18.2 ± 8.0 in the control and treatment groups, respectively.


CONCLUSIONS
Palliative resection-stimulated HCC metastasis may occur, in part, by up-regulation of VEGF and MMP2/TIMP2. "Songyou Yin" reinforced the ability of IFN-α to inhibit the metastasis-enhancing potential induced by palliative resection, which indicated its potential postoperative use in patients with HCC.
Huang
Xiu-Yan
XY
Department of General Surgery, 6th People's Hospital of Shanghai, Shanghai Jiaotong University, Shanghai 200233, PR China.
Huang
Zi-Li
ZL
Wang
Lu
L
Xu
Yong-Hua
YH
Huang
Xin-Yu
XY
Ai
Kai-Xing
KX
Zheng
Qi
Q
Tang
Zhao-You
ZY
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000601:surgery*; D015536:Down-Regulation; D004365:Drugs, Chinese Herbal / Q000494:pharmacology / Q000627:therapeutic use*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism / Q000627:therapeutic use*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000601:surgery*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000601:surgery; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D004365:Drugs, Chinese Herbal; D016898:Interferon-alpha; D042461:Vascular Endothelial Growth Factor A; C551424:songyou yin; D019716:Tissue Inhibitor of Metalloproteinase-2