Abstract
BackgroundLiver 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.MethodsPalliative 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.ResultsIn 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.ConclusionPalliative 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.
Highlights
Liver resection is a widely accepted treatment for hepatocellular carcinoma (HCC)
Increasing numbers of reports indicate that partial hepatectomy accelerates tumor growth and stimulates tumor metastasis [3,4,5,6,7], one report claimed that major hepatic resection may suppress the growth of tumors remaining in the residual liver [8]
We found that cells (MHCC97H) treated with serum from the palliative resection group (Figure 1C, left) presented the most invasive potential through Matrigel as compared to cells in controls (Figure 1C, right), with invasive ability increased by 25.7% (46.9/37.3, 1.3fold, P < 0.05, Figure 1D), which was intervalidated by several HCC cell lines (HCCLM3, HCC7721, HCC7402, and Hep3B)
Summary
Liver resection is a widely accepted treatment for hepatocellular carcinoma (HCC). 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. Liver resection is a widely accepted treatment modality for HCC; at the authors’ institution, 53 patients with HCC with a 20year survival all underwent curative resection [2]. The influence of liver resection on tumor growth and metastasis remains controversial. Increasing numbers of reports indicate that partial hepatectomy accelerates tumor growth and stimulates tumor metastasis [3,4,5,6,7], one report claimed that major hepatic resection may suppress the growth of tumors remaining in the residual liver [8]. A report demonstrated that surgical therapy is associated with improved survival in patients with HCC [10]
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