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

Article (PDF Available)inBMC Cancer 10(1):580 · October 2010with20 Reads
DOI: 10.1186/1471-2407-10-580 · Source: PubMed
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. 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. 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. 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.
    • "Some of these effects could include vessel normalization. We have reported that an herbal formula, Songyou Yin, can attenuate HCC metastases [17] , and S. miltiorrhiza is one of the five constituents of the formula [18]. Tan IIA exhibits direct vasoactive [19,20] and certain antitumor properties [21]. "
    [Show abstract] [Hide abstract] ABSTRACT: Promotion of endothelial normalization restores tumor oxygenation and obstructs tumor cells invasion, intravasation, and metastasis. We therefore investigated whether a vasoactive drug, tanshinone IIA, could inhibit metastasis by inducing vascular normalization after palliative resection (PR) of hepatocellular carcinoma (HCC). A liver orthotopic double-tumor xenograft model in nude mouse was established by implantation of HCCLM3 (high metastatic potential) and HepG2 tumor cells. After removal of one tumor by PR, the effects of tanshinone IIA administration on metastasis, tumor vascularization, and survival were evaluated. Tube formation was examined in mouse tumor-derived endothelial cells (TECs) treated with tanshinone IIA. PR significantly accelerated residual hepatoma metastases. Tanshinone IIA did not inhibit growth of single-xenotransplanted tumors, but it did reduce the occurrence of metastases. Moreover, it inhibited PR-enhanced metastases and, more importantly, prolonged host survival. Tanshinone IIA alleviated residual tumor hypoxia and suppressed epithelial-mesenchymal transition (EMT) in vivo; however, it did not downregulate hypoxia-inducible factor 1α (HIF-1α) or reverse EMT of tumor cells under hypoxic conditions in vitro. Tanshinone IIA directly strengthened tube formation of TECs, associated with vascular endothelial cell growth factor receptor 1/platelet derived growth factor receptor (VEGFR1/PDGFR) upregulation. Although the microvessel density (MVD) of residual tumor tissue increased after PR, the microvessel integrity (MVI) was still low. While tanshinone IIA did not inhibit MVD, it did dramatically increase MVI, leading to vascular normalization. Our results demonstrate that tanshinone IIA can inhibit the enhanced HCC metastasis associated with PR. Inhibition results from promoting VEGFR1/PDGFR-related vascular normalization. This application demonstrates the potential clinical benefit of preventing postsurgical recurrence.
    Full-text · Article · Nov 2012
  • [Show abstract] [Hide abstract] ABSTRACT: OBJECTIVE: To investigate the effects of IFN-α on the expression of MMP-2/TIMP-2 and the ratio of MMP-2/TIMP-2 in human hepatocellular carcinoma (HCC) cell line HepG2 cells, and explore its molecular mechanism of inhibiting the growth and metastasis of HCC. METHODS: MMP-2/TIMP-2 concentration were measured in the supernate of HepG2 cells incubated in DMEM or exposure to differing dosages of IFN-α by ELISA. The expression of MMP-2 and TIMP-2 mRNA were semiquantitatively detected by reverse transcription polymerase chain reaction (RT-PCR). RESULTS: MMP-2 concentration were (1 725.3±300.7) and (2 899.8±343.2) ρg/mL in the supernate of HepG2 cells incubated for 24 and 48 h, exposure to IFN-α 3 000 IU/mL. There were significant differences compared with the controls (P=0.001 and P=0.000), and no significant differences were found between TIMP-2 concentration of intervention groups and the control groups. But significant differences were found between MMP-2/TIMP-2 ratio after incubation for 24 or 48 h (P=0.003 and P=0.001). Furthermore, there was significant difference of MMP-2 mRNA levels between 48 h group (3 000 IU/mL) and the controls (F=2.711, P=0.005). CONCLUSIONS: IFN-α treatment significantly lower MMP-2/TIMP-2 ratio by inhibiting the expression of MMP-2 in HepG2 cells in a dose-dependent manner. The down-regulation of MMP-2 levels contributes, at least in part, to its activity of inhibiting the growth and metastasis of HCC.
    Article · Feb 2012
  • [Show abstract] [Hide abstract] ABSTRACT: Malignant peripheral nerve sheath tumors (MPNSTs) are usually located in the trunk, extremities, head, or neck, and most occur with neurofibromatosis type 1 (NF1; von Recklinghausen's disease). No biomarkers have previously been found to be associated with their progression. Retroperitoneal NF1-independent MPNSTs are rare; they are considered to be less aggressive and to have better prognoses compared to NF1-related tumors. Currently, en bloc excision is the only consensus treatment approach. In a 27-year-old male with a giant retroperitoneal MPNST and no stigmata or family history of neurofibromatosis type-1 (NF1), a remarkable elevation of serum CA125 was detected. The high-grade tumor displayed a striking progression: the primary lesion, 25 cm in diameter, recurred in its previous site as a 17-cm MPNST less than 50 days after total excision. Subsequent treatment with microwave ablation and huachansu, a traditional Chinese medication, proved ineffective, and the patient died within 3 months. Our case suggests that retroperitoneal MPNSTs can deteriorate rapidly even if NF1 independent, that aggressive treatment may not benefit large high-grade MPNSTs, and that novel and effective treatment is urgently needed. Our case also suggests the possibility of using serum tumor markers in the early detection and monitoring of MPNSTs.
    Article · Apr 2012
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