Long-term interferon-α treatment suppresses tumor growth but promotes metastasis capacity in hepatocellular carcinoma

Zhuang, Peng–Yuan; Zhang, Jubo; Zhang, Wei; Zhu, Xiao‐Dong; Li, Ying; Xu, Huaxiang; Xiong, Ye; Kong, Ling‐Bin; Wang, Lu; Wu, Wei‐Zhong; Tang, Zhao–You; Qin, Lun–Xiu; Sun, Hui‐Chuan

doi:10.1007/s00432-010-0848-1

Cited by 13 publications

(15 citation statements)

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“…It has been reported that MHCC97L and HepG2 cells surviving oxaliplatin treatment show enhanced migration and invasion in vitro and increase metastasis to the lung when reinoculated into nude mice [19]. Similar results have been observed in our previous study that IFN-α had contrasting aspects of consistently suppressing HCC growth but also promoting tumor metastasis capacity [20]. Therefore, it is urgent to investigate new agents with robust inhibitory effects on both HCC growth and metastasis.…”

Section: Discussionsupporting

confidence: 77%

Isomalto oligosaccharide sulfate inhibits tumor growth and metastasis of hepatocellular carcinoma in nude mice

et al. 2011

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BackgroundHepatocellular carcinoma (HCC) usually has a dismal prognosis because of its limited response to current pharmacotherapy and high metastatic rate. Sulfated oligosaccharide has been confirmed as having potent antitumor activities against solid tumors. Here, we explored the preclinical effects and molecular mechanisms of isomalto oligosaccharide sulfate (IMOS), another novel sulfated oligosaccharide, in HCC cell lines and a xenograft model.MethodsThe effects of IMOS on HCC proliferation, apoptosis, adhesion, migration, and invasiveness in vitro were assessed by cell counting, flow cytometry, adhesion, wound healing, and transwell assays, respectively. The roles of IMOS on HCC growth and metastasis in xenograft models were evaluated by tumor volumes and fluorescent signals. Total and phosphorylated protein levels of AKT, ERK, and JNK as well as total levels of c-MET were detected by Western blotting. IMOS-regulated genes were screened by quantitative reverse-transcription PCR (qRT-PCR) array in HCCLM3-red fluorescent protein (RFP) xenograft tissues and then confirmed by qRT-PCR in HepG2 and Hep3B cells.ResultsIMOS markedly inhibited cell proliferation and induced cell apoptosis of HCCLM3, HepG2, and Bel-7402 cells and also significantly suppressed cell adhesion, migration, and invasion of HCCLM3 in vitro. At doses of 60 and 90 mg/kg/d, IMOS displayed robust inhibitory effects on HCC growth and metastasis without obvious side effects in vivo. The levels of pERK, tERK, and pJNK as well as c-MET were significantly down-regulated after treatment with 16 mg/mL IMOS. No obvious changes were found in the levels of pAkt, tAkt, and tJNK. Ten differentially expressed genes were screened from HCCLM3-RFP xenograft tissues after treatment with IMOS at a dose of 90 mg/kg/d. Similar gene expression profiles were confirmed in HepG2 and Hep3B cells after treatment with 16 mg/mL IMOS.ConclusionsIMOS is a potential anti-HCC candidate through inhibition of ERK and JNK signaling independent of p53 and worth studying further in patients with HCC, especially at advanced stages.

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Section: Discussionsupporting

confidence: 77%

Isomalto oligosaccharide sulfate inhibits tumor growth and metastasis of hepatocellular carcinoma in nude mice

et al. 2011

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“…CTCs were enumerated by flow cytometry and expressed as percent CTCs/TV (%) [6]. Twelve mice (IE 1, n = 6) were sacrificed 2 d after resection to examine CTCs shortly after PR.…”

Section: Methodsmentioning

confidence: 99%

“…The surgery is actually palliative resection (PR), owing to the existence of satellites and microvascular invasion, and these residual tumor nests can actually be stimulated to grow by the PR [2,3]. Although several treatments, such as interferon-alpha and sorafenib, have been proposed to diminish relapse [4,5], prometastatic side effects of these options have also been observed [6,7]. …”

Section: Introductionmentioning

confidence: 99%

Tanshinone IIA inhibits metastasis after palliative resection of hepatocellular carcinoma and prolongs survival in part via vascular normalization

et al. 2012

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BackgroundPromotion 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).MethodsA 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.ResultsPR 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.ConclusionsOur 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.

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“…Third, whether IFN is accompanied by other effects should be investigated. Zhuang et al [50] reported that IFN-α treatment significantly suppresses tumor growth of HCC but relatively increases the number of circulating tumor cells. This result might be attributed to the enhanced tumor hypoxia as well as the up-regulation of metastasis-related genes, such as HIF-1α, c-met, u-PA, PDGF-A, and IL-8.…”

Section: Discussionmentioning

confidence: 99%

Effect and Safety of Interferon for Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis

et al. 2013

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BackgroundThe effect of interferon(IFN) in the management of hepatocellular carcinoma (HCC) remains controversial, and no clear recommendations have been proposed.ObjectivesTo evaluate the effect and safety of IFN for HCC.MethodsPubMed, OvidSP, and Cochrane Library were searched from their establishment date until August 30, 2012. Studies that met the inclusion criteria were systematically evaluated and then subjected to meta-analysis.ResultsThirteen randomized control trials (RCTs) involving 1344 patients were eligible for this study. When IFN was used as an adjuvant therapy for HCC patients after curative therapy, the meta-analysis showed that IFN reduced the 1-, 2-, 3-, 4-, and 5-year recurrence rates. Subgroup analysis showed that IFN reduced the 2-, 3-, 4-, and 5-year recurrence rates of hepatitis C viral (HCV)-related HCC. The effect of IFN for on hepatitis B virus(HBV)-related HCC patients could not be determined because of isufficient data. After surgical resection, adjuvant IFN therapy reduced the 4- and 5- recurrence rates. All studies reported that IFN could not improve the overall survival of HCV-realated HCC patients after curative therapies. Only one study showed that IFN was associated with better overall survival in HCC patients after curative therapy and subgroup of HCC patients after surgical resection. Thus, meta-analysis was not performed. Different treatment options were used as control to study the effect of IFN for intermediate and advanced HCC patients, thus meta-analysis was not appropriate. All included studies, except for one, reported that IFN treatment was well tolerated.ConclusionsAfter curative therapies, adjuvant IFN reduced the recurrence of HCC. IFN did not improve the survival of HCV-related HCC patients after curative therapy. Whether IFN is effective for intermediate and advanced HCC patients could not be determined because of insufficient data. The toxicity of IFN was acceptable.

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Long-term interferon-α treatment suppresses tumor growth but promotes metastasis capacity in hepatocellular carcinoma

Abstract: IFN-α has janus face of consistently suppressing HCC growth, however, promoting tumor metastasis capacity, which is of clinical indication for the scientific administration of IFN-α and the similar antiangiogenesis drugs for their dual effect on tumor growth and metastasis.

Cited by 13 publications

References 45 publications

Isomalto oligosaccharide sulfate inhibits tumor growth and metastasis of hepatocellular carcinoma in nude mice

Isomalto oligosaccharide sulfate inhibits tumor growth and metastasis of hepatocellular carcinoma in nude mice

Tanshinone IIA inhibits metastasis after palliative resection of hepatocellular carcinoma and prolongs survival in part via vascular normalization

Effect and Safety of Interferon for Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis

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