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The Clinical Impact of Transcatheter Arterial Chemoembolization (TACE)-Induced c-Met Upregulation on TACE Refractoriness in Hepatocellular Carcinoma

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Abstract

Background

Transcatheter arterial chemoembolization (TACE) is a widely used and well-established treatment for hepatocellular carcinoma (HCC). However, TACE loses its therapeutic efficacy when performed repeatedly, a phenomenon termed TACE refractoriness. c-Met is associated with malignant potential and with resistance to anti-tumor therapies in some kinds of cancers.

Aims

The aim of this study is to investigate the clinical impact of TACE on c-Met expression with the aim of understanding the mechanism underlying TACE refractoriness.

Methods

The effect of TACE on the c-Met expression level was investigated in vitro in HCC cell lines, and it was shown that c-Met expression is upregulated in HCC cell lines cultured under hypoxia and/or exposed to chemotherapeutic agents. The in vitro results were validated using 82 clinical samples of HCC with and without preoperative TACE treatment.

Results

c-Met upregulation was observed significantly more frequently in clinical samples of HCC that were treated with preoperative TACE than in samples with no TACE treatment. Increased c-Met expression was significantly associated with poor prognosis. Furthermore, the incidence of c-Met-positive expression was significantly higher in TACE-refractory HCC samples.

Conclusions

TACE treatment upregulates c-Met expression in HCC and the upregulated c-Met expression may be responsible for TACE refractoriness.

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References

  1. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med. 1999;340:745–750.

    Article  CAS  PubMed  Google Scholar 

  2. Poon RT, Fan ST, Lo CM, et al. Improving survival results after resection of hepatocellular carcinoma: a prospective study of 377 patients over 10 years. Ann Surg. 2001;234:63–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kudo M, Matsui O, Izumi N, et al. Transarterial chemoembolization failure/refractoriness: JSH-LCSGJ criteria 2014 update. Oncology. 2014;87:22–31.

    Article  CAS  PubMed  Google Scholar 

  4. Lencioni R. Chemoembolization in patients with hepatocellular carcinoma. Liver Cancer. 2012;1:41–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Camma C, Schepis F, Orlando A, et al. Transarterial chemoembolization for unresectable hepatocellular carcinoma: meta-analysis of randomized controlled trials. Radiology. 2002;224:47–54.

    Article  PubMed  Google Scholar 

  6. Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology. 2003;37:429–442.

    Article  CAS  PubMed  Google Scholar 

  7. Arii S, Sata M, Sakamoto M, et al. Management of hepatocellular carcinoma: report of Consensus Meeting in the 45th Annual Meeting of the Japan Society of Hepatology (2009). Hepatol Res. 2010;40:667–685.

    Article  PubMed  Google Scholar 

  8. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology. 2005;42:1208–1236.

    Article  PubMed  Google Scholar 

  9. Omata M, Lesmana LA, Tateishi R, et al. Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma. Hepatol Int. 2010;4:439–474.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Kudo M, Izumi N, Kokudo N, et al. Management of hepatocellular carcinoma in Japan: Consensus-Based Clinical Practice Guidelines proposed by the Japan Society of Hepatology (JSH) 2010 updated version. Dig Dis. 2011;29:339–364.

    Article  PubMed  Google Scholar 

  11. Raoul JL, Gilabert M, Piana G. How to define transarterial chemoembolization failure or refractoriness: a European perspective. Liver Cancer. 2014;3:119–124.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Furge KA, Zhang YW, Vande Woude GF. Met receptor tyrosine kinase: enhanced signaling through adapter proteins. Oncogene. 2000;19:5582–5589.

    Article  CAS  PubMed  Google Scholar 

  13. Jeffers M, Schmidt L, Nakaigawa N, et al. Activating mutations for the met tyrosine kinase receptor in human cancer. Proc Natl Acad Sci USA. 1997;94:11445–11450.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Miyamoto M, Ojima H, Iwasaki M, et al. Prognostic significance of overexpression of c-Met oncoprotein in cholangiocarcinoma. Br J Cancer. 2011;105:131–138.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kaposi-Novak P, Lee JS, Gomez-Quiroz L, et al. Met-regulated expression signature defines a subset of human hepatocellular carcinomas with poor prognosis and aggressive phenotype. J Clin Investig. 2006;116:1582–1595.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Balan M, Teran EM, Waaga-Gasser AM, et al. Novel roles of c-Met in the survival of renal cancer cells through the regulation of HO-1 and PD-L1 expression. J Biol Chem. 2015;290:8110–8120.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Breindel JL, Haskins JW, Cowell EP, et al. EGF receptor activates MET through MAPK to enhance non-small cell lung carcinoma invasion and brain metastasis. Cancer Res. 2013;73:5053–5065.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Boccaccio C, Luraghi P, Comoglio PM. MET-mediated resistance to EGFR inhibitors: an old liaison rooted in colorectal cancer stem cells. Cancer Res. 2014;74:3647–3651.

    Article  CAS  PubMed  Google Scholar 

  19. Gholamin S, Fiuji H, Maftouh M, et al. Targeting c-MET/HGF signaling pathway in upper gastrointestinal cancers: rationale and progress. Curr Drug Targets. 2014;15:1302–1311.

    Article  CAS  PubMed  Google Scholar 

  20. Hara S, Nakashiro K, Klosek SK, et al. Hypoxia enhances c-Met/HGF receptor expression and signaling by activating HIF-1alpha in human salivary gland cancer cells. Oral Oncol. 2006;42:593–598.

    Article  CAS  PubMed  Google Scholar 

  21. Ide T, Kitajima Y, Miyoshi A, et al. Tumor-stromal cell interaction under hypoxia increases the invasiveness of pancreatic cancer cells through the hepatocyte growth factor/c-Met pathway. Int J Cancer. 2006;119:2750–2759.

    Article  CAS  PubMed  Google Scholar 

  22. Maxwell PH, Ratcliffe PJ. Oxygen sensors and angiogenesis. Semin Cell Dev Biol. 2002;13:29–37.

    Article  CAS  PubMed  Google Scholar 

  23. Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med. 2003;9:677–684.

    Article  CAS  PubMed  Google Scholar 

  24. Qin LX, Tang ZY. The prognostic molecular markers in hepatocellular carcinoma. World J Gastroenterol WJG. 2002;8:385–392.

    Article  CAS  PubMed  Google Scholar 

  25. Mariani M, McHugh M, Petrillo M, et al. HGF/c-Met axis drives cancer aggressiveness in the neo-adjuvant setting of ovarian cancer. Oncotarget. 2014;5:4855–4867.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Ke AW, Shi GM, Zhou J, et al. Role of overexpression of CD151 and/or c-Met in predicting prognosis of hepatocellular carcinoma. Hepatology. 2009;49:491–503.

    Article  CAS  PubMed  Google Scholar 

  27. Kondo M, Yamamoto H, Nagano H, et al. Increased expression of COX-2 in nontumor liver tissue is associated with shorter disease-free survival in patients with hepatocellular carcinoma. Clin Cancer Res. 1999;5:4005–4012.

    CAS  PubMed  Google Scholar 

  28. Tomimaru Y, Eguchi H, Nagano H, et al. MicroRNA-21 induces resistance to the anti-tumour effect of interferon-alpha/5-fluorouracil in hepatocellular carcinoma cells. Br J Cancer. 2010;103:1617–1626.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Eguchi H, Nagano H, Yamamoto H, et al. Augmentation of antitumor activity of 5-fluorouracil by interferon alpha is associated with up-regulation of p27Kip1 in human hepatocellular carcinoma cells. Clin Cancer Res. 2000;6:2881–2890.

    CAS  PubMed  Google Scholar 

  30. Yamamoto H, Kondo M, Nakamori S, et al. JTE-522, a cyclooxygenase-2 inhibitor, is an effective chemopreventive agent against rat experimental liver fibrosis1. Gastroenterology. 2003;125:556–571.

    Article  CAS  PubMed  Google Scholar 

  31. Schmitz KJ, Wohlschlaeger J, Lang H, et al. Activation of the ERK and AKT signalling pathway predicts poor prognosis in hepatocellular carcinoma and ERK activation in cancer tissue is associated with hepatitis C virus infection. J Hepatol. 2008;48:83–90.

    Article  CAS  PubMed  Google Scholar 

  32. Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10:25–34.

    Article  CAS  PubMed  Google Scholar 

  33. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–390.

    Article  CAS  PubMed  Google Scholar 

  34. Zhang B, Zhang X, Zhou T, Liu J. Clinical observation of liver cancer patients treated with axitinib and cabozantinib after failed sorafenib treatment: a case report and literature review. Cancer Biol Ther. 2015;16:215–218.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Harada T, Matsuo K, Inoue T, et al. Is preoperative hepatic arterial chemoembolization safe and effective for hepatocellular carcinoma? Ann Surg. 1996;224:4–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lee KT, Lu YW, Wang SN, et al. The effect of preoperative transarterial chemoembolization of resectable hepatocellular carcinoma on clinical and economic outcomes. J Surg Oncol. 2009;99:343–350.

    Article  PubMed  Google Scholar 

  37. Gupta S, Kobayashi S, Phongkitkarun S, et al. Effect of transcatheter hepatic arterial embolization on angiogenesis in an animal model. Investig Radiol. 2006;41:516–521.

    Article  Google Scholar 

  38. Sergio A, Cristofori C, Cardin R, et al. Transcatheter arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): the role of angiogenesis and invasiveness. Am J Gastroenterol. 2008;103:914–921.

    Article  PubMed  Google Scholar 

  39. Scagliotti GV, Novello S, von Pawel J. The emerging role of MET/HGF inhibitors in oncology. Cancer Treat Rev. 2013;39:793–801.

    Article  CAS  PubMed  Google Scholar 

  40. Smith DC, Smith MR, Sweeney C, et al. Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial. J Clin Oncol. 2013;31:412–419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wagner AJ, Goldberg JM, Dubois SG, et al. Tivantinib (ARQ 197), a selective inhibitor of MET, in patients with microphthalmia transcription factor-associated tumors: results of a multicenter phase 2 trial. Cancer. 2012;118:5894–5902.

    Article  CAS  PubMed  Google Scholar 

  42. Calin GA, Croce CM. MicroRNA-cancer connection: the beginning of a new tale. Cancer Res. 2006;66:7390–7394.

    Article  CAS  PubMed  Google Scholar 

  43. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136:215–233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Hoshino I, Matsubara H. MicroRNAs in cancer diagnosis and therapy: from bench to bedside. Surg Today. 2013;43:467–478.

    Article  CAS  PubMed  Google Scholar 

  45. Yan K, Gao J, Yang T, et al. MicroRNA-34a inhibits the proliferation and metastasis of osteosarcoma cells both in vitro and in vivo. PloS One. 2012;7:e33778.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Agostini M, Knight RA. miR-34: from bench to bedside. Oncotarget. 2014;5:872–881.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Wiggins JF, Ruffino L, Kelnar K, et al. Development of a lung cancer therapeutic based on the tumor suppressor microRNA-34. Cancer Res. 2010;70:5923–5930.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Misso G, Di Martino MT, De Rosa G, et al. Mir-34: a new weapon against cancer? Mol Ther Nucleic Acids. 2014;3:e194.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka E-2, Suita, Osaka, 565-0871, Japan

    Jun Kajihara, Yoshito Tomimaru, Hidetoshi Eguchi, Daisaku Yamada, Hiroshi Wada, Akira Tomokuni, Tadafumi Asaoka, Koichi Kawamoto, Shigeru Marubashi, Hiroaki Nagano, Yuichiro Doki & Masaki Mori

  2. Division of Health Sciences, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan

    Koji Umeshita

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  1. Jun Kajihara
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Correspondence to Hidetoshi Eguchi.

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10620_2015_4018_MOESM1_ESM.tif

Induction of less resistance to chemotherapy and hypoxia by c-Met inhibitor in HCC cell lines with increased c-Met expression driven by preculture. The resistance was evaluated by growth-inhibitory assay. The experiment used cells precultured for 72 hours under hypoxic condition and exposure of the chemotherapeutic drugs (CDDP, DXR), which were expected to have increased c-Met expression. The resistance to the drugs (CDDP, DXR) and hypoxia in the cells treated with c-Met inhibitor [SU11274 (+)] was compared to those without c-Met inhibitor [SU11274 (-)]. Data are mean ± SD of triplicates. *p < 0.05 (TIFF 65 kb)

10620_2015_4018_MOESM2_ESM.tif

Immunohistochemical analysis for HGF/c-Met signaling pathway-related protein in representative HCC samples. The panels show a representative case with negative phosphorylated c-Met expression in c-Met-negative case (left upper panel), that with positive phosphorylated c-Met expression in c-Met-positive case (right upper panel), that with negative phosphorylated Akt expression in c-Met-negative case (left lower panel), and that with positive phosphorylated Akt expression in c-Met-positive case (right lower panel). Bar = 100 μm (TIFF 1572 kb)

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Kajihara, J., Tomimaru, Y., Eguchi, H. et al. The Clinical Impact of Transcatheter Arterial Chemoembolization (TACE)-Induced c-Met Upregulation on TACE Refractoriness in Hepatocellular Carcinoma. Dig Dis Sci 61, 1572–1581 (2016). https://doi.org/10.1007/s10620-015-4018-9

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