International Journal of Clinical Oncology

, Volume 15, Issue 3, pp 235–241

Current status of molecularly targeted therapy for hepatocellular carcinoma: basic science

Review Article

Abstract

Conventional systemic chemotherapy has been developed with so-called anti-cancer agents, essentially screened for cytotoxicity to cultured cancer cells. However, in patients with hepatocellular carcinoma (HCC), the role of chemotherapy is quite limited because most anti-cancer agents are ineffective and relatively toxic to HCC patients with chronic liver diseases. On the other hand, accumulated understanding of the molecular mechanisms regulating cancer progression has led to novel development of molecularly targeted therapies with cytostatic agents. Recently, a phase III clinical trial revealed a multi-kinase inhibitor, Sorafenib, as the first agent leading to improved overall survival of patients with advanced HCC. A new era of HCC treatment has arrived, based on identification of deranged signaling pathways of cancer cells or their microenvironment. This review summarizes the molecular hallmarks of HCC with a focus on angiogenesis, growth signals, and mitotic stress, and a novel concept “synthetic lethality” for the targeted therapy strategy.

Keywords

Angiogenesis Growth signals Mitotic stress Aurora Synthetic lethality 

References

  1. 1.
    Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70CrossRefPubMedGoogle Scholar
  2. 2.
    Kroemer G, Pouyssegur J (2008) Tumor cell metabolism: cancer’s Achilles’ heel. Cancer Cell 13(6):472–482CrossRefPubMedGoogle Scholar
  3. 3.
    Luo J, Solimini NL, Elledge SJ (2009) Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 136(5):823–837CrossRefPubMedGoogle Scholar
  4. 4.
    Weinstein IB (2002) Cancer. addiction to oncogenes-the Achilles heal of cancer. Science 297(5578):63–64CrossRefPubMedGoogle Scholar
  5. 5.
    Weinstein IB, Joe AK (2006) Mechanisms of disease: oncogene addiction—a rationale for molecular targeting in cancer therapy. Nat Clin Pract Oncol 3(8):448–457CrossRefPubMedGoogle Scholar
  6. 6.
    Tanaka S, Arii S (2009) Molecularly targeted therapy for hepatocellular carcinoma. Cancer Sci 100(1):1–8CrossRefPubMedGoogle Scholar
  7. 7.
    Llovet JM, Bruix J (2008) Molecular targeted therapies in hepatocellular carcinoma. Hepatology 48:1312–1327CrossRefPubMedGoogle Scholar
  8. 8.
    Yau T, Chan P, Epstein R et al (2009) Management of advanced hepatocellular carcinoma in the era of targeted therapy. Liver Int 29(1):10–17 ReviewCrossRefPubMedGoogle Scholar
  9. 9.
    Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86:353–364CrossRefPubMedGoogle Scholar
  10. 10.
    Tanaka S, Arii S (2006) Current status of perspective of antiangiogenic therapy for cancer; hepatocellular carcinoma. Int J Clin Oncol 11:82–89CrossRefPubMedGoogle Scholar
  11. 11.
    Ferrara N (2002) VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer 2(10):795–803CrossRefPubMedGoogle Scholar
  12. 12.
    Mise M, Arii S, Higashituji H et al (1996) Clinical significance of vascular endothelial growth factor and basic fibroblast growth factor gene expression in liver tumor. Hepatology 23(3):455–464CrossRefPubMedGoogle Scholar
  13. 13.
    Schmitt M, Horbach A, Kubitz R et al (2004) Disruption of hepatocellular tight junctions by vascular endothelial growth factor (VEGF): a novel mechanism for tumor invasion. J Hepatol 41(2):274–283CrossRefPubMedGoogle Scholar
  14. 14.
    Kaplan RN, Riba RD, Zacharoulis S et al (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438(7069):820–827CrossRefPubMedGoogle Scholar
  15. 15.
    Hiratsuka S, Watanabe A, Aburatani H et al (2006) Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nat Cell Biol 8(12):1369–1375CrossRefPubMedGoogle Scholar
  16. 16.
    Arii S (2004) Role of vascular endothelial growth factor on the invasive potential of hepatocellular carcinoma. J Hepatol 41(2):333–335CrossRefPubMedGoogle Scholar
  17. 17.
    Andrae J, Gallini R, Betsholtz C (2008) Role of platelet-derived growth factors in physiology and medicine. Genes Dev 22(10):1276–1312CrossRefPubMedGoogle Scholar
  18. 18.
    Kuhnert F, Tam BY, Sennino B et al (2008) Soluble receptor-mediated selective inhibition of VEGFR and PDGFRbeta signaling during physiologic and tumor angiogenesis. Proc Natl Acad Sci USA 105(29):10185–10190CrossRefPubMedGoogle Scholar
  19. 19.
    Uematsu S, Higashi T, Nouso K et al (2005) Altered expression of vascular endothelial growth factor, fibroblast growth factor-2 and endostatin in patients with hepatocellular carcinoma. J Gastroenterol Hepatol 20(4):583–588CrossRefPubMedGoogle Scholar
  20. 20.
    Poon RT, Ng IO, Lau C et al (2001) Correlation of serum basic fibroblast growth factor levels with clinicopathologic features and postoperative recurrence in hepatocellular carcinoma. Am J Surg 182:298–304CrossRefPubMedGoogle Scholar
  21. 21.
    Llovet JM, Ricci S, Mazzaferro V et al (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–390CrossRefPubMedGoogle Scholar
  22. 22.
    Tanaka S, Mori M, Sakamoto Y et al (1999) Biologic significance of angiopoietin-2 expression in human hepatocellular carcinoma. J Clin Investig 103(3):341–345CrossRefPubMedGoogle Scholar
  23. 23.
    Tanaka S, Wands JR, Arii S (2006) Induction of angiopoietin-2 gene expression by COX-2: A novel role for COX-2 inhibitors during hepatocarcinogenesis. J Hepatol 44(1):233–235CrossRefPubMedGoogle Scholar
  24. 24.
    Tanaka S, Sugimachi K, Yamashita Yi et al (2002) Tie2 vascular endothelial receptor expression and function in hepatocellular carcinoma. Hepatology 35(4):861–867CrossRefPubMedGoogle Scholar
  25. 25.
    Seegar TC, Eller B, Tzvetkova-Robev D et al (2010) Tie1–Tie2 interactions mediate functional differences between angiopoietin ligands. Mol Cell 37(5):643–655CrossRefPubMedGoogle Scholar
  26. 26.
    Holash J, Maisonpierre PC, Compton D et al (1999) Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 284(5422):1994–1998CrossRefPubMedGoogle Scholar
  27. 27.
    Oliner J, Min H, Leal J et al (2004) Suppression of angiogenesis and tumor growth by selective inhibition of angiopoietin-2. Cancer Cell 6(5):507–516CrossRefPubMedGoogle Scholar
  28. 28.
    Herbst RS, Hong D, Chap L et al (2009) Safety, pharmacokinetics, and antitumor activity of AMG 386, a selective angiopoietin inhibitor, in adult patients with advanced solid tumors. J Clin Oncol 27(21):3557–3565CrossRefPubMedGoogle Scholar
  29. 29.
    Pawson T (2004) Specificity in signal transduction: from phosphotyrosine–SH2 domain interactions to complex cellular systems. Cell 116:191–203CrossRefPubMedGoogle Scholar
  30. 30.
    Tanaka S, Sugimachi K, Maehara S et al (2002) Oncogenic signal transduction and therapeutic strategy for hepatocellular carcinoma. Surgery 131:S142–S147CrossRefPubMedGoogle Scholar
  31. 31.
    Schagdarsurengin U, Wilkens L, Steinemann D et al (2003) Frequent epigenetic inactivation of the RASSF1A gene in hepatocellular carcinoma. Oncogene 22:1866–1871CrossRefPubMedGoogle Scholar
  32. 32.
    Farazi PA, DePinho RA (2006) Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer 6:674–687CrossRefPubMedGoogle Scholar
  33. 33.
    Luo J, Manning BD, Cantley LC (2003) Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell 4:257–262CrossRefPubMedGoogle Scholar
  34. 34.
    Chiang GG, Abraham RT (2007) Targeting the mTOR signaling network in cancer. Trends Mol Med 13:433–442CrossRefPubMedGoogle Scholar
  35. 35.
    Foster KG, Fingar DC (2010) mTOR: conducting the cellular signaling symphony. J Biol ChemGoogle Scholar
  36. 36.
    Schvartzman JM, Sotillo R, Benezra R (2010) Mitotic chromosomal instability and cancer: mouse modelling of the human disease. Nat Rev Cancer 10(2):102–115CrossRefPubMedGoogle Scholar
  37. 37.
    Tanaka S, Arii S, Yasen M et al (2008) Aurora kinase B is a predictive factor for the aggressive recurrence of hepatocellular carcinoma after curative hepatectomy. Br J Surg 95:611–619CrossRefPubMedGoogle Scholar
  38. 38.
    Keen N, Taylor S (2004) Aurora-kinase inhibitors as anticancer agents. Nat Rev Cancer 4:927–936CrossRefPubMedGoogle Scholar
  39. 39.
    Nguyen HG, Makitalo M, Yang D et al (2009) Deregulated Aurora-B induced tetraploidy promotes tumorigenesis. FASEB J 23(8):2741–2748CrossRefPubMedGoogle Scholar
  40. 40.
    Harrington EA, Bebbington D, Moore J et al (2004) VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo. Nat Med 10(3):262–267CrossRefPubMedGoogle Scholar
  41. 41.
    Aihara A, Tanaka S, Yasen M et al (2010) The selective Aurora B kinase inhibitor AZD1152 as a novel treatment for hepatocellular carcinoma. J Hepatol 52(1):63–71CrossRefPubMedGoogle Scholar
  42. 42.
    Tanaka S, Mogushi K, Yasen M et al (2010) Gene-expression phenotypes for vascular invasiveness of hepatocellular carcinomas. Surgery 147(3):405–414CrossRefPubMedGoogle Scholar
  43. 43.
    Luo J, Emanuele MJ, Li D et al (2009) A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 137(5):835–848CrossRefPubMedGoogle Scholar
  44. 44.
    Dobzhansky T (1946) Genetics of natural populations. XIII. Recombination and variability in populations of Drosophila pseudoobscura. Genetics 31:269–290PubMedGoogle Scholar
  45. 45.
    Kaelin WG Jr (2005) The concept of synthetic lethality in the context of anticancer therapy. Nat Rev Cancer 5(9):689–698CrossRefPubMedGoogle Scholar
  46. 46.
    Fong PC, Boss DS, Yap TA et al (2009) Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 361(2):123–134CrossRefPubMedGoogle Scholar
  47. 47.
    Iglehart JD, Silver DP (2009) Synthetic lethality—a new direction in cancer-drug development. N Engl J Med 361(2):189–191CrossRefPubMedGoogle Scholar
  48. 48.
    Bryant HE, Schultz N, Thomas HD et al (2005) Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434(7035):913–917CrossRefPubMedGoogle Scholar
  49. 49.
    Farmer H, McCabe N, Lord CJ et al (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434(7035):917–921CrossRefPubMedGoogle Scholar
  50. 50.
    Ince N, Wands JR (1999) The increasing incidence of hepatocellular carcinoma. N Engl J Med 340:798–799CrossRefPubMedGoogle Scholar
  51. 51.
    Arii S, Yamaoka Y, Futagawa S et al (2000) Results of surgical and nonsurgical treatment for small-sized hepatocellular carcinomas: a retrospective and nationwide survey in Japan. The Liver Cancer Study Group of Japan. Hepatology 32:1224–1229CrossRefPubMedGoogle Scholar
  52. 52.
    Tanaka S, Arii S (2010) Medical treatments: in association or alone, their role and their future perspectives: novel molecular-targeted therapy for hepatocellular carcinoma. J Hepatobiliary Pancreat SurgGoogle Scholar

Copyright information

© Japan Society of Clinical Oncology 2010

Authors and Affiliations

  1. 1.Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of MedicineTokyo Medical and Dental UniversityTokyoJapan

Personalised recommendations