Serum levels of angiogenic and anti-angiogenic factors: their prognostic relevance in locally advanced hepatocellular carcinoma

详细信息    查看全文

• 作者：Bal Krishan Sharma ; Radhika Srinivasan ; Shweta Kapil…
• 关键词：Hepatocellular carcinoma ; VEGF ; Ang ; 2 ; Endostatin ; Angiostatin
• 刊名：Molecular and Cellular Biochemistry
• 出版年：2013
• 出版时间：November 2013
• 年：2013
• 卷：383
• 期：1-2
• 页码：103-112
• 全文大小：336KB
• 参考文献：1. Llovet JM, Burroughs A, Bruix J (2003) Hepatocellular carcinoma. Lancet 362:1907-917 CrossRef
  2. Tanigawa N, Lu C, Mitsui T, Miura S (1997) Quantitation of sinusoid-like vessels in hepatocellular carcinoma: its clinical and prognostic significance. Hepatology 26:1216-223
  3. Ramanujan S, Koenig GC, Padera TP, Stoll BR, Jain RK (2000) Local imbalance of proangiogenic and antiangiogenic factors: a potential mechanism of focal necrosis and dormancy in tumors. Cancer Res 60:1442-448
  4. Westphal JR, Van’t Hullenaar R, Peek R et al (2000) Angiogenic balance in human melanoma: expression of VEGF, bFGF, IL-8, PDGF and angiostatin in relation to vascular density of xenografts in vivo. Int J Cancer 86:768-76 CrossRef
  5. Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246:1306-309 CrossRef
  6. Asahara T, Chen D, Takahashi T et al (1998) Tie2 receptor ligands, angiopoietin-1 and angiopoietin-2, modulate VEGF-induced postnatal neovascularization. Circ Res 83:233-40 CrossRef
  7. Hu TH, Huang CC, Wu CL et al (2005) Increased endostatin/collagen XVIII expression correlates with elevated VEGF level and poor prognosis in hepatocellular carcinoma. Mod Pathol 18:663-72 CrossRef
  8. Schmidt A, Wenzel D, Thorey I, Werner S, Fleischmann BK, Bloch W (2005) Endostatin down-regulates soluble guanylate cyclase (sGC) in endothelial cells in vivo: influence of endostatin on vascular endothelial growth factor (VEGF) signaling. Endothelium 12:251-57 CrossRef
  9. Zatterstrom UK, Felbor U, Fukai N, Olsen BR (2000) Collagen XVIII/endostatin structure and functional role in angiogenesis. Cell Struct Funct 25:97-01 CrossRef
  10. O’Reilly MS, Boehm T, Shing Y et al (1997) Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88:277-85 CrossRef
  11. O’Reilly MS, Holmgren L, Shing Y et al (1994) Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79:315-28 CrossRef
  12. O’Reilly MS, Holmgren L, Chen C, Folkman J (1996) Angiostatin induces and sustains dormancy of human primary tumors in mice. Nat Med 2:689-92 CrossRef
  13. Lannutti BJ, Gately ST, Quevedo ME, Soff GA, Paller AS (1997) Human angiostatin inhibits murine hemangioendothelioma tumor growth in vivo. Cancer Res 57:5277-280
  14. Wu Z, O’Reilly MS, Folkman J, Shing Y (1997) Suppression of tumor growth with recombinant murine angiostatin. Biochem Biophys Res Commun 236:651-54 CrossRef
  15. Sim BK, O’Reilly MS, Liang H et al (1997) A recombinant human angiostatin protein inhibits experimental primary and metastatic cancer. Cancer Res 57:1329-334
  16. Xie H, Song J, Liu K et al (2008) The expression of hypoxia-inducible factor-1alpha in hepatitis B virus-related hepatocellular carcinoma: correlation with patients-prognosis and hepatitis B virus X protein. Dig Dis Sci 53:3225-233 CrossRef
  17. Huang GW, Yang LY, Lu WQ (2005) Expression of hypoxia-inducible factor 1alpha and vascular endothelial growth factor in hepatocellular carcinoma: impact on neovascularization and survival. World J Gastroenterol 11:1705-708
  18. Iavarone M, Lampertico P, Iannuzzi F et al (2007) Increased expression of vascular endothelial growth factor in small hepatocellular carcinoma. J Viral Hepat 14:133-39 CrossRef
  19. Poon RT, Lau C, Pang R, Ng KK, Yuen J, Fan ST (2007) High serum vascular endothelial growth factor levels predict poor prognosis after radiofrequency ablation of hepatocellular carcinoma: importance of tumor biomarker in ablative therapies. Ann Surg Oncol 14:1835-845 CrossRef
  20. Bruix J, Sherman M, Llovet JM et al (2001) EASL panel of experts on HCC. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol 35:421-30 CrossRef
  21. Kaido T, Uemoto S (2008) Recent evidence in the treatment of small hepatocellular carcinoma. Hepatogastroenterology 55:1460-462
  22. Wada H, Nagano H, Yamamoto H et al (2006) Expression pattern of angiogenic factors and prognosis after hepatic resection in hepatocellular carcinoma:importance of angiopoietin-2 and hypoxia-induced factor-1 alpha. Liver Int 26:414-23 CrossRef
  23. Kim HS, Park JW, Jang JS et al (2009) Prognostic values of alpha-fetoprotein and protein induced by vitamin K absence or antagonist-II in hepatitis B virus-related hepatocellular carcinoma: a prospective study. J Clin Gastroenterol 43:482-88 CrossRef
  24. Sterling RK, Jeffers L, Gordon F et al (2009) Utility of Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein and des-gamma-carboxy prothrombin, alone or in combination, as biomarkers for hepatocellular carcinoma. Clin Gastroenterol Hepatol 7:104-13 CrossRef
  25. Durazo FA, Blatt LM, Corey WG et al (2008) Des-gamma-carboxyprothrombin, alpha-fetoprotein and AFP-L3 in patients with chronic hepatitis, cirrhosis and hepatocellular carcinoma. J Gastroenterol Hepatol 23:1541-548 CrossRef
  26. Sharma B, Srinivasan R, Chawla YK et al (2010) Clinical utility of prothrombin induced by vitamin K absence in the detection of hepatocellular carcinoma in Indian population. Hepatol Int 4:569-76 CrossRef
  27. el-Houseini ME, Mohammed MS, Elshemey WM, Hussein TD, Desouky OS, Elsayed AA (2005) Enhanced detection of hepatocellular carcinoma. Cancer Control 12:248-53
  28. Li X, Feng GS, Zheng CS, Zhuo CK, Liu X (2004) Expression of plasma vascular endothelial growth factor in patients with hepatocellular carcinoma and effect of transcatheter arterial chemoembolization therapy on plasma vascular endothelial growth factor level. World J Gastroenterol 10:2878-882
  29. Zhao J, Hu J, Cai J (2001) Significance of vascular endothelial growth factor expression in serum of patients with hepatocellular carcinoma. Zhonghua Zhong Liu Za Zhi 23:389-92
  30. Chao Y, Li CP, Chau GY et al (2003) Prognostic significance of vascular endothelial growth factor, basic fibroblast growth factor, and angiogenin in patients with resectable hepatocellular carcinoma after surgery. Ann Surg Oncol 10:355-62 CrossRef
  31. Poon RT, Ho JW, Tong CS, Lau C, Ng IO, Fan ST (2004) Prognostic significance of serum vascular endothelial growth factor and endostatin in patients with hepatocellular carcinoma. Br J Surg 91:1354-360 CrossRef
  32. Tamesa T, Iizuka N, Mori N et al (2009) High serum levels of vascular endothelial growth factor after hepatectomy are associated with poor prognosis in hepatocellular carcinoma. Hepatogastroenterology 56:1122-126
  33. Niizeki T, Sumie S, Torimura T et al (2012) Serum vascular endothelial growth factor as a predictor of response and survival in patients with advanced hepatocellular carcinoma undergoing hepatic arterial infusion chemotherapy. J Gastroenterol 47:686-95 CrossRef
  34. Poon RT, Lau C, Yu WC, Fan ST, Wong J (2004) High serum levels of vascular endothelial growth factor predict poor response to transarterial chemoembolization in hepatocellular carcinoma: a prospective study. Oncol Rep 11:1077-084
  35. Kaseb AO, Hassan MM, Lin E, et al. (2011) V-CLIP: Integrating plasma vascular endothelial growth factor into a new scoring system to stratify patients with advanced hepatocellular carcinoma for clinical trials. Cancer 117:2478-488
  36. Dai CX, Gao Q, Qiu SJ et al (2009) Hypoxia-inducible factor-1 alpha, in association with inflammation, angiogenesis and MYC, is a critical prognostic factor in patients with HCC after surgery. BMC Cancer 9:418 CrossRef
  37. Scholz A, Rehm VA, Rieke S et al (2007) Angiopoietin-2 serum levels are elevated in patients with liver cirrhosis and hepatocellular carcinoma. Am J Gastroenterol 102:2471-481 CrossRef
  38. 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 20:583-88 CrossRef
  39. Yamagata M, Shiratori Y, Dan Y et al (2000) Serum endostatin levels in patients with hepatocellular carcinoma. Ann Oncol 11:761-62 CrossRef
  40. Dhar DK, Ono T, Yamanoi A et al (2002) Serum endostatin predicts tumor vascularity in hepatocellular carcinoma. Cancer 95:2188-195 CrossRef
  41. Lai R, Estey E, Shen Y et al (2002) Clinical significance of plasma endostatin in acute myeloid leukemia/myelodysplastic syndrome. Cancer 94:14-7 CrossRef
  42. Rosmorduc O, Wendum D, Corpechot C et al (1999) Hepatocellular hypoxia-induced vascular endothelial growth factor expression and angiogenesis in experimental biliary cirrhosis. Am J Pathol 155:1065-073 CrossRef
  43. Drenberg CD, Saunders BO, Wilbanks GD et al (2010) Urinary angiostatin levels are elevated in patients with epithelial ovarian cancer. Gynecol Oncol 117:117-24 CrossRef
  44. Schmitz V, Raskopf E, Gonzalez-Carmona MA et al (2007) Plasminogen fragment K1-5 improves survival in a murine hepatocellular carcinoma model. Gut 56:271-78 CrossRef
  45. Gorrin Rivas MJ, Arii S, Furutani M et al (1998) Expression of human macrophage metalloelastase gene in hepatocellular carcinoma: correlation with angiostatin generation and its clinical significance. Hepatology 28:986-93 CrossRef
  
• 作者单位：Bal Krishan Sharma (1)
  Radhika Srinivasan (2)
  Shweta Kapil (1)
  Bhupesh Singla (1)
  Nitin Saini (1)
  Yogesh Kumar Chawla (1)
  Anuradha Chakraborti (3)
  Ajay Duseja (1)
  Naveen Kalra (4)
  Radha Krishan Dhiman (1)
  
  1. Departments of Hepatology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India
  2. Department of Cytology and Gynecological Pathology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India
  3. Department of Experimental Medicine and Biotechnology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India
  4. Department of Radiodiagnosis, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India
  
• ISSN：1573-4919

文摘

Hepatocellular carcinoma (HCC) is a prototype tumor wherein angiogenesis plays a vital role in its progression. The role of VEGF, a major angiogenic factor in HCC is known; however, the role of anti-angiogenic factors simultaneously with the angiogenic factors has not been studied before. Hence, in this study, the serum levels of major angiogenic [Vascular Endothelial Growth Factor (VEGF), angiopoietin-2 (Ang-2)] and anti-angiogenic (endostatin, angiostatin) factors were analyzed and correlated with clinico-radiological features and with outcome. A total of 150 patients (50 HCC, 50 cirrhosis and 50 chronic hepatitis) and 50 healthy controls were enrolled in this study. Serum levels of VEGF, Ang-2, endostatin, and angiostatin were estimated by enzyme-linked immunosorbent assay. HCC shows significantly elevated serum levels of angiogenic factors VEGF and Ang-2 and of anti-angiogenic factors endostatin and angiostatin. ROC curve analysis for serum VEGF yielded an optimal cut-off value of 225.14?pg/ml, with a sensitivity of 78?% and specificity of 84.7?% for a diagnosis of HCC and its distinction from other group. Using this value, the univariate and multivariate analysis revealed significantly poor outcome in patients with higher levels of serum VEGF (p?=?0.009). Combinatorial analysis revealed that patients with higher levels of both angiogenic and anti-angiogenic factors showed poor outcome. Serum VEGF correlates with poor survival of HCC patients and, therefore, serves as a non-invasive biomarker of poor prognosis. Moreover, elevated levels of anti-angiogenic factors occur endogenously in HCC patients.