Liver Cancer pp 193-211 | Cite as

Expression of Vascular Endothelial Growth Factor in Hepatocellular Carcinoma: Correlation with Radiologic Findings

  • Masayuki Kanematsu
  • Richard C. Semelka
  • Shinji Osada
Part of the Methods of Cancer Diagnosis, Therapy and Prognosis book series (HAYAT, volume 5)

Angiogenesis is the process whereby new blood vessels develop from the preexisting vasculature. It takes place physiologically during embryonic development, during the normal growth of tissues and the wound healing, and during the female reproductive cycle (i.e., ovulation, menstruation, and placental development) as well as during the pathologic growth and metastatic spread of malignant neoplasms (Folkman, 1971). A variety of humoral agents need to be activated to generate a neovascular blood supply or angiogenesis in the human body, and vascular endothelial growth factor (VEGF) is one of the most important humoral agents to be activated to ensure the growth of the vascular endothelium.

Various types of hepatocellular nodules with malignant potential are known to develop in livers with chronic liver damage: they are large regenerative nodules, low-grade dysplastic nodules, high-grade dysplastic nodules, well-differentiated hepatocellular carcinoma (HCC), and moderately or poorly differentiated HCC (International Working Party, 1995). In the process of HCC development, the expression of proangiogenetic factors such as VEGF appears to play an important role. The expression of this factor in HCC tissues has been considered to be associated with tumor size or histological tumor grade (Yamaguchi et al., 1998). Even in the nontumorous liver parenchyma, VEGF is expressed by sinusoidal endothelial cells and hepatocytes (Yamane et al., 1994).


Dysplastic Nodule Hepatic Nodule Surrounding Liver Arterial Portography Hepatocellular Nodule 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. El-Assal, O.N., Yamanoi, A., Soda, Y., Yamaguchi, M., Igarashi, M., Yamamoto, A., Nabika, T., and Nagasue, N. 1998. Clinical significance of microvessel density and vascular endothelial growth factor expression in hepatocellular carcinoma and surrounding liver: possible involvement of vascular endothelial growth factor in the angiogenesis of cirrhotic liver. Hepatology 27: 1554–1562.PubMedCrossRefGoogle Scholar
  2. Folkman, J. 1971. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285: 1182–1186.PubMedGoogle Scholar
  3. Gwak, G.Y., Yoon, J.H., Kim, K.M., Lee, H.S., Chung, J.W., and Gores, G.J. 2005. Hypoxia stimulates proliferation of human hepatoma cells through the induction of hexokinase II expression. J. Hepatol. 42: 358–364.PubMedCrossRefGoogle Scholar
  4. Hayashi, M., Matsui, O., Ueda, K., Kawamori, Y., Kadoya, M., Yoshikawa, J., Gabata, T., Takashima, T., Nonomura, A., and Nakanuma, Y. 1999. Correlation between the blood supply and grade of malignancy of hepatocellular nodules associated with liver cirrhosis: evaluation by CT during intraarterial injection of contrast medium. Am. J. Roentgenol. 172: 969–976.Google Scholar
  5. International Working Party. 1995. Terminology of nodular hepatocellular lesions. Hepatology 22: 983–993.Google Scholar
  6. Jeng, K.S., Sheen, I.S., Wang, Y.C., Gu, S.L., Chu, C.M., Shih, S.C., Wang, P.C., Chang, W.H., and Wang, H.Y. 2004. Is the vascular endothelial growth factor messenger RNA expression in resectable hepatocellular carcinoma of prognostic value after resection? World J. Gastroenterol. 10: 676–681.PubMedGoogle Scholar
  7. Kanematsu, M., Hoshi, H., Imaeda, T., Murakami, T., Inaba, Y., Yokoyama, R., and Nakamura, H. 1997. Detection and characterization of hepatic tumors: value of combined helical CT hepatic arteriography and CT during arterial portogra-phy. Am. J. Roentgenol. 168: 1193–1198.Google Scholar
  8. Kanematsu, M., Semelka, R.C., Leonardou, P., Mastropasqua, M., Armao, D., Vaidean, G., Firat, Z., and Woosley, J.T. 2004a. Angiogenesis in hepatocellular nodules: correlation of MR imaging and vascular endothelial growth factor. J. Magn. Reson. Imaging 20: 426–434.CrossRefGoogle Scholar
  9. Kanematsu, M., Osada, S., Amaoka, N., Goshima, S., Kondo, H., Nishibori, H., Kato, H., Matsuo, M., Yokoyama, R., Hoshi, H., and Moriyama, N. 2004b. Expression of vascular endothelial growth factor in hepatocellular carcinoma and the surrounding liver: correlation with angi-ographically assisted CT. Am. J. Roentgenol. 183: 1585–1593.Google Scholar
  10. Kanematsu, M., Osada, S., Amaoka, N., Goshima, S., Kondo, H., Kato, H., Nishibori, H., Yokoyama, R., Hoshi, H., and Moriyama, N. 2005. Expression of vascular endothelial growth factor in hepatocellular carcinoma and the surrounding liver and correlation with MRI findings. Am. J. Roentgenol. 184: 832–841.Google Scholar
  11. Kutami, R., Nakashima, Y., Nakashima, O., Shiota, K., and Kojiro, M. 2000. Pathomorphologic study on the mechanism of fatty change in small hepa-tocellular carcinoma of humans. J. Hepatol. 33: 282–289.PubMedCrossRefGoogle Scholar
  12. Kwak, B.K., Shim, H.J., Park, E.S., Kim, S.A., Choi, D., Lim, H.K., Park, C.K., Chung, J.W., and Park, J.H. 2001. Hepatocellular carcinoma: correlation between vascular endothelial growth factor level and degree of enhancement by multiphase contrast-enhanced computed tomography. Invest. Radiol. 36: 487–492.PubMedCrossRefGoogle Scholar
  13. Lim, J.H., Kim, E.Y., Lee, W.J., Lim, H.K., Do, Y.S., Choo, I.W., and Park, C.K. 1999. Regenerative nodules in liver cirrhosis: findings at CT during arterial portography and CT hepatic arteriography with histopathologic correlation. Radiology 210: 451–458.PubMedGoogle Scholar
  14. Mise, M., Arii, S., Higashituji, H., Furutani, M., Niwano, M., Harada, T., Ishigami, S., Toda, Y., Nakayama, H., Fukumoto, M., Fujita, J., and Imamura, M. 1996. Clinical significance of vascular endothelial growth factor and basic fibroblast growth factor gene expression in liver tumors. Hepatology 23: 455–464.PubMedCrossRefGoogle Scholar
  15. Monacci, W.T., Merrill, M.J., and Oldfield, E.H. 1993. Expression of vascular permeability factor/vascular endothelial factor in normal rat tissues. Am. J. Physiol. 264: 995–1002.Google Scholar
  16. Morgan, B., Thomas, A.L., Drevs, J., Hennig, J., Buchert, M., Jivan, A., Horsfield, M.A., Mross, K., Ball, H.A., Lee, L., Mietlowski, W., Fuxuis, S., Unger, C., O'Byrne, K., Henry, A., Cherryman, G.R., Laurent, D., Dugan, M., Marme, D., and Steward, W.P. 2003. Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK222584, an inhibitor of the vascular endothe-lial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: results from two phase I studies. J. Clin. Oncol. 21: 3955–3964.PubMedCrossRefGoogle Scholar
  17. Mukhopadhyay, D., Tsiokas, L., Zhou, X.M., Foster, D., Brugge, J.S., and Sukhatme, V.P. 1995. Hypoxic induction of human vascular endothelial growth factor expression through c-Src activation. Nature 375: 577–581.PubMedCrossRefGoogle Scholar
  18. Murakami, T., Kim, T., Takamura, M., Hori, M., Takahashi, S., Federle, M.P., Tsuda, K., Osuga, K., Kawata, S., Nakamura, H., and Kudo, M. 2001. Hypervascular hepatocellular carcinoma: detection with double arterial phase multi- detector row helical CT. Radiology 218: 763–767.PubMedGoogle Scholar
  19. Ng, I.O., Poon, R.T., Lee, J.M., Fan, S.T., Ng, M., and Tso, W.K. 2001. Microvessel density, vascular endothelial growth factor and its receptors Flt-1 and Flk-1/KDR in hepatocellular carcinoma. Am. J. Clin. Pathol. 116: 838–845.PubMedCrossRefGoogle Scholar
  20. Rosmorduc, O., Wendum, D., Corpechot, C., Galy, B., Sebbagh, N., Raleigh, J., Housset, C., and Poupon, R. 1999. Hepatocellular hypoxia-induced vascular endothelial growth factor expression and angiogenesis in experimental biliary cirrhosis. Am. J. Pathol. 155: 1065–1073.PubMedGoogle Scholar
  21. Scarfo, L.M., Weller, P.F., and Farber, H.W. 2001. Induction of endothelial cell cytoplasmic lipid bodies during hypoxia. Am. J. Physiol. Heart Circ. Physiol. 280: 294–301.Google Scholar
  22. Semelka, R.C., Shoenut, J.P., Kroeker, M.A., Greenberg, H.M., Simm, F.C., Minuk, G.Y., Kroeker, R.M., and Micflikier, A.B. 1992. Focal liver disease: comparison of dynamic contrast-enhanced CT and T2-weighted fat-suppressed, FLASH, and dynamic gadolinium-enhanced MR imaging at 1.5 T. Radiology 184: 687–694.PubMedGoogle Scholar
  23. Shimizu, A., Ito, K., Koike, S., Fujita, T., Shimizu, K., and Matsunaga, N. 2003. Cirrhosis or chronic hepatitis: evaluation of small (< or = 2-cm) early-enhancing hepatic lesions with serial contrast-enhanced dynamic MR imaging. Radiology 226: 550–555.PubMedCrossRefGoogle Scholar
  24. Shweiki, D., Itin, A., Soffer, D., and Keshet, E. 1992. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated ang-iogenesis. Nature 359: 843–845.PubMedCrossRefGoogle Scholar
  25. Suzuki, K., Hayashi, N., Miyamoto, Y., Yamamoto, M., Ohkawa, K., Ito, Y., Sasaki, Y., Yamaguchi, Y., Nakase, H., Noda, K., Enomoto, N., Arai, K., Yamada, Y., Yoshihara, H., Tujimura, T., Kawano, K., Yoshikawa, K., and Kamada, T. 1996. Expression of vascular permeability factor/vascular endothelial growth factor in human hepatocellular carcinoma. Cancer Res. 56: 3004–3009.PubMedGoogle Scholar
  26. Ueda, K., Matsui, O., Kawamori, Y., Nakanuma, Y., Kadoya, M., Yoshikawa, J., Gabata, T., Nonomura, A., and Takashima, T. 1998. Hypervascular hepatocellular carcinoma: evaluation of hemodynamics with dynamic CT during hepatic arteriography. Radiology 206: 161–166.PubMedGoogle Scholar
  27. Viglietto, G., Maglione, D., Rambaldi, M., Cerutti, J., Romano, A., Trapasso, F., Fedele, M., Ippolito, P., Chiappetta, G., and Botti, G. 1995. Upregulation of vascular endothelial growth factor (VEGF) and downregulation of placenta growth factor (PlGF) associated with malignancy in human thyroid tumors and cell lines. Oncogene 11: 1569–1579.PubMedGoogle Scholar
  28. von Marschall, Z., Cramer, T., Hocker, M., Finkenzeller, G., Wiedenmann, B., and Rosewicz S. 2001. Dual mechanism of vascular endothelial growth factor upregulation by hypoxia in human hepatocellular carcinoma. Gut 48: 87–96.CrossRefGoogle Scholar
  29. Yamaguchi, R., Yano, H., Iemura, A., Ogasawara, S., Haramaki, M., and Kojiro, M. 1998. Expression of vascular endothelial growth factor in human hepatocellular carcinoma. Hepatology 28: 68–77.PubMedCrossRefGoogle Scholar
  30. Yamane, A., Seetharam, L., Yamaguchi, S., Gotoh, N., Takahashi, T., Neufeld, G., and Shibuya, M. 1994. A new communication system between hepatocytes and sinusoidal endothelial cells in liver through vascular endothelial growth factor and Flt tyrosine kinase receptor family (Flt-1 and KDR/Flk-1). Oncogene 9: 2683–2690.PubMedGoogle Scholar

Copyright information

© Springer Science + Business Media B.V. 2009

Authors and Affiliations

  • Masayuki Kanematsu
    • 1
  • Richard C. Semelka
    • 1
  • Shinji Osada
    • 1
  1. 1.Department of Radiology ServicesGifu University HospitalGifuJapan

Personalised recommendations