Expression of betacellulin and epidermal growth factor receptor in hepatocellular carcinoma: implications for angiogenesis

Hum Pathol. 2006 Oct;37(10):1324-32. doi: 10.1016/j.humpath.2006.04.022. Epub 2006 Jul 27.


Hepatocellular carcinoma (HCC) is becoming one of the common malignant tumors worldwide and is characterized by high vascularity. Angiogenesis (formation of new microvessels) is critical for growth and progression of various human solid tumors. Betacellulin (BTC) is a member of the epidermal growth factor (EGF) family, and its signal action is mediated through EGF receptors (EGFR). In this study, to understand the role of BTC in relation to EGFR in HCC, we examined localization, expression, and involvement in angiogenesis of BTC and EGFR. The results revealed that expression of BTC, EGFR, and tumor growth factor-alpha messenger RNA in HCC was increased by 80%, 60%, and 40%, respectively, as compared with those in the nontumorous tissues. Increased expression of BTC protein was observed in 31 (61%) of 51 HCC specimens, and the level of tumor growth factor-alpha protein was higher in 17 (33%) of 51 HCC specimens than in nonmalignant hepatocytes. Betacellulin was predominantly expressed in HCC cells, whereas EGFR was observed in sinusoidal endothelial cells of HCC in 25 tumors (49%). Betacellulin was secreted in all 4 examined HCC cell lines. The HCC specimens showing positive EGFR expression in tumor endothelial cells had a significantly higher microvessel density than those without EGFR expression (P < .005). A strong correlation was found between BTC expression in cancer cells and EGFR expression in tumor endothelial cells (P < .001). These findings suggest that overexpression of BTC by HCC cells and EGFR by tumor endothelial cells enhance vascularity in a paracrine manner.

MeSH terms

  • Adult
  • Aged
  • Betacellulin
  • Biomarkers, Tumor / metabolism
  • Blotting, Western
  • Carcinoma, Hepatocellular / blood supply
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / pathology
  • Cell Line, Tumor
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism*
  • Female
  • Fluorescent Antibody Technique, Direct
  • Fluorescent Antibody Technique, Indirect
  • Gene Expression
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Humans
  • Immunoenzyme Techniques
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Liver Neoplasms / blood supply
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Male
  • Middle Aged
  • Neovascularization, Pathologic / metabolism*
  • Neovascularization, Pathologic / pathology
  • RNA, Messenger / metabolism
  • Transforming Growth Factor alpha / genetics
  • Transforming Growth Factor alpha / metabolism


  • BTC protein, human
  • Betacellulin
  • Biomarkers, Tumor
  • Intercellular Signaling Peptides and Proteins
  • RNA, Messenger
  • Transforming Growth Factor alpha
  • ErbB Receptors