1. ¹Department of Biopharmaceutical Sciences, University of California San Francisco, San Francisco, CA, USA
2. ²Department of Pathology, Stanford University, Stanford, CA, USA
3. ³Department of Surgery, The University of Hong Kong, Hong Kong, China
4. ⁴Department of Surgery, The University of Hong Kong, Hong Kong, China
5. ⁵Asian Liver Center, Stanford University, Stanford, CA, USA

Correspondence: Professor S So, MD, FACS, Department of Surgery, Asian Liver Center and Stanford University School of Medicine, 300 Pasteur Drive, H3680 Stanford, CA 94305, USA. E-mail: samso@stanford.edu

^*These authors contributed equally to this work.

Received 16 December 2003; Revised 9 February 2004; Accepted 16 February 2004; Published online 21 May 2004.

Abstract

Hepatocellular carcinoma is characterized by hypervascularity and a propensity for vascular invasion. Detailed analysis of complementary DNA (cDNA) microarray global gene expression data and further validation on a smaller independent sample set by reverse transcription-polymerase chain reaction established the presence of two endothelial gene clusters in hepatocellular carcinoma. Cluster I, consists of 20 cDNA clones, representing 15 unique genes. Cluster II consists of nine unique genes. The expression of the cluster I genes appeared to be significantly upregulated in hepatocellular carcinoma compared with normal liver, cirrhotic liver, or nontumor liver tissues adjacent to the hepatocellular carcinoma. The pattern of gene expression of cluster I genes correlated positively with the 'proliferation gene cluster' and 'stromal cells cluster 2'. Expression of cluster II genes, in contrast, was not significantly different between hepatocellular carcinoma and non-neoplastic liver tissues. Studies conducted to localize the protein products of these genes by immunohistochemical staining of tissue arrays with up to 350 cores of tissues, and by in situ hybridization led to the discovery of novel sinusoidal endothelial cell markers in hepatocellular carcinoma: podocalyxin-like and regulator of G protein signaling-5. Our results underscore fundamental differences not only between neoplastic vs non-neoplastic liver cells but also between the hepatic sinusoidal endothelium of hepatocellular carcinoma and normal liver.