The angiogenic makeup of human hepatocellular carcinoma does not favor vascular endothelial growth factor/angiopoietin-driven sprouting neovascularization

Abstract

Quantitative data on the expression of multiple factors that control angiogenesis in hepatocellular carcinoma (HCC) are limited. A better understanding of the mechanisms underlying angiogenesis in HCC will improve the rational choice of anti-angiogenic treatment. We quantified gene and protein expression of members of the vascular endothelial growth factor (VEGF) and angiopoietin systems and studied localization of VEGF, its receptors VEGFR-1 and VEGFR-2, Angiopoietin (Ang)-1 and Ang-2, and their receptor, in HCC in noncirrhotic and cirrhotic livers. We employed real-time reverse transcription polymerase chain reaction (RT-PCR), western blot, and immunohistology, and compared the outcome with highly angiogenic human renal cell carcinoma (RCC). HCC in noncirrhotic and cirrhotic livers expressed VEGF and its receptors to a similar extent as normal liver, although in cirrhotic background, VEGFR-2 levels in both tumor and adjacent tissue were decreased. Ang-1 expression was slightly increased compared with normal liver, whereas Tie-2 was strongly down-regulated in the tumor vasculature. Ang-2 messenger RNA (mRNA) levels were also low in HCCs of both noncirrhotic and cirrhotic livers, implying that VEGF-driven angiogenic sprouting accompanied by angiopoietin-driven vascular destabilization is not pronounced. In RCC, VEGF-A levels were one order of magnitude higher. At the same time, endothelially expressed Ang-2 was over 30-fold increased compared with expression in normal kidney, whereas Ang-1 expression was decreased. Conclusion: In hepatocellular carcinoma, tumor vascularization is not per se VEGF/angiopoietin driven. However, increased CD31 expression and morphological changes representative of sinusoidal capillarization in tumor vasculature indicate that vascular remodeling is taking place. This portends that therapeutic intervention of HCC at the level of the vasculature is optional, and that further studies into the molecular control thereof are warranted. (HEPATOLOGY 2008;48: 1517-1527

The effects of hepatitis B virus integration into the genomes of hepatocellular carcinoma patients

“…2B). Overexpression of ANGPT1 in HCC has been previously reported (Zeng et al 2008). Interestingly, in patient 31656, the most abundant MIS is in a nongenic region.…”

Angiogenesis: multiple masks in hepatocellular carcinoma and liver regeneration

“…A recent study with human endothelial cells shows that chronic hypoxia attenuates VEGF signaling and angiogenic responses by down-regulation of VEGFR-2 [81]. As stated above, most of HCCs originate from fibrosis and cirrhosis, which undergo chronic hypoxia and VEGFR-2 levels were down-regulated in both tumor and in adjacent tissue [78], preferring intussusceptive angiogenesis instead of sprouting angiogenesis. Besides, the rate of endothelial cell proliferation is low in a cirrhotic background [82], further suggesting that another mechanism different from sprouting angiogenesis might exist.…”

“…2). However, a recent paper challenges this conception [78]. Zeng et al investigated gene and protein expression levels of VEGF-A, VEGFR-1, VEGFR-2, Ang-1, Ang-2, and Tie-2 using quantitative (real-time) reverse transcription polymerase chain reaction and Western blot analysis in tumors, adjacent liver tissues, and normal liver tissues.…”

“…The hypothesis that vessel co-option exists in HCC is put forward by Zeng et al without further testing due to the lack of a vascular marker for endothelial co-option [78]. However, accumulating evidence supports the hypothesis that co-option does exist in HCC.…”

The patterns and expression of KDR in normal tissues of human internal organs

“…Moreover, VEGFR-2 (KDR) has been implicated in playing an important role in the formation of new blood vessels in tumors and other diseases (Ferrara 2005;Shibuya 2001;Dvorak 2002). KDR expression has been reported in various types of solid tumor, such as human thyroid tumor (Donckier et al 2006;Jebreel et al 2007), tumors of the digestive system (Zhao et al 2003;Iavarone et al 2007;Yamaguchi et al 2000;Zeng et al 2008;von Marschall et al 2001;Amaoka et al 2006;Jia et al 2009;La Rosa et al 2003;Gockel et al 2008), tumors of the female genital system (Chen et al 2004;Yoshinaga et al 2008) and others. These results indicate that KDR expression may possibly be used as a potential diagnostic and therapeutic target for solid tumors (Kiselyov et al 2007).…”