Liver CancerThe mechanisms of angiogenesis in hepatocellular carcinoma: Angiogenic switch during tumor progression☆
Section snippets
Tumor angiogenesis
Angiogenesis is required for a variety of physiologic processes and for the progression of tumor growth.1 Direct experimental evidence shows that tumor growth and metastases require new blood vessels, hence blocking angiogenesis could be a strategy to arrest tumor growth, and some antiangiogenic therapies are currently under clinical trials as new antitumor strategies. An avascular tumor rarely grows larger than 2 to 3 mm2, but once a tumor becomes vascularized, the progression of tumor growth
Angiogenic switch in hepatocellular carcinoma
It is generally accepted that hepatocellular carcinoma (HCC) is a hypervascular tumor, and hepatic arterial embolization has been widely used as an effective therapy for HCC.6 However, HCC develops and progresses from a small-sized and well-differentiated HCC with no developed blood vessels to a larger and moderately or poorly differentiated HCC with a characteristic hypervascularity during the dedifferentiation process.7, 8, 9
In small-sized and well-differentiated HCC, arterial vessels are not
VEGFs
VEGF is a major inducer of angiogenesis, and there are 6 structurally related relatives: VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E (also called Orf virus-derived VEGF), and placenta growth factor.11 They interact differently with 3 known receptor tyrosine kinases (VEGFR-1/Flt-1, VEGFR-2/KDR/Flk-1, and VEGFR-3/Flt-4), as shown in Fig 2, A. VEGFR-1 and VEGFR-2
Other angiogenic factors and angiogenesis inhibitors
Other angiogenic factors include basic fibroblast growth factor, transforming growth factor α, and insulin-like growth factor II and antiangiogenic factors include thrombospondin 1, interleukin 12, interferon α/β, angiostatin, and endostatin.21, 35, 36 Thrombospondin 1 is important in the inhibition of angiogenesis both in vitro and in vivo, and Kawahara et al21 reported that the mRNA level of thrombospondin 1 had significantly increased in cholangiocarcinoma, which is known as a hypovascular
Antiangiogenic therapy for HCC
The rapid growth of tumors depends on the development of a neovascular supply, and thus the inhibition of angiogenesis was proposed as a valid strategy for tumor therapy for over 20 years. Various antiangiogenic therapies for cancers, including HCCs, such as the use of gene therapies, monoclonal antibodies, recombinant proteins, and drugs, have been investigated, mostly with animal models.4 Over 20 of these agents are now being tested in clinical trials, but no method has yet been made
Conclusions
HCC is characterized by its unique angiogenic process, and the angiogenic switch is critical for its dedifferentiation and progression. VEGFs and angiopoietins both play important roles in HCC angiogenesis, and as a result, the blocking of these signals could possibly be a promising antitumor therapy for HCC.
Acknowledgements
We thank Dr S. Aishima, Dr Y. Asayama, and Dr S. Matsuura (Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University) for their advice on the pathologic evaluation. We also thank Brian Quinn for his helpful comments on the manuscript.
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Reprint requests: Keishi Sugimachi, MD, Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.