Angiogenesis in the liver : molecular mechanisms and novel treatment strategies in liver regeneration and tumor metastasis

Angiogenesis in liver regeneration Liver regeneration involves the coordinated proliferation of all major hepatic cell types. There are many indirect but obvious indicators of the speculation that angiogenesis must play an important role in the regeneration process. In the first part of this thesis, we have employed various methods to directly analyze angiogenesis in the regenerating liver. In Chapter 2 we report that liver regeneration following partial hepatectomy is characterized by an increase in microvessel density. The second finding in this chapter has been a delay in regeneration in livers treated with angiostatin. Chapter 3 describes the changes in functional vessel morphology after partial hepatectomy. Functional vessel surface area does not change during the course of regeneration. suggesting that tissue perfusion is constant during this time. This is in contrast with other conditions of angiogenesis such as tumor angiogenesis, where microvessels are highly abnormal and display aberrant perfusion. Apparently, the vascular changes seen during liver regeneration activate an efficient repair mechanism to restore lost tissue without compromising tissue perfusion. In Chapter 4 we report on the contribution of plasminogen and urokinase plasminogen activator to the regeneration process. Mice with a deletion for either plasminogen or urokinase plasminogen activator displayed impaired liver regeneration. Plasminogen is required for revascularization of the hepatocyte clusters that have resulted from hepatocyte proliferation in the liver remnant. Chapter 5 describes that angiostatin can inhibit the development of fibrosis and fibrosis-associated angiogenesis, possibly by leading to a better perfusion of hepatocytes. These results suggest new possibilities to advance antifibrotic therapy. Angiogenesis in liver metastasis Tumor metastasis to the liver is currently associated with poor prognosis. In addition, autopsy studies show that the true prevalence of cancer is much higher than the clinical prevalence would suggest. In a report by Black et al, the prevalence of some cancers in autopsy studies (in non-cancer related deaths) is found to be remarkably higher than the clinical prevalence of these malignancies. It is tempting to speculate that angiogenesis is the rate-limiting step in the progression of these tumors from pre-clinical to clinical extent. This implies that long-term antiangiogenic therapy could be effective in the suppression of liver metatstasis to a subclinical level. In Chapter 6 we have reviewed current aspects of angiogenesis in primary and metastatic liver tumors. There is ample evidence indicating that tumor growth in the liver is influenced by angiogenesis. Rather than killing tumor cells, antiangiogenic agents build a diffusion-limited barrier for tumors by inhibiting new vessel growth. In Chapter 7 we describe the development and effects of a new anti-angiogenic agent, anti-Vn18. We have shown that anti-Vn18 inhibits the attachment of tumor cells and endothelial cells to a vitronectin-coated surface, and that mice treated with anti-Vn18 show reduced tumor cell seeding to the liver