Antiangiogenic cancer therapy
Section snippets
Tumor neovascularization and blood vessel architectures
Like in healthy tissues, tumor neovascularization may include angiogenesis, vasculogenesis, and intussusception. Angiogenesis represents the process of new blood vessels sprouting from existing vessels. Angiogenesis is the key event in establishment of the tumor vasculature [1], [2]. Recently, vasculogenesis, recruitment of circulating endothelial cells differentiated from stem cells into the newly formed blood vessels, has been found to be critical for tumor neovascularization [3]. In
Angiogenic factor antagonists
According to their targets, angiogenesis inhibitors can be divided into direct and indirect inhibitors. Indirect inhibitors include compounds that mainly antagonize the biological activity of angiogenic factors. More than a dozen of tumor angiogenic factors and cytokines are overexpressed in tumors [10]. Among these angiogenic factors, the vascular endothelial growth factor (VEGF) family has become a central focus in today’s tumor angiogenesis research, simply because most tumors, if not all,
Multiple angiogenic factors are switched on during tumor progression
As the genome of tumor cells is unstable, they constantly undergo genetic mutations which lead to alternations of gene expression patterns. As a result of the genetic mutations, tumors consist of heterogenous cell populations. Thus, expression patterns of pro-angiogenic factors can be altered along tumor progression, and single angiogenic factor antagonists may encounter drug-resistance problems. If a tumor produces angiogenic factors than VEGF such as FGF-2, the tumor may become resistant to
Direct angiogenesis inhibitors
In contrast to single angiogenic factor antagonists, angiogenesis inhibitors that block a common angiogenic pathway would be more effective for cancer treatment. Alternatively, those angiogenesis inhibitors that directly inhibit endothelial cell proliferation, migration, or differentiation would also overcome the drug resistance problem as the genome of endothelial cells is stable. Direct angiogenesis inhibitors include diverse categories of protein inhibitors and chemical compounds. Currently,
Endogenous antiangiogenic protein molecules
Most antiangiogenic protein molecules are endogenous angiogenesis inhibitors. In other words, these inhibitors are isolated from the body or tissue-derived cell lines. As endogenous angiogenesis inhibitors, they are usually not toxic when administered in the body and non-immunogenic [22], [23], [24]. In fact, toxicity or other side effects of endogenous angiogenesis inhibitors, such as angiostatin and endostatin, have not been reported. It appears that several of these angiogenesis inhibitors
Angiostatin and its related fragments
The structure of angiostatin includes the first four-kringle domain of plasminogen. A kringle (kringla in Swedish) is a type of Scandinavian cookie folded into two rings. This term was originally adopted to describe a triple loop structure linked by three pairs of disulfide bonds present in prothrombin. Kringle structure exists in many proteins that can contain anything from one to several kringles. The primary amino acid sequence of each kringle domain is composed of approximately 80 amino
Oral angiogenesis inhibitors
Although many antiangiogenic protein molecules have been shown to effectively block tumor growth and metastasis in mice, their therapeutic values in the treatment of human cancers are still questionable. Several dose and mechanistic related obstacles need to be resolved before a large number of cancer patients can be considered for therapy. According to animal studies, relatively large dosages (20–100 mg/kg) of these angiogenesis inhibitors have to be delivered in order to reach maximal effects
Conclusions
Antiangiogenesis has become one of the most exciting approaches in the development of cancer drugs. There is no doubt that blockage of tumor blood supply will be beneficial for cancer patients. Indeed, many available angiogenesis inhibitors have produced remarkable antitumor effects in animal models. However, it is uncertain if these angiogenesis inhibitors will produce similar effects in human cancer patients. According to cancer therapy history, translation of animal results into clinical
Acknowledgements
This work is supported by research grants of Yihai Cao’s laboratory received from the Human Frontier Science Program, the Swedish Research Council, The Swedish Heart and Lung Foundation, the Swedish Cancer Foundation, the Karolinska Institute Foundation, and the Åke Wibergs Foundation. Y.C. is supported by the Swedish Research Council.
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