Surrogate Markers of Angiogenesis and Metastasis
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Angiogenesis, the formation of new blood vessels from a preexisting vascular network, is a complex multistep process under the control of positive and negative factors (bi1 ,bi2 ). Growth, progression, and metastasis of malignant tumors are angiogenesis-dependent processes (3 -bi5 ). There is compelling evidence that development of angiogenic phenotype is a common pathway in the biology of tumor progression and metastasis, and the angiogenesis is correlated with other molecular mechanisms (e.g., the control of wild-type p53 on vascular endothelial growth factor or thrombospondin-1) (6 ,7 ). Angiogenesis can be directly determined, and so it may be useful as a biomarker (8 -bi10 ). Tumor microvessel density (11 -13 ) or tissue angiogenic factors expression may predict which patients are at different risk of metastasis (14 -16 ), and serum levels of angiogenic factors may serve as tumor markers (17 ,18 ).
At present the most widely used method to assess angiogenesis is quantification of intratumoral microvessel density (IMD) of the primary tumor by using specific markers for endothelial cells such as factor VIII-related antigen (FVIII-RA), anti-CD31 (platelet endothelial cell adhesion molecule, PECAM), or anti-CD34 antibodies (19 ,22 ), using a standard immunocytochemistry immunoperoxidase technique to stain micro vessels (23 ,24 ). The basic principles of immunocytochemistry are described in Chapter 2 by Brooks and use of immunocytochemistry employing antibodies against factor VIII-related antigen and CD31 is described in Chapter 8 by Turner and Harris.
