Use of Immunodeficient Mice for the Evaluation of CXC Chemokines in the Regulation of Tumor-associated Angiogenesis

Abstract

Angiogenesis, defined as the growth of new capillaries from pre-existing vessels, is a pervasive biological phenomenon that is at the core of many physiologic and pathologic processes such as tumor growth. The use of human tumor xenografts in immunodeficient mice has provided significant insight into the biology of angiogenesis as it relates to tumor growth and metastasis. Work reviewed in this article supports the notion that net tumor-derived angiogenesis during tumorigenesis of human tumors is determined, in part, by an imbalance in favor of the overexpression of angiogenic (compared with angiostatic) juxtaposed cysteine residue (CXC) chemokines. This paradigm predicts an environment that favors angiogenesis (tumorigenesis) and supports the potential for spontaneous metastases. The article describes the use of immunodeficient mice as an animal model system for characterizing the qualitative and quantitative presence of these angiogenic and angiostatic CXC chemokines during tumorigenesis, as well as determining their net contribution to human tumorigenesis and metastasis in vivo. Various cancer cell lines have been used and xenografted into immunodeficient mice to create human tumor/mouse chimeras, indicating that an imbalance in the biology of angiogenic versus angiostatic CXC chemokines supports a significant portion of human tumor-derived angiogensis that leads to augmented tumorigenesis and spontaneous metastases. It has also been possible to identify potentially therapeutic novel strategies to manipulate the imbalance of angiogenic (compared with angiostatic) CXC chemokines, which may be directly translational to human disease.