Abstract
The cellular and molecular mechanisms of tumor angiogenesis and its prospects for anti-angiogenic cancer therapy are major issues in almost all current concepts of both cancer biology and targeted cancer therapy. Currently, (1) sprouting angiogenesis, (2) vascular co-option, (3) vascular intussusception, (4) vasculogenic mimicry, (5) bone marrow-derived vasculogenesis, (6) cancer stem-like cell-derived vasculogenesis and (7) myeloid cell-driven angiogenesis are all considered to contribute to tumor angiogenesis. Many of these processes have been described in developmental angiogenesis; however, the relative contribution and relevance of these in human brain cancer remain unclear. Preclinical tumor models support a role for sprouting angiogenesis, vascular co-option and myeloid cell-derived angiogenesis in glioma vascularization, whereas a role for the other four mechanisms remains controversial and rather enigmatic. The anti-angiogenesis drug Avastin (Bevacizumab), which targets VEGF, has become one of the most popular cancer drugs in the world. Anti-angiogenic therapy may lead to vascular normalization and as such facilitate conventional cytotoxic chemotherapy. However, preclinical and clinical studies suggest that anti-VEGF therapy using bevacizumab may also lead to a pro-migratory phenotype in therapy resistant glioblastomas and thus actively promote tumor invasion and recurrent tumor growth. This review focusses on (1) mechanisms of tumor angiogenesis in human malignant glioma that are of particular relevance for targeted therapy and (2) controversial issues in tumor angiogenesis such as cancer stem-like cell-derived vasculogenesis and bone-marrow-derived vasculogenesis.
Highlights
In his landmark 1971 publication, Folkman [41] developed the idea that tumor growth is angiogenesis dependent and described for the first time the potential prospects of antiangiogenic cancer therapy
Napoleone Ferrara, one of the discoverers of vascular endothelial growth factor (VEGF), developed monoclonal antibodies to VEGF [70] that blocked tumor growth in vivo [71] and that paved the way for the development of bevacizumab, a monoclonal anti-VEGF antibody that is used in a large number of clinical cancer trials, including glioblastoma, where anti-angiogenesis represents one treatment arm [104, 131]
The idea that blockade of tumor angiogenesis is able to inhibit tumor growth in vivo has been confirmed in principal in both experimental and clinical settings; current evidence suggests that cancer cells are able to circumvent anti-angiogenic therapy and develop resistance to targeted mono-therapy [7, 129]
Summary
In his landmark 1971 publication, Folkman [41] developed the idea that tumor growth is angiogenesis dependent and described for the first time the potential prospects of antiangiogenic cancer therapy. It took 13 years before fibroblast growth factor (FGF)-2, the first heparinbinding angiogenic growth factor, was identified and 18 years before vascular endothelial growth factor (VEGF), which has turned out to be the single most important angiogenesis factor in both health and disease, was described (for review see [38]). The idea that blockade of tumor angiogenesis is able to inhibit tumor growth in vivo has been confirmed in principal in both experimental and clinical settings; current evidence suggests that cancer cells are able to circumvent anti-angiogenic therapy and develop resistance to targeted mono-therapy [7, 129]
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