[Frontiers in Bioscience E3, 549-561, January 1, 2011]

Complexity of tumor vasculature and molecular targeting therapies

Mitsuko Furuya1, Kiyotaka Nagahama1, Akihiro Ishizu2, Noriyuki Otsuka2, Yoji Nagashima1, Ichiro Aoki1

Department of Pathology1, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan, Department of Pathology2, Hokkaido University Graduate School of Medicine, Sapporo 060-0001, Japan


1. Abstract
2. Introduction
3. Tumor vasculature
3.1. EPCs, HSCs and Gr-1+ CD11b+ BM-derived cells
3.2. Tumor mosaic vessels and tumor vasculogenic mimicry
4. Inhibitory effects of VEGF and related signalings
4.1. VEGF- and PlGF
4.2. Other related molecules
5. G protein-coupled receptors (GPCRs) signalings
5.1. RAS signaling
5.2. Chemokine signaling
6. Symptoms associated with antiangiogenic molecules
6.1. Renal dysfunction
6.2. Hypertension
6.3. Reversible posterior leukoencephalopathy syndrome
7. Perspective
8. Acknowledgment
9. References


Malignant solid tumors require blood supply for their uncontrollable progression. Angiogenic blood vessels generally sprout from preexisting vascular cells. In addition, various types of precursor cells also participate in tumor neovascularization. They include endothelial progenitor cells, hematopoietic stem cells and mesenchymal stem cells that are stimulated and attracted into tumor lesion, in which a wide variety of proinflammatory factors are involved. Among key molecules, vascular endothelial growth factor (VEGF) works as a mastermind regulator. Humanized monoclonal antibodies targeting VEGF-mediated signaling pathways are currently used as the most pervasive drugs in several types of progressive tumors. Adverse effects of these drugs include hypertension and proteinuria. Such symptoms are widely observed in preeclamptic patients whose blood contain high amount of natural VEGF antagonist. Vasoactive G protein-coupled receptors (GPCRs)-mediated signalings such as renin-angiotensin system and chemokine axes are also noticed that they may become effective therapeutic targets. In this review, we discuss general view of angiogenic microenvironment in solid tumors, and highlight several key signaling molecules and inhibitory effects of them on the whole system.