Pathophysiology of tumor neovascularization

Abstract

Neovascularization is essential to the process of development and differentiation of tissues in the vertebrate embryo, and is also involved in a wide variety of physiological and pathological conditions in adults, including wound repair, metabolic diseases, inflammation, cardiovascular disorders, and tumor progression. Thanks to cumulative studies on vasculature, new therapeutic approaches have been opened for us to some life-threatening diseases by controlling angiogenesis in the affected organs. In cancer therapy, for example, modulation of factors responsible for tumor angiogenesis may be beneficial in inhibiting of tumor progression. Several antiangiogenic approaches are currently under preclinical trial. However, the mechanisms of neovascularization in tumors are complicated and each tumor shows unique features in its vasculature, depending on tissue specificity, angiogenic micromilieu, grades and stages, host immunity, and so on. For better understanding and effective therapeutic approaches, it is important to clarify both the general mechanism of angiogenic events and the disease-specific mechanism of neovascularization. This review discusses the general features of angiogenesis under physiological and pathological conditions, mainly in tumor progression. In addition, recent topics such as contribution of the endothelial progenitor cells, tumor vasculogenic mimicry, markers for tumor-derived endothelial cells and pericytes, and angiogenic/angiostatic chemokines are summarized.

Figure 1

Vasculogenesis and angiogenesis during development and differentiation. The mesodermal progenitor cells derived from embryonic stem cells (ESC) differentiate into various vascular and hematopoietic cells. Vascular progenitor cells (VPC) are bi-potentials that can differentiate into either pericyte/vascular smooth muscle cells (VSMC) or endothelial cells (EC) lineage. Hemangioblasts generate the blood island composed of endothelial progenitor cells, also called angioblasts (EPC) and hematopoietic stem cells (HSC). EPC differentiate into EC and form vessel tubes, whereas HSC further differentiate into lymphoid/myeloid lineage. Nascent vessels are stabilized by vascular mural cell coverage and extracellular matrix.

Figure 2

Pathological neovascularization during tumor progression. Tumor tissue secretes various proinflammatory factors and vasoactive substances that sustain neovascularization. Tumor vasculature is supported not only by angiogenesis derived from preexisting vasculature, but also by vasculogenic mimicry and neovascularization from progenitor cells/monocytes. Endothelial progenitor cells (EPC) from the bone marrow and in circulation, hematopoietic stem cells (HSC), and further differentiated cells of the monocytic lineage such as macrophages and dendritic cells potentially contribute to pathological neovascularization; although the percentage of progenitor cells is generally low. Abbreviations: EC, endothelial cells; EPC, endothelial progenitor cells; HSC, hematopoietic stem cells; VEGF, vascular endothelial growth factor; VEGFR-1⁺, fms-like tyrosine kinase-1; VEGFR-2⁺, fetal liver kinase-1/kinase insert domain protein receptor; VSMC, vascular smooth muscle cells.