Endothelial progenitor cells in tumor angiogenesis: another brick in the wall

Abstract

Until 15 years ago, vasculogenesis, the formation of new blood vessels from undifferentiated cells, was thought to occur only during embryonic development. The discovery of circulating cells that are able to promote vascular regeneration and repair-the so-called endothelial progenitor cells (EPCs)-changed that, and EPCs have since been studied extensively. It is already known that EPCs include many subtypes of cells that play a variety of roles in promoting vascular growth. Some EPCs are destined to differentiate into endothelial cells, whereas others are capable of promoting and sustaining angiogenesis through paracrine mechanisms. Vasculogenesis and angiogenesis might constitute complementary mechanisms for postnatal neovascularization, and EPCs could be at the core of this process. Although the formation of new blood vessels from preexisting vasculature plays a beneficial role in many physiological processes, such as wound healing, it also contributes to tumor growth and metastasis. However, many aspects of the role played by EPCs in tumor angiogenesis remain unclear. This review aims to address the main aspects of EPCs differentiation and certain characteristics of their main function, especially in tumor angiogenesis, as well as the potential clinical applications.

Figure 1

Adult endothelial progenitor cell phenotype (ACs: angiogenic cells; ECs: endothelial cells; EOCs: endothelial outgrowth cells; HSCs: hematopoietic stem cells; VEGFR: vascular endothelial growth factor receptor). Hemangioblasts derived from pluripotent stem cell can differentiate into HSCs and angioblasts. The HSCs give rise to blood cells, such as monocytes and ACs. Whether monocytes can act as ACs and vice versa is still controversial. Angioblasts give rise to endothelial cell lineage, including EOCs. Circulating endothelial cells can arise from the detachment of mature ECs and repair other areas of endothelium damage or can arise from the differentiation of ACs.

Figure 2

EPCs are the major players in new vessel formation contributing to tumor growth and metastasis. They might be recruited from bone marrow and migrate to the tumor (on the left) or either reside within tumor stroma, where there are other stem/progenitor cells that promote and/or contribute to new vessel formation (on the right: ACs: angiogenic cells; BMSCs: bone marrow-derived stem cells; ECM: extracellular matrix; EOCs: endothelial outgrowth cells; EPCs: endothelial progenitor cells; HSCs: hematopoietic stem cells; MMP: metalloproteinase; MSCs: mesenchymal stem cells; NO: nitric oxide; VEGF: vascular endothelial growth factor). Figure adapted from Melero-Martin and Dudley [30] (license number 3593771424850).