Tumor angiogenesis: pericytes and maturation are not to be ignored

Abstract

Angiogenesis, an essential component of tumor growth and survival, is regulated by complex interactions between several cell types and soluble mediators. Heterogeneous tumor vasculature originates from the collective effect of the nature of carcinoma and the complexity of the angiogenic network. Although the application of angiogenesis inhibitors in some types of cancers has shown clinical benefits, predictive markers to assess treatment effects have yet to be established. In this review, we focus on tumor vessel maturity as a potential marker for evaluating treatment response.

Figure 1

Hypoxia inducible factors (HIFs) and their role in endothelial cell proliferation. HIF-1α is hydroxylated by prolyl hydroxylase domain proteins (PHDs) and degraded in proteasomes under oxygenated conditions. When the oxygen level decreases, PHD activity is reduced, which leads to the accumulation of HIF-1α. Upon formation, the HIF-1α/β complex activates the transcription of numerous genes. Hypoxia and HIF-1α enhance the expression of VEGFR2, which induces DLL4 expression in the tip cell. Furthermore, DLL4 interacts with the Notch intracellular domain and increases its activity, which increases endothelial cell proliferation. Upregulation of HIF-2α due to lower degradation activates the junctional protein vascular endothelial cadherin (VE cadherin). VE cadherin induces a normalized endothelial phenotype by inhibiting VEGF-driven proliferation and upregulating the soluble isoform of the VEGF-trap VEGFR1 [12].

Figure 2

Delta-like ligand 4 (DLL4) and its expression in bone marrow-derived cells. The expression level of DLL4 dictates the role of bone marrow-derived cells in the neovasculature. DLL-4-Notch signaling controls tip cell versus stalk cell fate in endothelial cells and has a regulatory effect on pericyte formation [66].

Figure 3

Tumor cell-derived PDGF-B induced pericyte differentiation. Incorporation of pericytes into newly formed vessels is one of the key steps to terminate angiogenesis. Studies in animal models have shown that PDGF-B is responsible for (1) differentiation of pericytes from mesenchymal stem cells through the PDGF-B-NRP-1 signaling pathway (2) increased recruitment and attachment of newly differentiated pericytes into newly formed tumor vessels. In addition, Flk1+ cells differentiate into endothelial cells or pericytes upon stimulation by VEGF or PDGF-B [72].

Figure 4

Negative regulation of angiogenesis by the PlGF-VEGFR1-mediated signaling pathway. In PlGF-producing mouse Lewis lung and human tumors, the tumor vasculature that is induced by PlGF-1 and -2 is covered by pericytes and is less leaky compared to the tumor vasculature that is induced by VEGF-A. This result might be caused by the formation of angiogenically inactive PlGF-VEGF heterodimers [74].

Figure 5

Double-immunostaining of pericytes and endothelial cells in breast cancer. Double immunostaining for CD31 (red) and α-SMA (brown) is shown. The blue arrow indicates a vessel that is CD31+/α-SMA+; the red arrowheads indicate vessels that are only CD31+. Magnification × 200.