Signaling through all the receptors for VEGFs may be active in endothelial cells in tumors. VEGF pathways are critical for developmental neovascularization, and is the only known factor to produce embryonic lethality after heterozygous deletion [67,68]. In fact, even mutations that result in subtle changes in VEGF expression, regardless of direction, result in embryonic lethality . Similarly, embryos null for VEGFRs are embryonically lethal [70,71]. Generally, VEGFR-1 and VEGFR-2 are expressed on vascular endothelium, whereas VEGFR-3 is expressed on lymphatic endothelial cells, but this specificity does not apply to tumor endothelial cells. All these three VEGFRs are tyrosine kinase receptors, in contrast to NP-1 and NP-2, which lack an intracellular tyrosine kinase domain. VEGF homo- or heterodimers bind to VEGFR-1 or VEGFR-2, resulting in receptor dimerization and activation. NP-1 can associate with the VEGFRs and modulate their signaling . This stimulates cellular signaling cascades that direct the migration and proliferation of vascular endothelial cells into organized vascular structures. Signaling via VEGFR-2 in endothelial cells is recognized as the main angiogenic pathway. Activation of this pathway leads to increased vascular permeability, endothelial cell survival and, to a lesser extent, proliferation. Signaling via VEGFR-1 is distinct from VEGFR-2 and is thought to be involved primarily in cell migration and production of proteases such as matrix metalloproteinase 9 (MMP-9 or gelatinase B ). Nevertheless, an interaction between VEGFR-1 and VEGFR-2 signaling has also been reported . Several downstream pathways have been described for VEGFRs, some of which are common to VEGF-VEGFR and other pathways such as Ang-1-Tie-2, FGF-FGFR, and others. They include MAPK, Raf, PI3K, Src, and eNOS, among others, and their activation is responsible for the increase in vascular permeability, and the proliferation, survival, and migration of endothelial cells .
Tie-2 is a receptor ubiquitously expressed by endothelial cells, including endothelial cells in tumors. Ang-1 activation of Tie-2 conveys a potent survival signal, which mediated via PI3K. Both the Ang-1 and Tie-2 deficiencies cause embryonic lethality in mice [74,75]. Ang-2 is a hypoxia-responsive product, and it is believed to antagonize with the effect of Ang-1 (i.e., including induction of apoptosis in endothelial cells ). Nevertheless, it has been shown also to activate Tie-2, in a context-dependent manner [77,78].
Other proangiogenic factors affect, in addition to endothelial cells, a variety of other cells. Signaling by FGFs (which comprise over 20 family members) via the FGFRs potently induces endothelial cell proliferation. The chemokine IL-8 (also referred to as CXCL8) has been shown to be expressed in response to nuclear factor kappa B (NFkB) activation and to mediate angiogenesis in some tumors such as gliomas by signaling through IL-8R on tumor endothelial cells . In the absence of hypoxia-inducible factor-1a (HIF-1a) IL-8 may be mediated by hypoxia and be an alternative angiogenic pathway to VEGF . Another hypoxia-responsive factor is SDF-1, which may signal through its receptor CXCR4, and stimulates angiogenesis in a synergistic manner with VEGF . The bidirectional Eph-Ephrin signaling in endothelial cells has also been shown to play a role in tumor angiogenesis, although the mechanisms are poorly understood . Recently, Notch has been shown to be activated in endothelial cells via MAPK, and to be involved in tumor angiogenesis in multiple cancer types [65, summarized in 80b]. PDGF is another complex pathway that can be active in endothelial cells. PDGF receptor-a (PGDFR-a) is typically present on endothelial cells, but endothelial cells in some tumors may also express PGDFR-p [80c]. These two pathways may play important roles in tumor angiogenesis [61,81]. BDNF and neurotrophin-4 (NT-4) can act on their cognate receptor tyrosine kinase TrkB in endothelial cells and induce angiogenesis [66,82]. In fact, in addition to BDNF and Ephrins, a series of molecules common to neurogenesis and angiogenesis have been recently described for their role in vascular branching, and they include semaphorins, netrins, and slits . Finally, certain integrins may play important roles in tumor angiogenesis. Integrins are heterodimeric receptors, which connect cells to extracellular matrices and transduce intracellular signals important for cell survival, adhesion, and migration. In tumors, expression of avp3, avp5, a5Pj, and a6p4 has been described for both endothelial and tumor cells [84,85]. Surprisingly, integrin knockout mice showed enhanced pathological angiogenesis, whereas antiangiogenic results were obtained with the inhibitors . Nevertheless, disruption of individual integrins using antibodies or small-molecule inhibitors produced encouraging results in animal models, and some of these drugs are now in clinical trials . The results in clinical trials of the avp5 and avp3 antagonists will be the key in establishing the appropriate targeting approach for integrins.
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