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Angiogenesis, the formation and maintenance of blood vessel structures, is indispensable for the physiological functions of tissues and is crucial for the progression of diseases such as inflammation and cancer. In recent decades, varieties of signaling molecules, such as VEGF-VEGFRs, angiopoietin-Tie, ephrin-Eph receptors, and the Delta-Notch system, have been identified as playing important roles in angiogenesis. Among these, vascular endothelial growth factors (VEGFs) and receptors (VEGFRs) regulate both vasculogenesis, the development of blood vessels from precursor cells during early embryogenesis, and angiogenesis, the formation of blood vessels from pre-existing vessels at a later stage.
Figure 1. The VEGF and VEGFR system.
This VEGF, also referred to as VEGFA, is a member of a larger family of growth factors that also includes VEGFB, VEGF-C, VEGF-D, PlGF (placental growth factor), VEGF-E (Orf-VEGF), and Trimeresurus flavoviridis svVEGF. These family members differ in their expression pattern, biological functions and receptor specificity. Except for the latter 2 members, 5 genes of the VEGF family exist in mammalian genomes, including humans. Basically, all the VEGFs have 8 conserved cysteine residues at fixed positions, which are very similar to the PDGF family such as M-CSF (CSF-1), Flt3L (Flt3 ligand), and SCF (stem cell factor). Among the 8 cysteines, 6 residues form 3 S-S intramolecular bonds and generate 3 loop structures. The remaining 2 cysteines form 2 S-S intermolecular bonds, contributing to the stable homodimer structure of VEGF.
VEGF receptors on tumor cells
It has become apparent that the function of VEGF is not limited to angiogenesis and vascular permeability. For example, VEGF can affect the function of immune cells that are present in the tumor microenvironment and, therefore, it can affect the host response to tumors. Furthermore, VEGF receptors could regulate the function of fibroblasts in the tumor stroma. One of the most interesting developments is the discovery that autocrine and paracrine VEGF signaling occurs in tumor cells and that this signaling contributes to pivotal aspects of tumorigenesis, especially the function of cancer stem cells, independently of angiogenesis. Signaling downstream of VEGF in tumor cells is mediated by VEGF receptor tyrosine kinases (RTKs) and neuropilins (NRPs). The NRPs have a major role in this signaling because of their ability to interact with and to affect the function of multiple integrins and RTKs.
Figure 2. VEGF functions in tumors
A number of studies that have observed VEGF signaling in tumor cells have characterized this signaling as autocrine, although paracrine signaling does occur. In addition, the existence of autocrine VEGF signaling in human tumors is supported by the observation that VEGF is expressed in tumor cells, as shown by immunohistochemical data, as well as by in situ hybridization and by analysis of microdissected tumor cells. This reliance on autocrine signaling might reflect the importance of VEGF in sustaining the self-sufficiency or autonomy of tumor cells — a consideration that is highly relevant to aggressive cancers and to the biology of cancer stem cells. Indeed, autocrine VEGF signaling is generally characteristic of more aggressive cancers, including poorly differentiated carcinomas. More fundamentally, poorly differentiated carcinomas show an embryonic gene expression pattern and the activation of key developmental pathways. There are some data that implicate such pathways in the regulation of VEGF and VEGFR expression in tumor cells. Therefore, these data provide a causal link between tumor dedifferentiation and the activation of autocrine VEGF signaling, but further investigation is needed.
VEGF-targeted therapy is used for the treatment of a number of cancers. Currently, antibody-mediated inhibition of VEGF using bevacizumab is the predominant mode of VEGF-targeted therapy. The prevailing idea is that such therapy targets angiogenesis and other endothelial cell functions, and this aspect of VEGF-targeted therapy has been extensively studied. It was approved for the treatment of previously untreated metastatic colorectal cancer (mCRC), in combination with chemotherapy. And it is also approved to treat advanced non-squamous non-small cell lung (NSCLC), metastatic renal cell carcinoma (RCC), and, only in Europe, metastatic breast cancer, in conjunction with chemotherapy, and as a single agent in adult patients with recurrent multiforme glioblastoma.
Recently, a new anti-angiogenic molecule able to block the activity of VEGF-A, VEGF-B and PlGF, previously known as VEGF-trap, has been approved for cancer therapy. Aflibercept is a recombinant fusion protein consisting of VEGF-A-binding extracellular domains of VEGFR1 and VEGFR2 fused to the Fc portion of human. It plays as a decoy receptor and has been approved in combination with chemotherapy for the treatment of mCRC, which results resistant to or has progressed following treatment with chemotherapy. The other class of anti-angiogenic drugs approved for cancer therapy is represented by the tyrosine kinase inhibitors (TKIs) able to interfere with VEGFR-1 and/or VEGFR-2 signaling (Figure 3). The TKIs are per definition multitarget drugs, and, interestingly, some of the approved molecules can also interfere with other receptors involved in angiogenic signaling, such as PDGF, FGF and TIE receptors. Subsequently, several anti-angiogenic TKIs have been approved for cancer therapy.
Figure 3. Pro-angiogenic growth factors and receptors of VEGF family and anti-VEGF drugs.
Indeed, because of VEGF pathways inhibition, hypoxia increases resulting in the upregulation of proangiogenic factors, such as FGFs, PlGF, ephrins, and chemokines, and in the recruitment of proangiogenic bone marrow-derived cells, including TAMs and TEMs, which induce the rescue of tumor vascularization. Furthermore, it has been reported that after VEGF blockade cancer cells can aggressively migrate into normal tissue, while tumor vessel normalization prevents metastatic spread, data that open a key question on whether anti-angiogenic treatment may result in more invasive and metastatic tumors.
Conclusions and future perspectives
The realization that autocrine VEGF signaling can be important for tumor initiation and for the characteristics of highly aggressive cancers offers a promising opportunity for the development of new therapeutic approaches. Such approaches are particularly intriguing because NRPs seem to be essential for this VEGF signaling and can be therapeutically targeted using currently available reagents. Nevertheless, this excitement is tempered by the complexities that are associated with targeting VEGF and VEGF receptors, including potential toxicity, the possibility that cells resistant to such therapy can be highly aggressive and the possibility that compensatory signaling mechanisms may offset potential benefits. The development of more effective strategies will probably involve approaches that target tumor cells more specifically and the use of a combination of therapeutic reagents that overcome the resistance caused by targeting single molecules.