Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), was originally described as an endothelial cell-specific mitogen. VEGF is produced by many cell types including tumor cells, macrophages, platelets, keratinocytes, and renal mesangial cells. The activities of VEGF are not limited to the vascular system; VEGF plays a role in normal physiological functions such as bone formation, hematopoiesis, wound healing, and development. Therapeutics targeting VEGF have improved the therapy of several types of human cancer during recent years. VEGF was identified as the main regulator of tumor angiogenesis over decades ago.
Among all ligand-receptor interactions of VEGF family members, the binding of VEGF to VEGFR2 is regarded as being critical for the regulation of tumor angiogenesis and the inhibition of this interaction is the main target of anti-VEGF therapeutics. In fact, VEGFR2 has been shown to regulate vascular endothelial cell proliferation and migration as well as vascular permeability. These effects are mediated through downstream activation of various signaling pathways including the PI3K pathway, the MAPK/extracellular-signal-regulated kinase (ERK) pathway, and others. In addition to VEGFR2, the activation of Neuropilin, an additional receptor for VEGF-A, has been reported to enhance VEGFR2 signaling in vascular endothelial cells.
Several experimental studies have shown the effect of anti-VEGF treatment on various aspects of tumor angiogenesis. These include the inhibition of vessel growth and endothelial proliferation, the induction of endothelial cell apoptosis and the blockade of the incorporation of haematopoietic and endothelial progenitor cells. Furthermore, anti-VEGF therapeutics induce vasoconstriction through the inhibition of a VEGF-dependent release of vasodilatators and counteract the VEGF-dependent increase in vascular permeability. Another important observation is the 'normalization' of the tumor vasculature through anti-VEGF treatment. This concept is based on the observation that the irregular vessel architecture of tumors can be converted to a hierarchical and highly ordered structure as seen in normal vascular networks following VEGF-inhibition. This vessel normalization has been proposed to redistribute blood flow in tumor tissue and to improve the delivery of anti-neoplastic agents to individual tumor cells.
Beside the effect on tumor vessels, VEGF can also modulate the immune system. For instance, VEGF inhibits dendritic cell differentiation and thereby prevents an efficient host anti-tumor immune response. Furthermore, VEGF promotes the adherence of leukocytes to the vascular endothelium and the release of pro-inflammatory cytokines, such as IL-6 and TNFa, which support tumor development in chronic inflammatory diseases.
Furthermore, several studies have shown that VEGF can regulate tissue repair and organ regeneration through the release of several endothelial mediators. These factors include various growth factors, such as platelet-derived growth factor or hepatocyte growth factor, vasoactive factors, factors that are critical for coagulation and fibrinolysis, various cytokines, adhesion molecules and many others.
Current studies additionally suggest a direct influence of VEGF on tumor cells. Various types of cancer cells can express VEGFR1 or VEGFR2 VEGF promotes tumor cell proliferation through activation of VEGFR1 in addition to EGFR signaling. Furthermore, we found upregulation of VEGFR2 on intestinal epithelial cells through the proinflammatory cytokine IL-6 with a subsequent contribution of VEGF-signaling to tumor cell proliferation in a mouse model of colitis-associated cancer .
In addition to the effects of VEGF on angiogenesis and tumor growth, a systemic role for VEGF has been shown that might contribute to the so-called cancer-associated systemic syndrome (CASS), which affects most patients with advanced tumor stages. Elevated circulating levels of VEGF in patients with cancer induce vascular alterations in non-tumor-bearing organs, which contribute to the development of CASS, and anti-VEGF treatment can reverse these effects of VEGF.
Although VEGF is involved in the pathophysiology of tumor development through all these mechanisms, the relative contribution of individual modes of action may vary among different tumor types.
Bevacizumab was approved for the first-line treatment of metastatic colorectal cancer by the FDA in 2004. Following these encouraging results, bevacizumab was tested for the treatment of several other types of cancer and, in addition to metastatic colorectal cancer, finally approved for the treatment of metastatic renal cell carcinoma, glioblastoma and NSCLC as stated above.
Aflibercept (also called VEGF-Trap) is a recombinant fusion protein composed of a decoy receptor based on VEGF receptors fused to an Fc segment of IgG1. The primary endpoint for the second-line treatment of metastatic colorectal cancer was met in the VELOUR Phase III trial (aflibercept versus placebo in combination with irinotecan and 5-FU [FOLFIRI] in the treatment of patients with metastatic colorectal cancer after failure of an oxaliplatin based regimen) and therefore supports an approval of aflibercept for the treatment of this type of cancer.
Multi-targeted tyrosine kinase inhibitors: several multitargeted tyrosine kinase inhibitors (TKIs) have been developed, which block the signal transduction of VEGF receptors. These include sorafenib, which has been approved for the treatment of metastatic renal cell cancer and unresectable hepatocellular carcinoma, sunitinib, which has been approved for the treatment of metastatic renal cell cancer, progressive neuroendocrine tumors of the pancreas and gastrointestinal stromal tumors, and pazopanib, which has been approved for the treatment of advanced renal cell carcinoma.
Although anti-VEGF therapy has improved the treatment of several types of cancer during recent years, several questions still remain unanswered. For instance, in some patients, cancer develops resistance to anti-VEGF therapeutics following initially successful therapy, whereas others never show a response. Therefore, a more detailed knowledge of the molecular mechanisms involved in VEGF signaling and predictive biomarkers for a response to anti-VEGF therapy are among the most important challenges for VEGF research today.
Waldner M J, et al. Targeting the VEGF signaling pathway in cancer therapy[J]. Expert opinion on therapeutic targets, 2012, 16(1): 5-13.
Duffy A M, et al. Vascular endothelial growth factor (VEGF) and its role in non-endothelial cells: autocrine signalling by VEGF[J]. VEGF and Cancer, 2004: 133-144.