Angiogenesis: a necessary part of the process in the progression of cancer⁴

Figure 1. Tumor angiogenesis

Angiogenesis is a hallmark of tumor development

Angiogenesis is a necessary part of the process in the progression of cancer from small, localized neoplasms to larger, growing, and potentially metastatic tumors. To grow beyond 1 to 2 mm in diameter, a tumor needs an independent blood supply, which is acquired by the expression of growth factors that recruit new vasculature from existing blood vessels (Figure 1). This process continues even as the tumor matures. Thus, upregulation of angiogenesis is a key step in sustained tumor growth and may also be critical for tumor metastasis.^1,4

VEGF is an activator of tumor angiogenesis⁴

VEGF (also known as VEGF-A, but commonly referred to simply as VEGF) stands for "vascular endothelial growth factor." As its name suggests, VEGF stimulates vascular endothelial cell growth, survival, and proliferation.^3,5

VEGF is a member of a family of 6 structurally related proteins (Table 1) that regulate the growth and differentiation of multiple components of the vascular system, especially blood and lymph vessels. The angiogenic effects of the VEGF family are thought to be primarily mediated through the interaction of VEGF with VEGFR-2.^5-8

Table 1. The VEGF protein family^5-7,9,10

The VEGF signaling pathway

VEGF ligands mediate their angiogenic effects by binding to specific VEGF receptors, leading to subsequent signal transduction.¹¹

1. Upstream activators stimulate the production of VEGF.
2. VEGF binds to receptors on endothelial cells.
3. Angiogenesis is mediated primarily through the interaction of VEGF-A with VEGFR-2.
4. Other variants of the VEGF ligand and receptor play a secondary role in this process.

As demonstrated in preclinical models, VEGF plays a central role in tumor development

VEGF may affect tumor vasculature in 3 essential ways⁷:

1. Early in tumor development, VEGF may help establish new vasculature.
2. As the vasculature network develops, VEGF may continue to help new vasculature grow, providing the blood supply needed to drive further tumor growth and metastasis.
3. Throughout tumor development, VEGF may also help existing vasculature survive, allowing tumors to sustain their metabolic requirements over their entire life cycle.

As the tumor develops, it may begin to activate secondary angiogenic pathways, such as basic fibroblast growth factor (bFGF), transforming growth factor beta (TGFβ), placental growth factor (PlGF), and platelet-derived endothelial cell growth factor (PD-ECGF). As these secondary pathways emerge, VEGF continues to be expressed and remains one of the critical mediators of angiogenesis (Figure 1).¹²

Figure 1. Continuous VEGF expression throughout tumor development^12-13

The role of VEGF across tumor types, as demonstrated in preclinical models

Expression of VEGF has been observed across a range of tumor types and has been widely correlated with tumor development and/or poor cancer prognosis.^4,5,7

Inhibition of new and recurrent tumor vessel growth, as demonstrated in preclinical models

Targeting VEGF may result in ongoing inhibition of both new and recurrent tumor vessel growth (Table 1). It has been proposed that these effects may help inhibit tumor growth and metastasis.^1,14

Research also suggests that blockade of VEGF signaling may help inhibit tumor growth by preventing new vessel growth at both primary and metastatic sites.¹

Table 1. Proposed effects of VEGF inhibition^15,16

Regression of existing tumor vasculature, as demonstrated in preclinical models¹⁴

Based on preclinical models, it has also been proposed that VEGF inhibition may regress existing tumor vessels (Table 1). These reductions in microvascular density have been associated with a reduction in tumor volume and weight (Figure 1).^14,17

Figure 1. Microcomputed tomography image showing effect of VEGF inhibition in a preclinical model³