Understanding Angiogenesis and the VEGF Ligand

Fig. 1. Pathologic angiogenesis^2-4

To grow beyond 1 to 2 mm in diameter, a tumor needs an independent blood supply, which is acquired by expressing growth factors that recruit new vasculature from existing blood vessels. This process continues even as the tumor matures.

Angiogenesis is a hallmark of tumor development

While there are more than 100 distinct types of cancer (and considerable heterogeneity within each tumor type), the mechanisms that fuel tumor growth and survival are relatively similar. Across most—if not all—malignancies, sustained angiogenesis is considered to be one of these central "hallmarks" of cancer.¹

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 (Fig. 1). The disruption of the delicate balance of pro- and anti-angiogenic factors, which is often referred to as the angiogenic switch, results in the creation and maintenance of a growing vascular network.^2-4

The VEGF ligand is a predominant regulator of tumor angiogenesis

While numerous pro-angiogenic factors have been characterized, the VEGF ligand has been identified as a predominant regulator of tumor angiogenesis.³

The VEGF ligand may affect tumor vasculature in 3 essential ways (Table 1). Early in tumor development, VEGF may help new vasculature establish. Specifically, VEGF has been shown to stimulate tumor growth at both primary and metastatic sites through the recruitment of bone-marrow–derived progenitor cells that form the building blocks of a new vascular network. As this network develops, VEGF may continue to help new vasculature grow, providing the blood supply needed to drive further tumor growth and metastasis. Throughout tumor development, VEGF may also help existing vasculature survive, allowing tumors to sustain their metabolic requirements over their entire life cycle.⁵

Table 1: Proposed effects of the VEGF ligand⁵

The VEGF ligand is continuously expressed and genetically stable

The VEGF ligand is known to be present throughout the tumor life cycle
(Fig. 2). 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 (PIGF), and platelet-derived endothelial cell growth factor (PD-ECGF). As these secondary pathways emerge, the VEGF ligand continues to be expressed and remains one of the critical mediators of angiogenesis.^6-12

Fig. 2. VEGF is known to be expressed throughout the tumor life cycle^6-8

VEGF is expressed throughout the tumor life cycle. As the tumor matures, secondary angiogenic factors may be increasingly produced.

The observation that some tumors are 1) highly dependent on VEGF early in development and 2) continuously dependent on VEGF throughout their life cycle is reflected by preclinical research with VEGF inhibitors. In these experiments, VEGF inhibition has demonstrated significant antitumor effects when administered throughout tumor development.^13,14

Finally, although the amount of VEGF that is produced and released may change in response to certain stimuli within the tumor environment, VEGF is thought to be a genetically stable protein that may be relatively unsusceptible to mutation.^3,15 This genetic stability may make continued targeting of the VEGF ligand a rational antitumor strategy.

High levels of VEGF expression have been observed across a wide range of solid tumors

Expression of the VEGF ligand has been observed across a range of tumor types and has been widely correlated with tumor development and/or poor prognosis.^2,3,16

Because it drives tumor growth through multiple stages of development, direct and continuous inhibition of the VEGF ligand is a rational antitumor strategy.

References:

1.

Hanahan D, Weinberg RA. Cell. 2000;100:57-70. PMID: 10647931

2.

Ferrara N. Endocr Rev. 2004;25:581-611. PMID: 15294883

3.

Hicklin DJ, Ellis LM. J Clin Oncol. 2005;23:1011-1027. PMID: 15585754

4.

Bergers G, Benjamin LE. Nat Rev Cancer. 2003;3:401-410. PMID: 12778130

5.

Ellis LM, Hicklin DJ. Nat Rev Cancer. 2008;8:579-591. PMID: 18596824

6.

Folkman J. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles & Practice of Oncology. Vol 2. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:2865-2882.

7.

Hanrahan V, Currie MJ, Gunningham SP, et al. J Pathol. 2003;200:
183-194. PMID: 12754739

8.

Fontanini G, Vignati S, Boldrini L, et al. Clin Cancer Res. 1997;3:861-865. PMID: 9815760

9.

Rini BI, Small EJ. J Clin Oncol. 2005;23:1028-1043. PMID: 15534359

10.

Jain RK, Duda DG, Clark JW, Loeffler JS. Nat Clin Pract Oncol. 2006;3:
24-40. PMID: 16407877

11.

Bergers G, Brekken R, McMahon G, et al. Nat Cell Biol. 2000;2:737-744. PMID: 11025665

12.

Inoue M, Hager JH, Ferrara N, et al. Cancer Cell. 2002;1:193-202. PMID: 12086877

13.

Gerber HP, Ferrara N. Cancer Res. 2005;65:671-680. PMID: 15705858

14.

Shojaei F, Ferrara N. Drug Resist Updat. 2008,11:219-230. PMID: 18948057

15.

Mukhopadhyay D, Datta K. Semin Cancer Biol. 2004;14:123-130. PMID: 15018896

16.

Margolin K. Curr Oncol Rep. 2002;4:20-28. PMID: 11734110