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Why is the VEGF ligand essential throughout tumor development?

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 overexpression 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 the predominant regulator of tumor angiogenesis

While numerous pro-angiogenic factors have been characterized, the VEGF ligand has been identified as the 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

	Helps tumor vessels ESTABLISH	Helps tumor vessels GROW	Helps tumor vessels SURVIVE
Proposed mechanism	Recruitment of progenitor cells to primary and metastatic sites	Stimulation of endothelial cell proliferation, migration, and invasion	Inhibition of endothelial cell apoptosis
Effect on tumor growth	Helps tumor cells seed and form premetastatic niches	Provides the blood supply needed for tumors to grow beyond 1 to 2 mm	Maintains a vascular network that fuels continued tumor growth and survival

The VEGF ligand is continuously expressed and genetically stable

The VEGF ligand is the only angiogenic factor known to be present throughout the entire 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 (TGFß), placental growth factor (PlGF), and platelet-derived endothelial cell growth factor (PD-ECGF). As these secondary pathways emerge, the VEGF ligand continues to be overexpressed and remains one of the critical mediators of angiogenesis.^6-9

Fig. 2. Only VEGF is known to be expressed throughout the entire tumor life cycle⁶

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

The observation that 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.^10,11

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.^3,12 This genetic stability may make continued targeting of the VEGF ligand a rational antitumor strategy.

VEGF ligand overexpression has been observed across a wide range of solid tumors

Overexpression of the VEGF ligand has been observed across a range of tumor types—including colon, lung, breast, renal, glioblastoma, ovarian, prostate, and other cancers—and has been widely correlated with tumor development and/or poor prognosis.^2,3,13

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

Further exploration

• Detailed look: The VEGF ligand and angiogenesis
• Related topic: What are the strategies for inhibiting the VEGF pathway?
• Detailed look: The history of VEGF and angiogenesis research

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References:

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

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

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

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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.

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

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

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

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

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

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

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