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Cancer and Angiogenesis

Introduction

In general, tumor vasculature is more chaotic and less effective than normal vasculature. In normal tissue, new blood vessels are constructed in a systematic way, so circulation is able to deliver oxygen and nutrients, and remove waste products and excessive fluid (see Figure 1). Tumor vasculature is characterized by blood vessels connected in apparently random ways, creating loops and dead ends. The structure of the capillaries is also inconsistent due to recruitment of tumor cells and incomplete assembly of basement membrane. The resulting capillaries are “leaky” and inefficient in removing lymph fluid (see Figure 2).
Angiogenesis is critical for tumors to evolve from a dormant (benign) to a malignant state. Those growths that do not initiate the growth of their own vasculature remain dormant. It is not until the composition of the tumor microenvironment shifts to encourage blood vessel growth that the tumor becomes malignant, increasing its growth rate and ability to metastasize. Hanahan and Folkman called this the "angiogenic switch", and hypothesized that the balance of angiogenic inducers and angiogenic inhibitors must shift from predominantly inhibitory to predominantly active.2
The tumor microenvironment is another crucial component in the development of vasculature. Changes in signaling and endothelial cell recruitment and evolution produce heterogeneous changes in the extracellular matrix of the tumor. Folkman suggested a two-compartment system to create vasculature, requiring both tumor cells and endothelial cells in the microenvironment. The endothelial cells go into a rapid-growth, vascular construction state.3 This has provided another route to developing therapies; instead of targeting the solid tumor with its physical challenges, alternative therapies target the endothelial cells and microenvironment to prevent the construction of new capillaries.
The National Cancer Institute of the U.S. NIH has identified four strategies being used to identify and design anti-angiogenic therapies.
  • Block the ability of the endothelial cells to break down the surrounding matrix
  • Inhibit normal endothelial cells directly
  • Block factors that stimulate angiogenesis
  • Block the action of the endothelial cell surface protein, integrin.
Angiogenic pathways and mechanisms continue to be discovered. The secreted frizzle-related protein-2 (SFRP2) has been identified as an angiogenic activator protein, and FK506 (Cat. No. F4679) was successfully used to inhibit angiosarcoma by blocking SFRP2 signaling.5 Prosapondin, a protein secreted by tumor cells, stimulates the activity of the tumor suppressor enzyme p53, which subsequently increased the expression of the angiogenic inhibitor thrombospodin-1.6 Compounds that affect other cellular mechanisms not associated with cancer have been shown to have angiostatic or angiogenic properties. For example, the osteoclast-inhibiting bisphosphonates neridronate (Cat. No. N6037) and clodronate (Cat. No. D4434) demonstrated inhibition of angiogenesis in both in vitro and in vivo experiments.7,8
This issue of BioFiles discusses some of the main processes of angiogenesis, the contribution of the tumor microenvironment to angiogenesis, and recent theories and therapies being investigated to prevent angiogenesis or improve chemotherapeutic drug delivery to the tumor through changes in the microenvironment.

References

  1. Tumor angiogenesis: therapeutic implications. Folkman, J., N. Engl. J. Med., 285, 1182-6 (1971).
  2. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Hanahan, D., and Folkman, J., Cell, 86, 353-64 (1996).
  3. Tumor-vascular interactions and tumor dormancy (Review). Naumov, G.N., et al., APMIS, 116, 569-585 (2008).
  4. “Angiogenesis inhibitors in cancer research”, National Cancer Institute, U.S. National Institutes of Health, www.cancer.gov/newscenter/angio, accessed June 30, 2009
  5. Secreted frizzle-related protein 2 stimulates angiogenesis via a calcineurin/NFAT signaling pathway. Courtwright, A., et al., Cancer Res., 69, 4621-9 (2009).
  6. Prosaposin inhibits tumor metastasis via paracrine and endocrine stimulation of stromal p53 and Tsp-1. Kang, S.Y., et al., Proc. Natl. Acad. Sci. USA., 106, 12115-20 (2009).
  7. Neridronate inhibits angiogenesis in vitro and in vivo. Ribatti, D., et al., Clin. Rheumatol., 26, 1094-8 (2007).
  8. Clodronate inhibits angiogenesis in vitro and in vivo. Ribatti, D., et al., Oncol. Rep., 19, 1109-12 (2008).


Figure 1
. Illustration of normal vasculature. 
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Figure 2. Illustration of tumor vasculature.
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