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Regulation of Angiogenesis by Tumour Suppressor Pathways

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Experimental and Clinical Metastasis

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Abstract

Angiogenesis, the process of formation of new blood vessels from existing vasculature, is a normal process during embryogenesis, wound healing, and the female reproductive cycle. During cancer progression, tumour cells develop the capacity to stimulate pathological angiogenesis. This “angiogenic switch” allows tumours to rapidly grow from small, avascular lesions less than 2 mm in diameter into large, vascularized tumours.

The angiogenic switch is thought to be triggered by a change in the balance of pro- and anti-angiogenic factors found in the extracellular space. Tumour suppressor proteins negatively regulate angiogenesis by shutting down production of pro-angiogenic factors and stimulating anti-angiogenic ones. This chapter will focus on the mechanisms by which tumour suppressor proteins, including VHL, PTEN, RB, and p53 inhibit angiogenesis.

In the clinic, anti-angiogenic therapies are being developed with the goal of maintaining tumours in the dormant, avascular state that exists before the angiogenic switch. VEGF, a pro-angiogenic factor regulated by each of the tumour suppressor proteins discussed in this chapter (VHL, PTEN, RB, and p53), is a major target in anti-angiogenic therapy. However, inhibition of a single pro-angiogenic factor (such as VEGF) has limited clinical efficacy, in part due to acquired resistance mutations which result in upregulation of other pro-angiogenic factors. In addition, inhibition of angiogenesis can accelerate metastasis. Thus, more promising approaches to anti-angiogenic therapy would involve mimicking tumour suppressor function by utilizing multiple pathways to target tumour angiogenesis, or combination therapy with anti-angiogenic and anti-metastatic agents.

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Acknowledgements

Research in the lab of J.G.T. is supported by funding from the Canadian Institute of Health Research (CIHR) and the Natural Science and Engineering Council of Canada. K.J.L. and S.A. are both supported by studentship from the CIHR. W.E. is the recipient of a post-doctoral training award form the McGill Integrated Cancer Research Training Program.

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  1. Goodman Cancer Research Centre and Department of Biochemistry, McGill University, 1160 Pine Avenue, H3A 1A3, Montreal, QC, Canada

    Karen J. Lefebvre, Sarah Assadian & Jose G. Teodoro

  2. Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue, Montreal, QC H3A 1A3, Canada

    Wissal El-Assaad

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    Julia V. Burnier

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Lefebvre, K.J., Assadian, S., El-Assaad, W., Teodoro, J. (2013). Regulation of Angiogenesis by Tumour Suppressor Pathways. In: Burnier, J., Burnier, Jr., M. (eds) Experimental and Clinical Metastasis. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-3685-0_8

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