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  • Review Article
  • Published:

VEGF-targeted cancer therapeutics—paradoxical effects in endocrine organs

Nature Reviews Endocrinology volume 10, pages 530–539 (2014)Cite this article

Subjects

Key Points

  • Antiangiogenic drugs that target vascular endothelial growth factor A (VEGF-A; VEGF) signalling are widely used, either alone or in combination with chemotherapy, to treat various types of cancer

  • Vasculatures in endocrine organs are dependent on the VEGF–VEGF receptor signal transduction pathway for their survival, architecture and function

  • Systemic delivery of anti-VEGF drugs has the potential to adversely affect vasculatures in healthy tissues and organs, including the density and structure of capillary networks in endocrine organs

  • Tumour-derived VEGF can act as a hormone that modulates the structure and function of microvessels in endocrine organs

  • Understanding the mechanisms by which anti-VEGF drugs affect endocrine vasculatures is crucial to minimize the adverse effects associated with their use

Abstract

Systemic administration of antiangiogenic drugs that target components of the vascular endothelial growth factor A (VEGF-A; VEGF) signal transduction pathway has become a viable therapeutic option for patients with various types of cancer. Nevertheless, these drugs can drive alterations in healthy vasculatures, which in turn are associated with adverse effects in healthy tissues. VEGF is crucial for vascular homeostasis and the maintenance of vascular integrity and architecture in endocrine organs. Given these critical physiological functions, systemic delivery of drugs that target VEGF signalling can block VEGF-mediated vascular functions in endocrine organs, such as the thyroid gland, and lead to endocrine dysfunction, including hypothyroidism, adrenal insufficiency and altered insulin sensitivity. This Review discusses emerging evidence from preclinical and clinical studies that contributes to understanding the mechanisms that underlie the vascular changes and subsequent modulations of endocrine function that are induced by targeted inhibition of VEGF signalling. Understanding these mechanisms is crucial for the design of antiangiogenic drugs with minimal associated adverse effects that will enable effective treatment of patients with cancer.

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Figure 1: Paracrine interactions between endocrine cells and vascular endothelial cells.
Figure 2: VEGF mediates physiological and pathological functions during embryogenesis and in adult tissues.
Figure 3: VEGF mediates tumour-derived endocrine functions.
Figure 4: Effects of targeting VEGF signalling in the thyroid gland.
Figure 5: Development of antiangiogenic drugs that target the VEGF–VEGFR-2 signalling axis.

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Acknowledgements

Y.C. thanks Dr S. Lim, at the Department of Microbiology, Tumour and Cell Biology, Karolinska Institute, for the design of Figure 3. Y.C.'s laboratory is supported by research grants from the Swedish Research Council, the Swedish Cancer Foundation, the Karolinska Institute Foundation, the Karolinska Institute Distinguished Professor Award, the Torsten Söderbergs Foundation, the Novo Nordisk Foundation, and the European Research Council advanced grant ANGIOFAT (Project no. 250,021).

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  1. Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet, Nobels vag 16, Stockholm, 17177, Sweden

    Yihai Cao

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Y.C. receives grant support from the Novo Norodisk Foundation and is the founder and a share holder of Clanotech, a Karolinska Development-based biotechnology company that focuses on developing drugs for the treatment of ocular diseases.

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Cao, Y. VEGF-targeted cancer therapeutics—paradoxical effects in endocrine organs. Nat Rev Endocrinol 10, 530–539 (2014). https://doi.org/10.1038/nrendo.2014.114

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