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Non-angiogenic tumours and their influence on cancer biology

Abstract

Solid tumours need a blood supply, and a large body of evidence has previously suggested that they can grow only if they induce the development of new blood vessels, a process known as tumour angiogenesis. On the basis of this hypothesis, it was proposed that anti-angiogenic drugs should be able to suppress the growth of all solid tumours. However, clinical experience with anti-angiogenic agents has shown that this is not always the case. Reports of tumours growing without the formation of new vessels can be found in the literature dating back to the 1800s, yet no formal recognition, description and demonstration of their special biological status was made until recently. In 1996, we formally recognized and described non-angiogenic tumours in lungs where the only blood vessels present were those originating from normal lung tissue. This is far from an isolated scenario, as non-angiogenic tumour growth has now been observed in tumours of many different organs in both humans and preclinical animal models. In this Opinion article, we summarize how these tumours were discovered and discuss what we know so far about their biology and the potential implications of this knowledge for cancer treatment.

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Figure 1: Classification of the different mechanisms of tumour vascularization.
Figure 2: Patterns of tumour growth in relation to blood vessels.
Figure 3: Mechanisms of vascular co-option.
Figure 4: A schematic identikit of the biological and phenotypic differences between the angiogenic and non-angiogenic cancer cell.

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Acknowledgements

The authors thank their funding bodies, Cancer Research UK and Breast Cancer Research Foundation (A.L.H.); Norwegian Cancer Society and Northern Norway Health Region Authority (T.D.); Breast Cancer Now (A.R.R.); and Worldwide Cancer Research and the Canadian Breast Cancer Foundation (E.A.K.).

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T.D., F.P. and K.G. wrote the first drafts of the manuscript, while A.R.R., E.A.K., P.B.V., R.S.K. and A.L.H. provided comments and corrections before submission. All the authors contributed substantially to discussions of the content and to reviewing and/or editing the manuscript. With great sadness, Professor Kevin Gatter passed away during the preparation of the manuscript, which has been dedicated to his memory.

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Correspondence to Francesco Pezzella.

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Donnem, T., Reynolds, A., Kuczynski, E. et al. Non-angiogenic tumours and their influence on cancer biology. Nat Rev Cancer 18, 323–336 (2018). https://doi.org/10.1038/nrc.2018.14

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