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Inactivation of endothelial cell phosphoinositide 3-kinase β inhibits tumor angiogenesis and tumor growth

Oncogene volume 39, pages 6480–6492 (2020)Cite this article

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Abstract

Angiogenesis inhibitors, such as the receptor tyrosine kinase (RTK) inhibitor sunitinib, target vascular endothelial growth factor (VEGF) signaling in cancers. However, only a fraction of patients respond, and most ultimately develop resistance to current angiogenesis inhibitor therapies. Activity of alternative pro-angiogenic growth factors, acting via RTK or G-protein coupled receptors (GPCR), may mediate VEGF inhibitor resistance. The phosphoinositide 3-kinase (PI3K)β isoform is uniquely coupled to both RTK and GPCRs. We investigated the role of endothelial cell (EC) PI3Kβ in tumor angiogenesis. Pro-angiogenic GPCR ligands were expressed by patient-derived renal cell carcinomas (PD-RCC), and selective inactivation of PI3Kβ reduced PD-RCC-stimulated EC spheroid sprouting. EC-specific PI3Kβ knockout (ΕC-βKO) in mice potentiated the sunitinib-induced reduction in subcutaneous growth of LLC1 and B16F10, and lung metastasis of B16F10 tumors. Compared to single-agent sunitinib treatment, tumors in sunitinib-treated ΕC-βKO mice showed a marked decrease in microvessel density, and reduced new vessel formation. The fraction of perfused mature tumor microvessels was increased in ΕC-βKO mice suggesting immature microvessels were most sensitive to combined sunitinib and PI3Kβ inactivation. Taken together, EC PI3Kβ inactivation with sunitinib inhibition reduces microvessel turnover and decreases heterogeneity of the tumor microenvironment, hence PI3Kβ inhibition may be a useful adjuvant antiangiogenesis therapy with sunitinib.

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Fig. 1: Inhibition of PI3Kβ decreases sprouting angiogenesis in HUVECs co-cultured with patient-derived renal cancer (PD-RCC) samples.
Fig. 2: Inactivation of endothelial PI3Kβ potentiates sunitinib treatment to delay tumor growth and reduce tumor vessel density.
Fig. 3: Inactivation of endothelial PI3Kβ promotes tumor vessel normalization in sunitinib-treated mice.
Fig. 4: Inactivation of endothelial PI3Kβ reduces tumor angiogenesis.
Fig. 5: Cancer cell epithelial-to-mesenchymal transition (EMT) is reduced in EC-βKO mice.
Fig. 6: Inactivation of endothelial PI3Kβ decreases lung metastases, tumor vessel density, and tumor hypoxia in sunitinib-treated mice.

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Acknowledgements

AKA was supported by a Translational Research Fellowship award from the Department of Medicine at the University of Alberta. Operating funding was provided by the Canadian Cancer Society Research Institute to AGM. The authors acknowledge the technical assistance of Jessica DesAulniers.

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Authors and Affiliations

  1. Department of Medicine, University of Alberta, Edmonton, AB, Canada

    Abul K. Azad, Pavel Zhabyeyev, Gavin Y. Oudit & Allan G. Murray

  2. Department of Physiology, University of Alberta, Edmonton, AB, Canada

    Pavel Zhabyeyev & Gavin Y. Oudit

  3. UCL Cancer Institute, University College, London, UK

    Bart Vanhaesebroeck

  4. Department of Cell Biology, University of Alberta, Edmonton, AB, Canada

    Gary Eitzen

  5. Department of Oncology, University of Alberta, Edmonton, AB, Canada

    Ronald B. Moore

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Concept: AKA, GE, GYO, RBM, AGM; methodology: AKA, PZ; data acquisition: AKA; analysis: AKA, AGM; reagents: BV, RBM; writing: AKA, BV, AGM.

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Correspondence to Allan G. Murray.

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BV is a consultant for Karus Therapeutics (Oxford, UK), iOnctura (Geneva, Switzerland) and Venthera (Palo Alto, US) and has received speaker fees from Gilead (Foster City, US). The other authors declare no conflict of interest relating to this work.

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Azad, A.K., Zhabyeyev, P., Vanhaesebroeck, B. et al. Inactivation of endothelial cell phosphoinositide 3-kinase β inhibits tumor angiogenesis and tumor growth. Oncogene 39, 6480–6492 (2020). https://doi.org/10.1038/s41388-020-01444-3

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