Upregulated WEE1 protects endothelial cells of colorectal cancer liver metastases

Abstract

Surgical resection of colorectal cancer liver metastases (CLM) can be curative, yet 80% of patients are unsuitable for this treatment. As angiogenesis is a determinant of CLM progression we isolated endothelial cells from CLM and sought a mechanism which is upregulated, essential for angiogenic properties of these cells and relevant to emerging therapeutic options. Matched CLM endothelial cells (CLMECs) and endothelial cells of normal adjacent liver (LiECs) were superficially similar but transcriptome sequencing revealed molecular differences, one of which was unexpected upregulation and functional significance of the checkpoint kinase WEE1. Western blotting confirmed that WEE1 protein was upregulated in CLMECs. Knockdown of WEE1 by targeted short interfering RNA or the WEE1 inhibitor AZD1775 suppressed proliferation and migration of CLMECs. Investigation of the underlying mechanism suggested induction of double-stranded DNA breaks due to nucleotide shortage which then led to caspase 3-dependent apoptosis. The implication for CLMEC tube formation was striking with AZD1775 inhibiting tube branch points by 83%. WEE1 inhibitors might therefore be a therapeutic option for CLM and could be considered more broadly as anti-angiogenic agents in cancer treatment.

DOI: 10.18632/oncotarget.15039

Cite this paper

@inproceedings{Webster2017UpregulatedWP, title={Upregulated WEE1 protects endothelial cells of colorectal cancer liver metastases}, author={Peter John Webster and Anna Tiffany Littlejohns and Hannah Jane Gaunt and Richard Shih-Hung Young and Baptiste Rode and Judith E. Ritchie and Lucy F Stead and Sally M. Harrison and Alastair P. Droop and Heather Martin and Darren Charles Tomlinson and Adam J. Hyman and Hollie L. Appleby and Sally A. Boxall and Alexander F. Bruns and Jing Li and Raj Kumar Prasad and J. Peter A. Lodge and Dermot Anthony Burke and David Beech}, booktitle={Oncotarget}, year={2017} }