Abstract
ABSTRACTMetastasis requires tumour cells to cross endothelial cell (EC) barriers using pathways similar to those used by leucocytes during inflammation. Cell surface CD99 is expressed by healthy leucocytes and ECs, and participates in inflammatory transendothelial migration (TEM). Tumour cells also express CD99, and we have analysed its role in tumour progression and cancer cell TEM. Tumour cell CD99 was required for adhesion to ECs but inhibited invasion of the endothelial barrier and migratory activity. Furthermore, CD99 depletion in tumour cells caused redistribution of the actin cytoskeleton and increased activity of the Rho GTPase CDC42, known for its role in actin remodelling and cell migration. In a xenograft model of breast cancer, tumour cell CD99 expression inhibited metastatic progression, and patient samples showed reduced expression of the CD99 gene in brain metastases compared to matched primary breast tumours. We conclude that CD99 negatively regulates CDC42 and cell migration. However, CD99 has both pro- and anti-tumour activity, and our data suggest that this results in part from its functional linkage to CDC42 and the diverse signalling pathways downstream of this Rho GTPase. This article has an associated First Person interview with the first author of the paper.
Highlights
Ninety percent of cancer deaths are attributable to metastatic progression (Lambert et al, 2017)
Immunoblotting and flow cytometry demonstrated that expression of CD99 was not significantly different between two cell lines (Fig. 1A,B), and we subsequently focused on the role of CD99 in the invasive activity of MDA-MB-231 cells, a cell line frequently used to dissect pathways of metastasis, including the analysis of transendothelial migration (TEM) (Bos et al, 2009; Kang et al, 2003; Minn et al, 2005a,b; Neve et al, 2006; Reymond et al, 2012)
Our results identify a functional link between CD99, CDC42 and cytoskeletal dynamics in cancer cells and demonstrate that breast cancer CD99 negatively regulates CDC42 activity and TEM
Summary
Ninety percent of cancer deaths are attributable to metastatic progression (Lambert et al, 2017). From the primary tumour, migrating cancer cells intravasate, gaining access to the lymphatic and haematogenous vasculature (Strilic and Offermanns, 2017). Handling Editor: Daniel Billadeau Received 4 October 2019; Accepted 6 July 2021 reach distant sites where they can extravasate and potentially seed a metastasis (Lambert et al, 2017). The intravasation and extravasation of tumour cells require intimate interactions between cancer cells and endothelial cells (ECs), with both cell types contributing to the initial adhesive interactions and subsequent transendothelial migration (TEM) (Reymond et al, 2013). Leucocytes undergo TEM when extravasating from blood to infected tissues as part of the inflammatory process, and this extensively studied mechanism provides a model for how cancer cell TEM might operate during metastasis (Madsen and Sahai, 2010; Vestweber, 2015)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
