Journal
JOURNAL OF CELL SCIENCE
Volume 134, Issue 15, Pages -Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.240135
Keywords
CD99; CDC42; Actin cytoskeleton; Transendothelial migration; Metastasis; Breast cancer
Categories
Funding
- University of Leeds
- Faculty of Medicine and Health PhD Scholarship
- Cancer Research UK
- Wellcome Trust Institutional Strategic Support Fund
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CD99 plays a complex role in tumor progression, by promoting adhesion between tumor cells and endothelial cells while inhibiting invasion and migratory activity. It negatively regulates CDC42 and cell migration, demonstrating its dual pro- and anti-tumor activities, with implications in inhibiting metastatic progression in breast cancer.
Metastasis 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.
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