Breast cancer is the most commonly diagnosed cancer in Australian women and kills eight Australians every day. For breast cancer to grow and metastasise it needs access to the circulating blood supply for oxygen, nutrients as well as delivery of leukocytes to control cancer progression. It is well documented that tumours with a high vascular content metastasise quicker and have poor outcomes for patients, thus targeting tumour vasculature is clinically important.
Cancer cells promote tumour vascularisation through two processes; (i) angiogenesis (the proliferation of endothelial cells (ECs) and existing vasculature) and (ii) vasculogenic mimicry (VM, wherein cancer cells themselves form vascular-like structures). Triple negative breast cancer (TNBC), is the most highly vascularised of all the breast cancers and contains both angiogenesis and VM. Tumours are known to use VM for the delivery of oxygen and nutrients, but whether these VM structures circulate leukocytes to control tumour growth is largely unknown.
Our data suggest that VM-competent TNBC cells (e.g. MDA-MB231, SUM159, HCC70) express high levels of adhesion molecules such as ICAM1. Interestingly VM-incompetent breast cancer cells (e.g. MCF7, T47D) express little? To no adhesion molecules. In vitro testing of cell adhesion under shear flow suggests that ICAM1 expression by VM-competent TNBC cells supports the active recruitment CD14+ monocytes and CD3+ T lymphocytes. To confirm this, we used a 4T1.13 syngeneic mouse model of TNBC without or with CRISPR/CAS9 ICAM1-knockout cells. Taken together, our data suggest that cancer cells that can mimic vascular ECs by expressing the adhesion molecules required to recruit circulating leukocytes into the tumour. Future work will reveal whether VM structures bias their selection of leukocytes to recruit to promote cancer progression.
Identification of ICAM-1 as a target for TNBC may potentially lead to the formation of a novel strategy to fill a critical gap in TNBC patient care.