Cancer progression is controlled, in part, by infiltrating leukocytes which can either actively kill the cancer cells or promote their survival. Our current understanding of leukocyte recruitment into tumours is largely limited to the adhesion molecules and chemokines expressed by conventional endothelial cell (EC)-lined blood vessels. However, there is increasing evidence that cancer cells themselves can form vascular structures (a process known as vasculogenic mimicry (VM)); but whether VM vessels actively participate in the recruitment of leukocytes remains largely unknown.
We have building evidence that the most aggressive and difficult to treat tumours are more likely to be VM-competent and that these cancer cells often express multiple adhesion molecules (e.g. CD44, ICAM-1 and JAMs), cytokines (e.g. IL-6, TNF) and chemokines (e.g. CXCL8, CXCL12) relevant for leukocyte recruitment. Microfluidic-based adhesion assays reveal that, similar to ECs, VM-competent cancer cells facilitate the rolling and adhesion of leukocytes, particularly monocytes. Moreover, we identify ICAM-1 to be a key participant in this process. Transwell assays further suggest that VM-competent cancer cells facilitate monocyte transmigration towards a chemotactic gradient. Immunostaining of patient tissue microarrays reveal that tumours with high VM content also contain higher numbers of leukocytes (including macrophages). We have also identified an important transporter protein that selectively carries pro-cancerous proteins to the surface of the cell and into the secretome. Inhibiting this transporter has proven effective in combating mouse models of melanoma and pancreatic cancer.
Taken together, this body of work suggests an underappreciated role of VM vessels in solid tumours via their active participation in leukocyte recruitment and begins to identify key transporter proteins, adhesion molecules, cytokines and chemokines that facilitate this deadly process.