The tumour microenvironment has been shown to influence cancer stem cell properties. Ellis and colleagues now report that endothelial cells promote cancer stem cell properties in colorectal cancer cells, through the action of a secreted form of Jagged-1 (Cancer Cell 23, 171–185; 2013).
The authors used cell co-culture experiments and treatment of colorectal carcinoma cells with endothelial-cell-derived conditioned media to show that endothelial cells could promote the de-differentiation of non-stem cancer cells towards a cancer stem cell phenotype. These endothelial-cell-influenced colorectal cancer stem cells exhibited increased tumorigenicity and metastatic colonization ability in vivo and chemoresistance in vitro.
Induction of cancer stem cell properties by endothelial cells depended on the activation of Notch signalling in colorectal cancer cells through the paracrine action of an endothelial-cell-produced factor, which was identified as the Notch ligand Jagged-1. Although Jagged-1 is usually membrane-associated, the authors demonstrated that in this setting, endothelial cells produced a soluble form through the action of the ADAM17 protease, and further showed that Jagged-1 cleavage by ADAM17 was necessary for promoting the cancer stem cell properties of colorectal cancer cells. Colorectal cancer stem cells with activated Notch signalling were also observed adjacent to endothelial cells in human primary and metastatic colon cancer samples, indicating that endothelial cells are important in establishing a perivascular niche for colorectal cancer stem cells.