Endothelial Cells Promote the Colorectal Cancer Stem Cell Phenotype through a Soluble Form of Jagged-1

SummaryWe report a paracrine effect whereby endothelial cells (ECs) promote the cancer stem cell (CSC) phenotype of human colorectal cancer (CRC) cells. We showed that, without direct cell-cell contact, ECs secrete factors that promoted the CSC phenotype in CRC cells via Notch activation. In human CRC specimens, CD133 and Notch intracellular domain-positive CRC cells colocalized in perivascular regions. An EC-derived, soluble form of Jagged-1, via ADAM17 proteolytic activity, led to Notch activation in CRC cells in a paracrine manner; these effects were blocked by immunodepletion of Jagged-1 in EC-conditioned medium or blockade of ADAM17 activity. Collectively, ECs play an active role in promoting Notch signaling and the CSC phenotype by secreting soluble Jagged-1.

Graphical AbstractFigure optionsDownload high-quality image (153 K)Download as PowerPoint slideHighlights
► ECs secrete soluble Jagged-1 promoting the colon cancer stem cell phenotype
► EC ADAM17 cleaves Jagged-1 to activate Notch in CRC cells via angiocrine signaling
► CD133-positive and NICD-positive CRC cells are located in the perivascular niche