Like blood vessels that supply oxygen and nutrients to normal tissue, tumor blood vessels were originally thought to do likewise to fuel tumor growth. As scientists developed strategies to kill tumors by cutting off their blood supply, they soon discovered their valiant efforts were thwarted by the tumor's ability to quickly recover.

The recovery is caused by a population of tumor-initiating cancer cells dubbed the cancer stem cells (CSCs); a population that can communicate with blood vessels via the Notch signaling pathway to drive tumor vascularization.

It turns out that this "Notch" communication can go both ways. In a Cancer Cell study, scientists discovered that tumor-blood vessels can communicate with cancer cells via Notch signaling, and direct their transformation into cancer stem cells. Specifically, the authors found that when colorectal cancer cells are exposed to tumor endothelial cell directly or indirectly via conditioned medium, these cells acquire features that resemble CSCs.

Some of these features include their expression of the stem cell marker CD133, their ability to initiate colorectal cancer when transplanted elsewhere, and their marked resistance to chemotherapy.

The authors further found that the Notch signaling is driven by the release of soluble Jagged-1 from the surface of endothelial cells, a process driven by a membrane enzyme ADAM17. Jagged-1 binds to Notch-1 and triggers downstream activation of the transcription factors Hes1 and NICD in cancer cells to drive their transformation into CSCs.  

Supporting this preclinical data, the authors found that colorectal CSCs are closely associated tumor blood vessels in clinical surgical specimens of colorectal cancer. Using a Notch signaling reporter system to track Hes1 and NICD in surgical specimens, the authors were able to confirm that Notch signaling is indeed active in colorectal cancer cells/stem cells surrounding tumor blood vessels.

This study first evidence suggesting that tumor-blood vessels are not merely conduits of nutrients and oxygen, but are also a communication hub that orchestrates the birth of cancer stem cells- the drivers of tumor initiation.


Lu et al., Endothelial Cells Promote the Colorectal Cancer Stem Cell Phenotype through a Soluble Form of Jagged-1, Cancer Cell (2013),