Editors' ChoicePerivascular Niche

A Jagged Edge to Cancer Chemoresistance

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Science Translational Medicine  13 Mar 2013:
Vol. 5, Issue 176, pp. 176ec42
DOI: 10.1126/scitranslmed.3006076

By the time the intruder is unmasked, most of the audience already knows the identity of the knife-wielding killer in the film Jagged Edge—just as physicians know that metastatic disease is the key intruder on cancer-patient survival. But there are still surprises when it comes to deadly intruders in the metastatic niche. Lu et al. fingered an unexpected player from an unsuspected source as a prime mediator of chemoresistance in colorectal cancers (CRCs) and their metastases.

CRC kills 50,000 patients yearly because metastatic cells resist or become resistant to systemic chemotherapy. A key to stemming chemoresistance is an understanding of how it evolves. Selection of a genetic mutation is not the answer. Instead, it has become clear that specialized cellular microenvironments facilitate chemoresistance. These niches are typically enriched for extracellular matrix molecules and secreted factors that hyperstimulate cell survival signaling.

In human surgical specimens, CRC cells that express the putative cancer stem cell marker CD133 are found concentrated on the microvasculature within the colon and in liver metastases. Given the mounting evidence that cells with stem-like properties reside in perivascular niches, the authors asked whether endothelial cell–derived factors steer CRC cells toward a stemlike, chemoresistant phenotype. Medium conditioned by liver endothelial cells enriched for CD133-positive CRC cells in culture, and limiting dilution assays showed that CRC cells treated with endothelial cell–conditioned medium were particularly efficient at initiating tumors. Importantly, conditioned tumor cells were also four times more resistant to chemotherapeutics 5-fluorouracil and oxaliplatin than were control-treated cells. The endothelial-derived culprit promoted Notch signaling within tumor cells, which should not come as a surprise. But it was quite surprising that the endothelial-derived Notch ligand is a proteolytically shed form of Jagged-1. Inhibiting the protease (ADAM17) that cleaves Jagged-1 abrogated survival properties conferred by tumor endothelium.

This finding opens the door for trials aimed at identifying therapeutic regimens that combine hard-hitting chemotherapies with agents that deprive CRC cells of endothelial-derived survival signals. It should also prompt investigation of whether Jagged-1 cleavage is a unique property of tumor-associated endothelium or whether it occurs also in normal endothelium and is involved in maintaining perivascular stem cell populations. Addressing these questions could affect the cancer biology and regenerative medicine fields.

J. Lu et al., Endothelial cells promote the colorectal cancer stem cell phenotype through a soluble form of Jagged-1. Cancer Cell 23, 171–185 (2013). [Abstract]

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