Research ArticleCancer

Tumor-derived circulating endothelial cell clusters in colorectal cancer

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Science Translational Medicine  29 Jun 2016:
Vol. 8, Issue 345, pp. 345ra89
DOI: 10.1126/scitranslmed.aad7369

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A new type of circulating tumor cluster

Setting out to isolate circulating tumor cells (CTCs) in the blood of cancer patients, Cima et al. instead noticed that clusters, rather than single cells, were present in their sorting device. However, these clusters were not like others reported previously: The cells did not express the cell marker epithelial cell adhesion molecule (EpCAM), and they did not have the same mutations seen in the primary tumor—two features that are typical of CTCs. Instead, these clusters matched the expression profile and phenotype of endothelial cells, which are the cells lining the blood vessels. The authors first confirmed that these endothelial cells were shed by the tumor, through a series of experiments using patient-derived samples and in vivo studies in mice, and then demonstrated that the clusters did not form by coagulation after being shed; it was the tumor that was shedding intact clusters. Moving back to patients, Cima and colleagues also found that the presence of endothelial cell clusters correlated with early-stage disease, suggesting that these groups of cells might be a unique indicator of cancer, before treatment starts.


Clusters of tumor cells are often observed in the blood of cancer patients. These structures have been described as malignant entities for more than 50 years, although their comprehensive characterization is lacking. Contrary to current consensus, we demonstrate that a discrete population of circulating cell clusters isolated from the blood of colorectal cancer patients are not cancerous but consist of tumor-derived endothelial cells. These clusters express both epithelial and mesenchymal markers, consistent with previous reports on circulating tumor cell (CTC) phenotyping. However, unlike CTCs, they do not mirror the genetic variations of matched tumors. Transcriptomic analysis of single clusters revealed that these structures exhibit an endothelial phenotype and can be traced back to the tumor endothelium. Further results show that tumor-derived endothelial clusters do not form by coagulation or by outgrowth of single circulating endothelial cells, supporting a direct release of clusters from the tumor vasculature. The isolation and enumeration of these benign clusters distinguished healthy volunteers from treatment-naïve as well as pathological early-stage (≤IIA) colorectal cancer patients with high accuracy, suggesting that tumor-derived circulating endothelial cell clusters could be used as a means of noninvasive screening for colorectal cancer. In contrast to CTCs, tumor-derived endothelial cell clusters may also provide important information about the underlying tumor vasculature at the time of diagnosis, during treatment, and throughout the course of the disease.

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