Common Circulating Cell Clusters in Cancer Patients Characterized Anew

In a study of blood samples from colorectal cancer patients, researchers have now discovered the source of these cells and that they are not malignant, potentially opening up a new path to detect and inhibit the spread of cancer.

Circulating cell clusters (CCCs) commonly found in the blood of cancer patients have long been regarded as malignant cells (i.e. CTCs – circulating tumor cells) that have broken off from the primary tumor, spreading cancer to other parts of the body. This was the working assumption, but due to technical challenges of separating these clusters from normal blood cells, limited research has been performed.


Now a multi-institute research team, led by Dr. Min-Han Tan, a principal research scientist at the Institute of Bioengineering and Nanotechnology (IBN; Singapore) of Singapore’s A*STAR (Agency for Science, Technology & Research), has shown that these CCCs come from the blood vessels that line the tumor rather than from the tumor itself. The team includes researchers from IBN, A*STAR’s Genome Institute of Singapore, Concord Cancer Hospital, National University of Singapore, National Cancer Centre Singapore, and Singapore General Hospital.

The researchers studied these CCCs at a single-cell-scale in 80 colorectal cancer patients. They first separated out the CCCs from the blood samples using a custom-designed microdevice, developed by Prof Jackie Y. Ying’s laboratory at IBN, that enables quick and efficient capture and retrieval of the CCCs. Next they used high-throughput DNA and RNA sequencing and computational modeling to determine the identity of these cells.

The results showed that in colorectal cancer, these CCCs are endothelial cells from the blood vessels lining the tumor and are non-cancerous. Unexpectedly, the researchers also discovered that more endothelial CCCs were found in patients who have not received any treatment, compared to those who have received treatment, suggesting that these CCCs could be used for early-stage cancer detection.

“The goal of cancer research is to understand how cancer spreads in order to curb the disease. Our institute has been focusing on evaluating cancer in a non-invasive way through blood testing using our novel microfiltration technique. Knowing exactly where these CCCs come from will lead us towards better approaches of diagnosing and treating cancer,” said Prof. Jackie Y. Ying, executive director, IBN.

“Scientific orthodoxy has maintained for decades that these cell clusters commonly observed in cancer patients were malignant tumor cells. In contrast, we found that these cell clusters are not malignant, but come from the blood vessels lining the tumor that presumably peeled off during blood flow through the tumor. This insight requires a reconsideration of decades of data, and gives scientists new opportunities to investigate and starve the cancer through drugs that manipulate the blood vessels of tumors. This method also gives physicians a new understanding and method of monitoring tumor blood supply in cancer patients receiving treatment,” said Dr Min-Han Tan.

Dr Poh Koon Koh of Concord Cancer Hospital said, “I am glad that our public-private collaboration has yielded such key insights into cancer biology. Meaningful innovation comes about when focused teams are willing to challenge and disrupt existing dogmas, and the insights here allow for Singapore to develop its key technologies in the liquid biopsy domain.”

The next stage of this research is to determine if the same finding applies to other types of cancer besides colorectal cancer, and to develop new liquid biopsy technologies for cancer detection and drug treatment based on these CCCs.

The study, by Cima I et al, was published June 29, 2016, in the journal Science Translational Medicine.

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