Circulating tumor cells (CTCs) represent the metastatic seed that can break away from the primary tumor site, move through a patient’s bloodstream, and spread to other parts of the body—often causing more pathological symptoms than the primary cancer from which the CTCs were derived.
Single CTCs are extremely rare, typically fewer than 1 in 1 billion cells, with clusters being even less common. While the existence of CTC clusters has been known for more than 50 years, isolating and investigating their role in metastasis has been difficult. However, researchers from Harvard Medical School have developed a microfluidic chip that can capture CTC clusters, which could yield important new insights into how different cancers spread.
“Very little is known about CTC clusters and their role in the progression and metastasis of cancer. This unique technology presents an exciting opportunity to capture these exceptionally rare groups of cells for further analysis in a way that is minimally-invasive,” explained Roderic Pettigrew,M.D., Ph.D., director at the National Institute of Biomedical Imaging and Engineering who helped find the current study. “This is the kind of breakthrough technology that could have a very large impact on cancer research.”
The findings from this study were published recently in Nature Methods through an article entitled “A microfluidic device for label-free, physical capture of circulating tumor cell clusters.”
The investigators used this new technology, which they dubbed Cluster-Chip, to capture and analyze CTC clusters from a group of 60 patients with metastatic breast, prostate, and melanoma cancers. The researchers observed CTC clusters ranging from 2-19 cells among 30–40% of the patients.
“The presence of these clusters is far more common than we thought in the past,” said senior author Mehmet Toner, Ph.D., professor of surgery and health sciences and technology at Harvard Medical School, Massachusetts General Hospital. “The fact that we saw clusters in this many patients is really a remarkable finding.”
The chip is designed to funnel blood through a field of microscopic triangle-shaped posts. The posts are arranged so that every two posts channels cells towards the tip of a third post. At the tip, single cells easily slide to either side and continue through the chip until reaching the next tip. However, CTC clusters are left stuck at the tip due to forces pulling them down the post in opposite directions.
After initial tests provided information that the Cluster-Chip design was efficient at capturing cell clusters composed of 3 cells or greater, Dr. Toner and his colleagues went on to test the technique in a small trial of 60 patients with metastatic cancer. The assay was able to capture CTC clusters from 40% of breast cancer, 31% of prostate and 30% of melanoma patients—suggestive of a greater role for CTC clusters in metastatic cancers than previously thought. Interestingly, the data from this small study also showed a rare presence of non-tumor derived immune cells within clusters, for less than 5% of patients
“The fact that some CTC clusters contain immune cells is of particular interest,” said Dr. Pettigrew. “Given the increasing number of cancer therapies that engage the immune system, the ability to monitor tumor-immune cell interactions via the blood could be of great value.”
Dr. Toner and his colleagues anticipate that the Cluster-Chip will have an increasingly important role in stimulating new research on CTC cluster biology, stating that “it's like poking a sleeping bear. It could really awaken the field to go after clusters and to develop even better technologies to understand their biology in cancer metastasis.”