Cluster-chip captures a fluorescently marked CTC cluster.
Image credit: Mehmet Toner, BioMicroElectroMechanical Systems Resource Center at MGH
One way cancer spreads from the primary tumor to other parts of the body is when tumor cells break off and travel through the bloodstream. These circulating tumor cells (CTCs) are very rare, and travel either singly or in clusters.
Single CTCs occur in typically fewer than 1 in 1 billion cells. Clusters of CTCs are thought to be even rarer.
However, while we have known about CTC clusters for decades, researchers have not had the tools to capture these elusive cells and study their role in metastasis.
There has been progress in developing devices that capture single CTCs, and this has renewed interest in capturing clusters.
A stumbling block in developing the technology has been how to snare the clusters. One way that has been tried is to target proteins or antigens that the cells bear on their surfaces. But this has not proved satisfactory because CTCs do not all don the same uniform - there can be a lot of difference in the types of antigens they wear.
The new device - called the Cluster-Chip - uses microfluid technology to snare CTCs from whole, unprocessed blood.
Cluster-Chip is the brainchild of a group led by Mehmet Toner, professor of surgery at Massachusetts General Hospital (MGH) and the Harvard-MIT Division of Health & Sciences Technology in Boston, MA, who says their new chip will help spur new research on CTC cluster biology:
"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."
Prof. Toner and colleagues describe their new chip, how they tested it and discovered new clues about CTC clusters in a paper published in the journal Nature Methods.
The National Institute of Biomedical Imaging and Bioengineering (NIBIB), part of the National Institutes of Health, helped fund the study.
CTC clusters may be more common than previously thought
The team used the new chip to capture and analyze CTC clusters from 60 patients with metastatic breast, prostate and melanoma cancers.
They found CTC clusters in 30-40% of the patients. The clusters ranged from two to 19 cells in size.
Prof. Toner says finding CTC clusters in this many patients is a "remarkable finding," showing that clusters are more common than we thought.
The chip uses microfluid technology - where flows of the tiny currents of fluid through the structure of the chip are manipulated and balanced precisely so as to hold the target particles in place and allow non-targeted particles to pass through.
The patient's blood sample travels slowly through the chip, which comprises many rows of tiny triangular posts arranged in threes so that two posts funnel the cells toward the tip of a third post.
The target particles - clusters of CTCs - are held at the tip by finely tuned balances in the fluid forces pulling them down the post in opposite directions. Other particles - such as single CTCs and blood cells - slide easily to either side of the post and continue on their journey.
Chip captured 99% of CTC clusters of four or more cells
The team tested the efficiency of the new device by using CTC clusters comprising two to 30 cells tagged with fluorescent markers. They counted the number the device managed to snare and the number that passed through undetected.
Their results showed that at a blood flow rate of 2.5ml/hr, the chip captured 99% of CTC clusters of four or more cells, 70% of three or more, and 41% of two-cell clusters.
Another measure of the usefulness of such a device is the extent to which the capture mechanism destroys or maintains the integrity of the cells so they can be studied.
The researchers note how they compared the CTC clusters before and after capture and concluded the device did not damage their overall integrity.
The team also compared the efficiency of the new chip against two other methods that have shown a measure of success in capturing CTC clusters: one based on a filter and the other - that Prof. Toner had developed - also using microfluid technology, but to target surface antigens. In both cases, the new chip proved significantly more efficient.
The researchers conclude that their new device - because it focuses on structural properties of CTC clusters and not their size or presence of surface proteins - makes it well suited to capturing CTC clusters from a range of cancer types, particularly those that never express surface proteins - such as melanoma - and those that lose surface proteins.
The team also made other discoveries. For example, they found in less than 5% of patients, their CTC clusters contained immune cells as well as cancer cells. Could this be significant in metastasis? NIBIB Director Dr. Roderic I. Pettigrew notes:
"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. Pettigrew sums up the significance of the new device:
"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. This is the kind of breakthrough technology that could have a very large impact on cancer research."
Medical News Today recently learned how a blood test that predicts cancer years in advance may result from the discovery of a telomere biomarker.
Writing in the new journal EBioMedicine, a team from Northwestern and Harvard Universities describes how a distinct pattern of changes in blood telomeres appears to anticipate cancer years before diagnosis. Telomeres are the protective ends of DNA strands that stop them unraveling and causing cells to malfunction.