Imagine that as part of a routine physical exam, a technician screens your blood for any cancer lurking in your body. Using a small amount of a patient’s blood, doctors figure out the best therapy to treat a person’s particular form of cancer. With emerging circulating tumor cell (CTC) microchip technology, these scenarios might soon become reality.
First discovered in 1869, CTCs have grabbed the attention of scientists and physicians alike. These cells break off from the main tumor and are carried by the bloodstream. Their presence in the blood may suggest that cancer has progressed or relapsed (returned), and this information can influence clinical decisions. Because these cells are very rare (only one CTC per billion blood cells), capturing even one of them seems harder than finding a needle in a haystack and, in many cases, no CTCs might be discovered at all. Scientists are not sure whether some tumors truly do not release CTCs or the available technology is not sensitive enough to detect very low numbers of CTCs in the blood. To help answer this question, researchers from Massachusetts General Hospital designed the microfluidics based CTC-chip, a device that isolates CTCs from whole blood.
Sieving Blood to Find CTCs
The business-card sized CTC-chip contains tens of thousands of microposts (miniature pillars) coated with antibodies that adhere to EpCAM, a protein found on the surface of cells in more than 85% of all cancers. These antibodies act like biological glue, binding CTCs to the microposts as blood flows over the chip. Captured cells can then be analyzed further.
After laborious technical improvements, including adjusting the blood flow rate and the spatial arrangement of microposts, the CTC-chip has proven sensitive enough to detect CTCs in over 99% of metastatic cancer patients’ blood samples. This greatly exceeds the capabilities of all currently available CTC isolation techniques. Captured CTCs look like typical malignant cells; namely, with a large nucleus and overall size. Further analysis showed that CTCs contained tumor markers – proteins that are characteristic for a particular kind of cancer. For example, CTCs from prostate cancer and lung cancer patients contained prostate-specific antigen and thyroid transcription factor-1, respectively.
Sensitive Diagnostic Tool
Although it is thought that CTCs are involved in the metastatic process, “not every single CTC will kill the patient,” explains Mehmet Toner, Professor of Surgery (Biomedical Engineering) at Massachusetts General Hospital and Harvard Medical School, principal investigator on the project. The sensitivity of the CTC-chip will enable scientists to determine whether low levels of CTCs are present early in cancer development, before metastasis begins. Toner’s team has already detected CTCs in non-metastatic prostate cancer. “We want to improve this technology to create a diagnostic tool. It will be like a blood screening test for any onset of tumors, even in the absence of symptoms,” adds Sunitha Nagrath, a postdoctoral fellow in Toner’s lab and lead scientist on the CTC project. By changing the antibodies on the chip, it will be possible to capture CTCs derived from any type of cancer.
Monitoring Therapy Effectiveness and Steering Clinical Decisions
During the course of therapy, doctors commonly monitor changes in tumor size to determine whether treatment is working. The imaging studies used for this purpose, such as PET and CT, cannot be performed frequently because they are toxic to patients. To find out whether CTCs could be used to monitor patient response to therapy, Toner’s research team followed cancer patients undergoing anticancer treatments over time and compared the number of CTCs to the size of the tumor measured by CT imaging. “We have shown that when patients respond to treatment, the number of tumor cells in circulation decreases dramatically. And when a patient does not respond to treatment and the tumor gets larger, the CTC number increases,” says Toner. Thus, in the future, real-time measurement of CTC numbers could allow doctors to promptly change or stop ineffective treatments.
Drug resistance, which can arise before or during therapy due to gene mutations in tumor cells, is a growing problem in the battle against cancer. To look for mutations, tumor cells have to be collected by biopsy. Being risky and painful, biopsies are typically performed only at the beginning and end of cancer treatment. In contrast, by using noninvasive CTC-chip technology, monitoring could be conducted as frequently as needed. In addition, analysis of CTC genetic sequences will enable discovery of new tumor markers and mutations in known resistance genes, providing a means of “detecting early relapse and determining whether a patient should get one treatment or another,” explains Toner. Scientists could also learn whether “drug-resistance mutations evolve over the course of treatment,” adds Nagrath.
CTC-Chip Enters the Clinic
Now that there is a way to collect sufficient numbers of cells from blood, scientists can explore many aspects of CTCs that could not be studied before. Discovery of new tumor markers and mutations may lead to development of new and improved cancer treatments. Toner’s ultimate goal is to take the CTC-chip technology to hospitals. “To get there, we need to reliably isolate CTCs and show that their presence (or absence) and molecular signature correlate with the clinical outcome,” says Nagrath. The CTC-chip is currently being tested in prostate and lung cancer clinical trials. As the technology becomes more streamlined, Toner envisions expanding its application to different solid (for example, breast and colon) tumors. Perhaps in the near future, physicians will use CTCs for early diagnosis and making treatment decisions and adjustments.
This work is supported in part by the National Institute of Biomedical Imaging and Bioengineering as part of the Quantum Grants program.
Nagrath S, Sequist LV, Maheswaran S, Bell DW, Irimia D, Ulkus L, Smith MR, Kwak EL, Digumarthy S, Muzikansky A, Ryan P, Balis UJ, Tompkins RG, Haber DA, Toner M. Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature. 2007 Dec 20;450(7173):1235–9.