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Monitoring Cancer Progression

By automating the tracking of tumor cells that circulate in the blood, doctors can see if a cancer treatment is working.

Researchers have developed an automated imaging system for analyzing changes in a tiny number of tumor cells floating through the bloodstream. They hope the analysis will provide clues to the success of cancer treatments.

Tumor cell snapshot: Prostate tumor cells circulating in the bloodstream are captured onto microscopic posts (gray) on a chip designed by researchers at Harvard University and the Massachusetts General Hospital Cancer Center. The cells are imaged using cancer-specific protein markers. The larger, green cell is positive for prostate-specific antigen; the blue cell is a white blood cell.

One way that cancer is thought to spread from its original site and metastasize elsewhere in the body is through cells that detach from the primary tumor and circulate in the bloodstream. Recent studies have shown that tracking blood levels of these circulating tumor cells could help monitor how well a cancer treatment is working. But because their concentration in the blood is so low, researchers have struggled to detect them with enough accuracy to be clinically relevant.

Three years ago, bioengineer Mehmet Toner and cancer biologist Daniel Haber of Harvard University reported making a microfluidic chip that captured these cells at a higher rate than other techniques. The chip had a good enough resolution for proof-of-principle studies, says Shannon Stott, a postdoc in Haber’s lab, but analysis required an individual to scan thousands of images with a microscope–a process that takes about eight hours per sample and is therefore not amenable to diagnostic use in the clinic.

In the current work, a pilot study of prostate cancer patients led by Stott and Shyamala Maheswaran at the Mass General Hospital Cancer Center, and published in Science Translational Medicine, the researchers tested an automated imaging system. In addition to reducing analysis time by more than 75 percent, the scientists could use the imaging to analyze the cancer cells at different points–before and after tumor removal surgery and during hormone-based therapy.

“It’s a very nice investigational study which shows really what kinds of analysis can be done in prostate cancer patients,” says Klaus Pantel, chairman of the Institute of Cancer Biology at the University of Hamburg, in Germany.

The new system uses the same device as in the group’s earlier work to capture tumor cells from a drop of blood–a microfluidic chip containing microscopic posts coated with an antibody to a protein found on tumor cells. The cells were then stained with an antibody for prostate-specific antigen (PSA), a molecule specific to prostate tumor cells, and imaged with a fluorescent marker and a marker for the cell’s nucleus. Though they used PSA, says Stott, the system is “completely universal,” and the researchers have begun testing it with antibodies for other types of cancer cells as well.

One diagnostic assay measuring circulating tumor cells is already on the market. That test, called CellSearch, received clearance from the U.S. Food and Drug Administration for metastatic breast cancer in 2004, and has since received the go-ahead for use in colorectal and prostate cancer.

But the Harvard system is more likely to detect tumor cells in patients before their tumor has metastasized, when there are far fewer circulating in the blood, says Alison Allan, an oncology scientist at the University of Western Ontario, who uses the CellSearch system. “It’s actually these patients that have the most chance of benefiting” from the technology, she notes, because it could allow them to get earlier treatment.

Also, unlike CellSearch, the Harvard technology quantifies the cells present and determines some of their molecular features. “I think that’s going to be really important moving forward in the field,” says Allan. “The capacity to allow subsequent molecular characterization is going to tell us more about patient’s individual diseases.”

Stott says the group hopes to finish fine-tuning the technology in the next six months, at which point they will disseminate it to six other cancer centers to conduct a larger-scale clinical trial. Also, she says, “we are working on making the machine that runs these devices much more user-friendly so clinicians can just put the blood in and press go.”

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