Scientific American by Larry Greenemeier
Cells that break away from a cancerous tumor and circulate in the bloodstream are a serious threat to helping cancer spread, or metastasize, throughout the body. Finding these circulating tumor cells (CTCs), however, can be like searching for a particular needle in a stack of needles. One milliliter of blood contains about five billion red blood cells, 10 million white blood cells and only 10 tumor cells.
Yet early cancer detection and treatment is a person's best chance of survival, And because metastasis is responsible for 90 percent of cancer deaths, researchers have spent decades trying to develop blood tests that can effectively spot CTCs before they can form new tumors. The biggest challenge has been quickly examining billions of rapidly moving blood cells in a sample at a resolution high enough to identify the cancerous intruders.
Researchers at the University of California, Los Angeles, (U.C.L.A.), are developing a system that combines an optical microscope with a device for counting and studying cells, along with a high-speed image processor they say can take blur-free images of fast-moving cells, a significant step toward catching CTCs in the act. The researchers described the system last month in Proceedings of the National Academy of Sciences (PNAS).
The heart of the U.C.L.A. system is an ultrafast microscopic camera the researchers introduced in 2009 that captures images at about six million frames per second. This "serial time-encoded amplified microscopy" (STEAM) camera creates each image using a very short laser pulse—a flash of light only a billionth of a second long. The STEAM camera's shutter speed is 27 picoseconds, about a million times faster than a current digital camera. (A picosecond it one trillionth of a second.)
An instrument must meet two major requirements to detect CTCs in a blood sample. Of course, it must have a high sensitivity or signal-to-noise ratio to identify the signals, says lead author Keisuke Goda, a U.C.L.A. program manager in electrical engineering and bioengineering. "And it must be high speed, otherwise it would take a ridiculously long time [to find a cancer cell] because the background cell count is huge." The STEAM flow analyzer is an automated microscope 100 times faster than the automated microscopes hospitals sometimes use for disease identification, he adds.
The U.C.L.A. camera converts each laser pulse into a data stream from which a high-speed image can be assembled. The team used this technology to identify breast cancer cells in a blood sample. "We look at the cell's shape, size and texture as well as its surface biochemistry," Goda explains. "We can tell through high-speed imaging that cancer cells tend to be larger than white or red blood cells. And we know that a cancer cell's shape is ill-defined compared to red and white blood cells."
The researchers are now doing clinical testing on breast, lung, stomach, prostate and intestinal cancer patients' blood samples. Longer term, they want to quickly diagnose additional cancer types, including ovarian and pancreatic cancers, which are fast-spreading and require early detection for a patient to survive, says Goda, who was recently appointed as a chemistry professor at the University of Tokyo but will continue his research with U.C.L.A. He adds that a relatively noninvasive blood test would encourage people to get screened frequently.
Such a blood test could provide a safer and more accurate alternative to mammographies and other imaging tests as well as painful biopsies. MRI and computed tomography (CT) scans can be effective in finding larger tumors, but a patient's prognosis is poor by the time a tumor is detected.
There is already one diagnostic tool on the market for identifying and counting CTCs in blood samples, but it is not optimized for early detection. The U.S. Food and Drug Administration (FDA) in 2004 approved the CellSearch system, made by Johnson & Johnson's Veridex unit, for identifying and counting CTCs in patients with metastatic breast cancer. The FDA has since cleared CellSearch to help guide treatment of metastatic forms of prostate and colorectal cancer as well. Last year Johnson & Johnson said it would invest $30 million in a partnership with Massachusetts General Hospital to further develop CellSearch.
Despite these planned upgrades, "the U.C.L.A. work has promise as an advance over what is currently available," says Leon Esterowitz, a program director at the National Science Foundation (NSF). CellSearch is used primarily to check the progress of cancer treatment, whereas U.C.L.A.'s imaging technology could find cancerous cells at an earlier stage, before they can form a new tumor. "They've greatly improved the sensitivity and speed of the techniques that are being used for instance by Johnson & Johnson," Esterowitz says.
Researchers at New York City's Weill Cornell Medical College and Cornell University College of Engineering in Ithaca are also developing a cancer blood test, although theirs uses a "geometrically enhanced differential immunocapture" (GEDI) silicon chip that can identify and collect cancer cells from a patient's blood sample. The chip works in a device that can determine when patients have a high concentration of rare cancer cells from metastatic prostate cancer, according to the researchers, who described their work in the April 2012 issue of PLoS ONE. GEDI, like CellSearch, would be used to determine the efficacy of the patients' chemotherapy rather than finding early-stage cancer cells.
Esterowitz notes that all these blood tests are effective only after cells have become cancerous. He points to a Northwestern University project that aims to illuminate precancerous cells. Northwestern researchers are analyzing tissue at the nano—as opposed to the micro—scale to root out cells whose nuclei have greatly expanded or otherwise show irregularities that could be signs of impending malignancy.
Northwestern's approach, led by biomedical engineer Vadim Backman, involves shining light on tissue either inside a patient's body or taken from it. The researchers use a combination of microscopy and spectroscopy to examine how that light is reflected. Fluctuations in the reflections indicate possible abnormalities in the sampled tissue's micromolecular density and may flag the presence of unhealthy cells, Backman says.
"Most effort in the past has been studying cancer cells and tumors themselves, but we're focusing on what precedes the tumor," Backman says. "The tumor is the tip of the iceberg. We want to look below the waterline."
Backman and his team claim to have already tested their technology on 2,000 patients with a high degree of accuracy. The next step is to develop a compact, easy-to-use version that could be commercialized, and then conduct additional tests to earn FDA approval for what could be an even more effective cancer early warning system.
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