A glass plate with a nanoscale roughness could be a simple way for scientists to capture and study the circulating tumor cells (CTC)that carry cancer around the body through the bloodstream (illustration). Engineering and medical researchers at theUniversity of Michigan have devised such a set-up, which, they say, takes advantage of thedifferential adhesion preference of cancer cells to nanorough surfaces when compared to normal blood cells (compared with normal blood cells, cancer cells havestronger drive to settle and bind). If successful, this research may offer a potential alternative to invasive biopsies as a source of tumor tissue for the detection, characterization and monitoring of cancers.

Circulating tumor cells (CTC) are believed to be essential for the establishment of cancer metastasis.They areconsidered to be theseeds, shed into the vasculature,which are responsible for metastasasingcancer from the primary tumor siteto vital distant organs, triggering a mechanism that leads tothe vast majority of cancer-related deaths.

Blood tests that count these cells can help doctors predict how long a patient with widespread cancer maylive. Therfore,detection and analysis of CTCsofferan invaluable tool for early stage detection of cancer as well as for neoplastic progression and recurrence monitoring. In contrast of analysis of solid tumors, whichrequire invasive procedures that strongly limited the patient compliance,a blood tests are relatively easy.Furthermore,the possibility to monitor over the time the disease progress allow to develop appropriate therapy modifications, potentially improving patient?s health related quality of life (HRQoL).

However, as important as the castaway cells are, scientists don’t know a lot about them. They’re rare, at about one per billion blood cells. And they are not all identical, even if they come from the same tumor. Existing tools for isolating them only catch certain types of cells?those that express specific surface proteins or are larger than normal blood cells.

Cancer Stem or Progenitor Cells
For example, the commonly used, FDA-approved CellSearch? CTC Test(Veridex, LLC)uses antibody- coated magnetic beads to seek out tumor cells and bind to them. But not all circulating tumor cells express the proteins these antibodies recognize. It is possible that the most dangerous ones, known as cancer stem or progenitor cells, may have shed that tell-tale coat, thereby evading approaches that rely on antibodies.

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CapturingCirculating Tumor Cells
The researchers say their system could likely trap these stealth cancer stem cells?a feat no research team has accomplished yet. “Our system can capture the majority of circulating tumor cells regardless of their surface proteins or their physical sizes, and this could include cancer progenitor or initiating cells,” said Jianping Fu, Assistant Professor of Mechanical Engineering and Biomedical Engineering and a senior author of a paper on the technique published online in ACS Nano.

Fu and his engineering colleagues teamed up with University of Michigan senior cancer researcher and breast cancer clinician Sofia D. Merajver, M.D. PhD., Scientific Director of the Breast Cancer Program and Director of the Breast and Ovarian Cancer Risk Evaluation Program at the UM Comprehensive Cancer Center. She is also Professor of Internal Medicine and Epidemiology.

This multidisciplinary group believes that while the device could one day improve cancer diagnosis and prognosis, its first uses would be for researchers to isolate live circulating tumor cells from blood specimens and study their biological and physical properties.

“Understanding the physical behavior and nature of these circulating tumor cells will certainly help us understand better one of the most difficult questions in cancer biology?the metastatic cascade, that is, how the disease spreads,” Fu noted. “Our system could provide an efficient and powerful way to capture the live circulating tumor cells and use them as a surrogate to study the metastatic process.”

Cell behaviour and metastases
But capturing them, as challenging as it has proven to be, is only the beginning, Merajver said, who has spent the last 18 years studying cell signaling and the physical properties of highly aggressive cancer cells. “The application of integrative biology is necessary to put together the story of how these cells behave in time to achieve successful metastases and thereby discover the routes to suppressing this deadly development,” Merajver noted. “Our collaboration with the Fu lab exemplifies the innovation needed for the war against cancer?team science from the lab all the way to the clinic.”

In their experiments, the researchers used a standard and inexpensive microfabrication technique called “reactive ion etching” to roughen glass slides with a nanoscale resolution. Then, they spiked different blood samples with cancer cells derived from human breast, cervical and prostate tissues. When they poured the samples over the glass plates, the nanorough glass surfaces captured an average of 88 percent to 95 percent of the cancer cells.

Fu suggests why. “Blood cells are intrinsically floating. Cancer cells including circulating tumor cells derived from solid tumors are presumably adherent cells. They can escape from the primary tumor while maintaining certain adhesion properties that allow them to attach and establish another tumor.”

In other studies, researchers have noticed that circulating tumor cells tend to stick to rough surfaces. But the rough surfaces in those studies were coated with capture antibodies. These new nanorough surfaces do not require capture antibodies. “Our method presents a significant improvement as it can be applied in principle to any cancer cell that comes from solid tumors,” Fu said.

For more information:
Chen W, Weng S, Zhang F, Allen S, Li X, Bao L, Lam RHW, Macoska JA, Merajver SD, Fu J. Nanoroughened Surfaces for Efficient Capture of Circulating Tumor Cells without Using Capture Antibodies. ACS Nano. 2012 Dec 5. [Epub ahead of print][Pubmed]

Photo 1: Jianping Fu, Assistant Professor of Mechanical Engineering and Biomedical Engineering. Photo 2: Sofia D. Merajver, M.D. PhD., Scientific Director of the Breast Cancer Program and Director of the Breast and Ovarian Cancer Risk Evaluation Program at the UM Comprehensive Cancer Center. Illustration: University of Michigan researchers have devised a way to capture for study the circulating tumor cells believed to lead to the spread of cancer. They’ve developed a nano-roughened glass plate that the cancer cells adhere to at greater rates than non cancerous cells.Illustration courtesy: Weiqiang Chen.

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