CLUES: An atomic force microscope (AFM) "feels" the cells, by pushing against a cell's surface to determine its degree of softness.
CONNECTED: When an AFM is connected to an optical microscope, the two can be used to perform nanomechanical analysis of cancer and normal cells.
Breast cancer has proved especially difficult to find and fight due to the cancer cells' ability to blend in with healthy ones. Careful examination of the chemical makeup and shape of normal and diseased cells, however, promises to help doctors draw cancer out of the shadows.
Researchers at University of Michigan's Comprehensive Cancer Center in Ann Arbor report in Cell Stem Cell that they found a marker that can be used to identify cancer stem cells in breast tumors. Even though they account for only 5 percent of cells in tumors, stem cells (defined by their ability to generate identical cells and to morph into other cell types) are believed to play a key role in the spread of cancer.
The Michigan study, which began in late 2004, indicates cells from normal and cancerous breast tissue that contain high levels of the enzyme group aldehyde dehydrogenase (ALDH) acted like stem cells. Of the 577 human breast cancer tissue samples studied, those with tumors that tested positive for ALDH1—a specific form of the enzyme—were less likely to survive and were 1.76 times more likely to develop metastases than patients with ALDH1-negative tumors. ALDH1 was found in 19 percent to 30 percent of the study samples.
The presence of ALDH1 in both normal and malignant stem cells supports the theory that they are the primary target of transformation to malignancy, says study senior author Gabriela Dontu, an assistant professor of internal medicine. "We believe it is only a very small population of cells that really are capable of unlimited growth and therefore drive cancer recurrence and metastasis," she says. "The fact that normal and cancer stem cells share a common feature gives more support that cancers arise from normal stem cells."
The clinical implications of this stem cell model of carcinogenesis "changes the way we approach early diagnostic prognosis and, very importantly, how we develop therapy," Dontu adds. As the research progresses, she and her colleagues plan to develop therapeutic strategies that might eliminate cancer stem cells in breast tumors and cancers from other tissues. The researchers acknowledge, however, that more work is needed before these findings can be applied in clinical tests or treatments.
In a related study, a group of University of California, Los Angeles, researchers are hunting specifically for the cancer cells in body cavity fluids. The team reports in the online edition of Nature Nanotechnology that conventional diagnostic methods—such as using cell markers—detect about 70 percent of cases in which cancer cells are present in the fluid, but miss the rest.
The U.C. Los Angeles researchers, using an optical microscope, found that normal and cancer cells extracted from chest cavity fluid of patients with lung, breast and pancreatic cancers looked very similar. But when they attached an atomic force microscope (AFM) to the ordinary optical scope, they were able to use its minute, sharp tip to "feel" the cells, by pushing against a cell's surface to determine its degree of softness, says study co-author Jianyu Rao, a researcher at U.C.L.A.'s Jonsson Comprehensive Cancer Center and an associate professor of pathology and laboratory medicine.
An AFM is not actually a microscope but rather a device with an extremely small silicon probe that can be attached to an optical microscope for imaging, measuring and manipulating matter at the nanoscale. "It's like a finger that feels the softness of a cell," says James Gimzewski, a U.C.L.A. professor of chemistry and biochemistry and a member of the school's California NanoSystems
After probing a cell, the AFM assigns a value that represents how soft a cell is based on the resistance encountered. The researchers found that the cancer cells are much softer than normal cells, which come in varying degrees of stiffness. This was true of all the pancreas, lung and breast cells studied.
Rao and his colleagues want to use the touchy-feely AFM to test primary tumors for malignancy and study how different cancers behave. "Some tumor cells might be more rigid than others, meaning that they may be less metastatic," and thereby the patient is in less danger, Rao says.
Looking ahead, the AFM is most likely to be used not as an initial detection tool, but rather as a means of checking whether cancer is spreading or in remission. Fluid buildup is not necessarily an indication of cancer, so understanding the nature of the cells in this fluid is very important to determining possible treatments, according to the scientists. "We have to check the fluid to see if it's positive for cancer," Rao says, "because this can determine if a treatment needs to be more aggressive."
U.C.L.A. researchers are also using the AFM to study the effects of different drugs on cancer cells. "We want to see how cells change with the drugs that we use on them," says study co-author Sarah Cross, a U.C.L.A. graduate student in the chemistry and biochemistry department. The goal is to develop less toxic drugs than currently
