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Microscopy Advances Open Up New Avenues of Cancer Discovery

, by NCI Staff

Imaged using a technique known as spectral karyotyping, these chromosomes, prepared from a glioblastoma sample, reveal an enormous degree of chromosomal instability—a hallmark of cancer.

Microscopes have come a long way since 17th-century English scientist Robert Hooke peered through his leather- and gold-tooled instrument and discovered the cell. 

Today’s high-powered microscopes, many of which are still based on Hooke’s lens configuration, allow researchers to see and study the fine details of individual cells and to peer into cells. With single-molecule imaging, researchers can track the movement of individual molecules in a cell, and with live-cell, or in vivo, imaging, researchers can even watch cellular processes in action, measuring the timescale at which proteins interact.

“Seeing is still believing,” Tom Misteli, Ph.D., of the Laboratory of Receptor Biology and Gene Expression at NCI’s Center for Cancer Research (CCR) said. “When you visualize what is happening inside a cell, you can see how things work in a way that you could never by biochemistry alone.”

Some examples of the images that result from advances in microscopy will be showcased in Cancer Close Up, a collection of microscopy images taken by NCI scientists that will be shown at the NCI exhibit booth during the American Association for Cancer Research annual meeting. The images can also be viewed and downloaded from NCI Visuals Online, a resource for free cancer-related images.

Dr. Misteli, who helped select the featured images, is part of a growing cadre of researchers using microscopy to open up new avenues of discovery about the inner workings of cells, including the events that can cause healthy cells to transform into cancer cells.

One of the most exciting recent advances in microscopy-aided science, Dr. Misteli said, is the ability to do high-throughput imaging, which has automated many of the once labor- and time-intensive steps needed to prepare biological samples for observation. Using robotics and automated imaging, hundreds of samples can be processed at one time. Data collection from the images is done by a computer, so in addition to studying the images themselves, scientists can analyze quantified data from the images as measured by the computer.

High-throughput imaging allows researchers to not only ask how their favorite protein behaves, but to conduct unbiased discovery assays, or screens, to identify genes that are responsible for any biological process of interest, as long as it can be visualized by light microscopy.

For example, scientists might be interested in the location of a specific protein inside the nucleus or cytoplasm of the cell. Using a technology known as RNA interference, the researchers can disrupt the activity of a particular gene and then examine how this affects the protein’s location.

Thanks to high-throughput methods, this experiment can be repeated for every gene in the genome, enabling researchers to identify all of the genes that play a role in regulating the location of the protein they’re studying.

Another discipline of microscopy that Dr. Misteli says is revolutionizing cancer biology is the observation of processes in living cells. The availability of fluorescent probes that can be attached to protein and DNA in living cells and the development of “gentle” microscopes that allow long-term observation of living cells and tissues has made it possible to follow what happens inside of cells over long periods.

One example of this approach is the research performed in Dr. Misteli’s lab to visualize the formation of chromosome translocations in living cells. To study this phenomenon, the scientists place fluorescent markers on two different parts of a chromosome and observe what happens when they force the chromosome to break near the two markers. The fate of broken chromosome ends has important implications for cancer biology. Cells have ways to repair their chromosomes, but sometimes the wrong ends get stuck together, resulting in a translocation—and translocations can sometimes cause cells to become cancerous.

Understanding the mechanisms by which chromosomes are repaired—correctly or incorrectly—will help researchers understand some of the genetic mechanisms by which healthy cells are transformed into cancer cells.

“Gone are the days when microscopy-aided science was merely observational and ‘pretty’,” Dr. Misteli said. “Now we can use imaging to actually figure out how cells work and for discovery of novel pathways.”

Related Resources

Chromosome translocations in a living cell (video)

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