Tiny models shed big light on colon cancer

The tools were as tiny as the subject mice. But the brightly fluoresced colon cancer cells brought huge smiles to the faces of investigators at the Center for Molecular Imaging Research at Massachusetts General Hospital.

Dr. Herlen Alencar's work under Dr. Umar Mahmood at the Center for Molecular Imaging Research illustrates how minimally invasive imaging catheters combined with optical probes can light up cancerous tissue.

The current trend in cancer detection is to identify molecular signatures of diseases that can be imaged, rather than relying on imaging anatomic changes indicative of abnormal cell growth.

Dr. Herlen Alencar, whose study won the Fellow Award Presentation at the 2004 RSNA meeting, successfully used minimally invasive imaging catheters in combination with protease activable "smart" probes to detect adenomas and adenocarcinomas in the colon based on the overexpression of these enzymes.

Alencar, who followed up two years of residency in general surgery with three years of urology, found that his background in surgery came in handy when navigating the small descending colon in mice with a miniaturized 2.7-French imaging catheter.

"We had some issues relating to size. The endoscope that we use is very tiny, and it doesn't emit a lot of light. The amount of light is critical for optical imaging," he said.

Two things are needed with optical imaging: a lot of light reaching the sample and a lot of light collected back from the target. The fact that Alencar's team was so successful at imaging such a small subject using so little light bodes well for the technique's entry into the larger clinical world, he said.

The 32-year-old Alencar was born in Brazil. He moved to the U.S. after his urology training and landed at the renowned Center for Molecular Imaging Research at MGH.

He joined the lab's ongoing optical imaging project and helped create a mouse that, unlike the traditional colon cancer model, does not develop spontaneous adenomas. This was important because researchers could not image mice beyond the descending colon, Alencar said.

Two weeks before imaging, investigators implanted colon cancer cells into the descending colon of the two types of mice. The day before imaging, they injected a "smart" optical probe into the mice that increased the fluorescent activity. The imaging agent is enzymatically activated by a broad range of proteases known to be overexpressed in a variety of diseases, including colon cancer in humans.

Four panels from a mouse colonoscopy using a dual-channel endoscope. In the upper row there is a larger exophytic colonic adenoma in an APC mouse in the white light channel (left) and near-infrared channel (right). The bottom panel depicts a smaller flat adenoma that cannot be seen in the white light channel (left) but is brightly fluorescent in the near-infrared channel (right) due to the activable optical "smart" probe used in the study.

The imaging catheter, capable of simultaneously acquiring full-spectrum white light and near-infrared images, was introduced per rectum and lesions were evaluated. White light images provide anatomic localization and visual cues for real-time imaging, while near-infrared images report upon molecular activity.

The optical technique easily captured the large pedunculated adenomas, while normal colonic mucosa produced virtually no near-infrared fluorescence signals.

Large pedunculated adenomas and advanced infiltrating adenocarcinomas were readily visible in both white light and near-infrared channels, but flat incipient adenomas and early-stage adenocarcinomas were visible only in the near-infrared channel.

"This is important," Alencar said. "We want to detect the early preneoplastic adenomas and early cancers. Near-infrared can differentiate between advanced stage cancer and early precancerous and cancerous lesions."

The researchers have also applied the technique to detect bladder and ovarian cancer using similar probes.

The technique shows promise for colon cancer detection because the equipment used is similar to that used in clinical practice and is completely translatable. However, the optical probe is not yet FDA-approved for human use.

The research Alencar completed at the lab has been a very important step in his clinical career, he said. While he is a clinician by training, the experience has given him some very good exposure to basic research.

"I'm excited that I'm helping to develop technologies that I may be using in my own clinical practice in the future," he said.