March 2005, Issue 4

Optical Spectroscopic Methods for Early Detection of Cancer

Irene Georgakoudi, PhD, joined the School of Engineering as an assistant professor of biomedical engineering in September 2004. She uses the properties of light to obtain detailed information about cells, especially cancer cells. “The main practical goal is to develop methods that will allow us to see into human tissues so that we can detect a disease and monitor its progress or regression as it is responding to therapy, and to do all this noninvasively,” says Georgakoudi. Her three main projects support this goal. The first is to use optical spectroscopic imaging to characterize biochemical and morphological biomarkers of cancer; the second is to develop and refine in vivo flow cytometry; and the third involves developing high-resolution, depth-resolved instruments for imaging animals and engineered tissues.

In 1999 Georgakoudi received her doctorate in biophysics from the University of Rochester School of Medicine and Dentistry, specializing in photodynamic therapy of cancer. Photodynamic therapy involves administration of a photosensitive drug that accumulates preferentially in a lesion. The drug is activated by irradiation with light, which leads to production of cytotoxic agents. This allows for delivery of the cancer-killing agents directly to the tumor and reduces harm to the rest of the body.

During her postdoctoral fellowship with Michael Feld at MIT’s Spectroscopy Laboratory, Georgakoudi worked on the development of optical spectroscopic methods for detecting cancer at an early stage. For the past 20 months, Georgakoudi has worked as an assistant in physics at the Wellman Laboratories of Photomedicine at Massachusetts General Hospital and as an instructor at Harvard Medical School.

Georgakoudi’s project to develop optical spectroscopic methods for detecting cancer at an early stage is part of a multi-institutional National Institutes of Health-funded grant headed by Michael Feld. The research team uses a variety of spectroscopic techniques, including fluorescence, light scattering, and reflectance, to understand and detect the fundamental biochemical and morphological changes that occur during a cell’s transformation from the normal to the precancerous state. Georgakoudi’s research group is working on fluorescence and light-scattering spectroscopic imaging systems for characterizing the intrinsic optical signatures of events such as apoptosis (programmed cell death) and genomic instability associated with very early, precancerous changes.

“Your cells, and the matrix that supports the cells, naturally emit fluorescence,” Georgakoudi says. “We’re using this intrinsic fluorescence from the cells and the extracellular matrix to get biochemical information about tissue. How metabolically active are the cells? How does their biochemistry change with the development of a precancer? In fact, we’re finding from patient studies that not only do the cells change, but they also start sending signals to the extracellular matrix and they modify its fluorescence and scattering properties at a very early stage, before invasion.”

“We’re also looking at light scattering, which is a method that was developed when I was at MIT,” says Georgakoudi. Light scattering gives detailed information about the cell nuclei, such as the number of nuclei, their size and size distribution, and their optical density, all of which change when a cell transforms from the normal to the precancerous stage. “What we found is that we can use light scattering to get all of this information noninvasively. We’ve shown that we can do that in vivo in the cervix, in the esophagus, in the oral cavity, and in the bladder.”

“So we have the biochemical information from the fluorescence, we have the morphological information from our light scattering, then we also look at another technique that’s called reflectance spectroscopy that looks at multiply-scattered photons,” says Georgakoudi. Reflectance gives information about the bulk scattering properties of the tissue, especially of the matrix.

“The beauty of light is that we have optical fibers now,” Georgakoudi says. “People are familiar with endoscopy, through which doctors use tiny optical-fiber probes to look at your insides. We use a probe that is about a millimeter in diameter, and within that millimeter there are many optical fibers. Some of them send the excitation light; others collect the reflected light. And this is done very fast – in about 0.3 seconds – and noninvasively.”

While Georgakoudi has worked on clinical studies in the past, she plans to work mostly with cells in the near future. “Here [at Tufts] I’m going back to the basics. I’m trying to identify optical signatures of some of the very basic processes that are typically associated with cancer development. We’re trying to take things to the cell and molecular level. Right now we’re looking at primary human keratinocytes, which are epithelial cells that Karl Münger, my colleague at Harvard Medical School, is also working with. He has developed a very nice model of transfecting the cells with human papillomavirus and looking at the cells as they transform.” (Transfection is a method of introducing foreign DNA into living cells.) Human papillomavirus infection is the major risk factor for development of cervical cancer and is associated with 95% of human cervical cancers. The multi-institutional research group is investigating early detection of oral and cervical cancers.

Georgakoudi’s second main project involves the development of in vivo flow cytometry as a noninvasive method for monitoring circulating cells without the need for an exogenous contrast agent. As part of a research group at Massachusetts General Hospital led by Charles Lin, Georgakoudi helped develop a way to look at cells while they are circulating through blood vessels. “We focus a beam of light across a blood vessel that is close to the surface of the skin,” Georgakoudi explains. “The cell that we’ve labeled, using GFP [green fluorescent protein] or fluorescently tagged antibodies, for example, crosses the beam of light, the light becomes absorbed by the chromophore on the cell, fluorescence is emitted, and we detect the fluorescence confocally from a single cell.”

The research team is interested in the process of metastasis, which is the spreading of cancer cells from one tissue to another, usually via the bloodstream or lymphatic system. Detecting cancer cells in the blood stream and obtaining biochemical and morphological information about the cells will contribute to our understanding of how circulating cancer cells are related to metastasis.

The third major project in Georgakoudi’s laboratory is the building of a microscope for acquiring confocal/multiphoton fluorescence, and second-harmonic generation images, at video-frame rates of acquisition. “With the spectroscopic techniques that we’re using, we’re not really doing imaging,” Georgakoudi says. “We’re getting information from points in the tissue. It’s also very useful to be able to obtain images. One of the main applications we’re going to be looking at is engineered tissues.” Georgakoudi will be collaborating with several of Tufts’ tissue engineers, including David Kaplan, chair of the Department of Biomedical Engineering, and Greg Altman, also of the Department of Biomedical Engineering. They’ll be looking at cell matrix interactions during ligament formation, bone formation, and cancer development. Georgakoudi has also started talking with Charlotte Kuperwasser of the School of Medicine about imaging breast cancer metastasis into bone.

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