Nov. 22, 2000 CHAPEL HILL - New laboratory research at the University of North Carolina appears to kindle prospects of finding ways to treat head and neck cancer with gene therapy.
The study published November 20 in the journal Human Gene Therapy suggests that gene therapy techniques may be developed to preferentially target cancer cells or pre-cancerous cells that are at high risk for becoming malignant.
"Right now there's no clinical application of our work in human gene therapy, but findings from our tissue culture model suggest there may be," said Wendell G. Yarbrough, MD, assistant professor of otolaryngology/head and neck surgery at UNC-CH School of Medicine and Hospitals.
The Carolina researcher, a member of the UNC Lineberger Comprehensive Cancer Center, said he and his collaborators developed a tissue culture system that mimicked how normal cells grow in the body. Using cultured cells, they created models that mimicked the three-dimensional structure of head and neck epithelium, the normal tissue that lines the inside of humans' mouths and throats. This allowed a more realistic investigation of a widely studied gene transfer technique that uses a common cold virus - adenovirus - to infect cells and deliver therapeutic payloads.
"If you take cells out of the body and put them in tissue culture, they typically grow as a monolayer, one cell layer thick," Yarbrough explained. "But that's not the way they are in the body. These can be infected by adenoviruses very easily. "But if you let cells start piling up on each other and differentiating the way they do in the body, then it's very hard to infect them."
Now it appears that the reason for that is linked to whether or not the cells show gene expression of a specific protein, a receptor site known as hCAR, human coxsackie and adenovirus receptor.
"And that's what we found. We correlated the ability of cells to be infected by adenovirus with the expression of hCAR, a receptor that's responsible for binding to adenovirus and getting it into the cells," Yarbrough said. "This is the first report of gene expression of this receptor in normal human epithelium."
But that was only part of the story.
The researchers found it much more difficult to infect normal human oropharyngeal (mouth) epithelial cells than it was to infect oropharyngeal tumor cells. "We wanted to know why. And we found that as normal cells differentiate, they lose expression of this hCAR receptor," Yarbrough explained. "Only the basal cells, the ones that are still dividing, express this receptor whereas the superficial cells that are differentiated do not," he said.
Thus, according to the researchers, the data suggest that in normal epithelium the overlying squamous cells act as a barrier preventing adenoviral infection of underlying cells that would otherwise be easily infected. This situation is in stark contrast to that observed in tumor cells. Tumor cells do not lose expression of the adenoviral receptor as they pile up and therefore are easily infected. The overlying tumor cells do not act as a barrier and therefore allow for infection of underlying tumor cells.
According to the researchers, the fact that tumor cells can be easily infected while normal cells are poorly infected offers an opportunity to use gene therapy to specifically treat cancer tissues without damaging normal tissues.
The findings also carry possible implications for treating severe cellular dysplasia, a precancerous condition characterized by cellular abnormalities. These cells are undifferentiated and like cancer cells express the hCAR receptor.
"So, theoretically, in people at high risk for cancer, adenoviral gene therapy would only infect the pre-cancerous sites and leave the normal, well-differentiated sites alone," Yarbrough said. "We think this model is useful for testing future gene therapy agents to determine the effects on normal epithelium and tumor cells. It's a great model to study gene therapy without having to test humans or animals. We wanted a model that best replicates what goes on in humans and we think our model does that."
Yarbrough's study collaborators included otolaryngology/head and neck surgeon Mark E. Hutchin, MD and Raymond J. Pickles, PhD, research associate with UNC's Cystic Fibrosis-Pulmonary Research and Treatment Center.
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