Apr. 22, 2002 A key signaling pathway appears to be critical to the earliest transformation of normal colon cells into growths called polyps that may advance to colon tumors, Vanderbilt-Ingram Cancer Center scientists have reported.
The findings suggest that, someday, doctors might use drugs that interrupt this pathway to treat individuals who are found to have colon cells on the verge of this transformation. The goal would be to prevent polyps -- and thus colon cancer -- from ever developing.
"Clearly, we’re a long way from doing that, but the prospects are very exciting," said Dr. Robert J. Coffey, Ingram Professor of Cancer Research and professor of Medicine and Cell Biology. Coffey’s laboratory, in collaboration with the laboratory of David Threadgill, Ph.D., reported their findings recently in the Proceedings of the National Academy of Sciences.
The signalling pathway involves the epidermal growth factor receptor and the "ligands" that bind to it. The receptor sits across the cell surface, much like a satellite dish. The ligand fits into the receptor to transmit signals into the cell that prompt its growth. Scientists are focused on this pathway as more is learned about how it is involved in cancer development and progression and as new drugs are developed to interrupt it.
The Vanderbilt work helps clarify contradictory findings reported more than a year ago by two different groups. One group observed a 90 percent reduction in polyp formation when they used an inhibitor of EGFr in Min mice, a strain that is genetically engineered to develop hundreds of colon polyps. The other group did a similar experiment with a similar drug and found no effect.
So the Vanderbilt researchers instead turned to genetics. They took advantage of a mouse called waved2 that has a naturally occurring mutation in the EGFr tyrosine kinase domain (the section beneath the cell surface) that results in a 90 percent reduction in EGFr activity. These mice were then bred with Min mice. The resulting offspring that had two copies of the defective EGFr developed 90 percent fewer polyps than the other offspring.
Like the other groups, the Vanderbilt group counted polyps when the mice were three months of age. But they went a step further and examined some of the mice at one month of age. In these samples, nothing abnormal was visible to the naked eye, but microscopic examination identified "microadenomas," which represent the very first change as normal cells make the transformation into polyps and then to cancer.
"We found no difference between the two groups in the number of microadenomas that were present," Coffey said. The microadenomas further developed into polyps in the mice with normal EGFr activity, but did not develop into polyps in the mice that had two defective copies of EGFr.
"What this suggests is that these microadenomas are at a precarious state, struggling for survival, and they depend on EGFr signalling to advance to the next stage," Coffey said. "EGFr is playing an important role in the establishment of intestinal neoplasia."
The mice were then followed until a year of age, and there was no difference in the size or progression of the polyps that developed in both groups. "So it appears that the next stage of tumor progression occurs independent of EGFr signalling," Coffey said.
However, the Vanderbilt scientists have demonstrated in other work with mouse models that blocking EGFr activity at a later stage – when a palpable tumor has formed – can shrink the tumors. Taken together, the findings suggest that use of drugs to block EGFr activity should be tailored to the stage of tumor development.
The work reported in PNAS was conducted at Vanderbilt and was supported by the National Cancer Institute. Threadgill is now a member of the faculty at Lineberger Cancer Center at the University of North Carolina. "It’s gratifying to see how well David’s work is progressing and that he now has four RO1 grants in hand," Coffey said.
Other collaborators were M. Kay Washington, Read B. Roberts, Lu Min, Sandra J. Olsen, and Stephen H. Settle.
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The above story is based on materials provided by Vanderbilt University Medical Center.
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