Cancer works its malignant will by standing cell life on its head. No form of cancer is better at flipping normal cell mechanisms for growth and movement into sinister contraptions for evasion and invasion than aggressive colorectal tumors. Kidnapping is a particular talent, especially along the cancer's invasive edges. That's where Avri Ben-Ze'ev and colleagues at the Weizmann Institute of Science in Israel and elsewhere found an unlikely hostage to colorectal cancer in L1, a protein more commonly produced by growing nerve cells. Their findings were presented recently at the 45th Annual Meeting of the American Society for Cell Biology in San Francisco.
Ben-Ze'ev and Nancy Gavert, a surgeon and current Ph.D. student--were led to the kidnapped nerve cell protein, L1, by their long-term interest in beta-catenin, a cadherin-binding protein, known to also activate genes in various types of cancer. In previous studies, the Ben-Ze'ev lab identified several beta-catenin target genes that are involved in development of malignant melanoma and colon cancer. The co-option of L1, though, was a surprise.
Analyzing patient samples of human colorectal cancer, the Ben-Ze'ev lab (in collaboration with Thomas Brabletz of the University of Erlangen in Germany) discovered L1 in large quantities exclusively in cancer cells at the aggressive and invasive front of tumors. In an additional surprise finding, the scientists found concentrations of nerve cell bundles, containing L1, located next to clusters of colon cancer cells that contain L1 on their surface. Localized on the cell membrane, L1 can serve both as a lock and a key in adhesion between cells: as a lock, it binds to L1 receptor molecules on the surface of like cells; as a key, it binds to different surface receptors of other cell types.
"That's what makes L1 so dangerous in tumors," says Ben-Ze'ev. "L1's special abilities in helping nerve cells wire up through intercellular space are hijacked by aggressive tumors to sharpen their invasive edge. The L1 protein makes them better at moving around and penetrating the body's connective tissues, as well as more resistant to adverse conditions during growth and metastasis. The discovery of L1's unwitting role in tumor cell motility and invasion may have important implications for diagnosing colon cancer and for designing new therapies," reports Ben-Ze'ev.
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