Protein holds back growth of head and neck tumors

January 31, 2006

A protein associated with the growth of head and neck tumors may be a tumor suppressor that could prevent the spread of cancer when it is expressed above normal levels, according to a study published in the Feb. 1 issue of the Journal of the National Cancer Institute (JNCI).

The study, led by University of Pittsburgh School of Medicine professor of otolaryngology and pharmacology, Jennifer Grandis, M.D., is the first to show that the expression of a protein called STAT1 may play a vital role in preventing head and neck tumor growth. STAT1 belongs to a family of proteins called signal transducers and activators of transcription that have been linked to tumor progression in many cancers.

"While the activation of STAT1 has been associated with increased survival in breast cancer patients, its role in head and neck cancer has not been clearly understood," said Dr. Grandis. "Our study reveals that it is a critical survival pathway in head and neck cancer and that therapeutic strategies to restore its functioning may be of benefit to patients."

Dr. Grandis, who also is director of the Head and Neck Cancer Program at the University of Pittsburgh Cancer Institute (UPCI), and colleagues compared the expression of STAT1 in squamous cell carcinoma of the head and neck (SCCHN) tumors to its expression in normal tissue samples. They found that STAT1 was expressed in lower levels in the tumor cells than in the normal cells. And, when they chemically altered the expression of STAT1 to increase its levels, the cancer cells diminished and died.

To alter the expression of STAT1, the researchers treated cells with an agent that removes methyl groups and modifies gene expression. Some of the SCCHN cells were then treated with chemotherapy alone and others in combination with azacytidine, an agent that reversed the process and increased STAT1 production. Those cells treated with chemotherapy and azacytidine were more responsive to the treatment and more likely to stop growing and eventually die.

"When STAT1 signaling was silenced, the tumor cells grew indicating to us that its loss promotes cancer growth," said Dr. Grandis. "On the other hand, when the signaling was increased and combined with chemotherapy, cancer cells were more likely to die."

More than two-thirds of head and neck cancer patients have a locally advanced stage when diagnosed. The disease has a poor five-year survival rate even after treatment. Current treatment options are limited and often cause disabling side effects.
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The study was funded in part by a specialized program of research excellence grant in head and neck cancer awarded to UPCI by the National Cancer Institute in 2004. Co-authors on the study include University of Pittsburgh researchers Sichuan Xi, Kevin F. Dyer, Mark Kimak, Qing Zhang, Ph.D., William E. Gooding, J. Richard Chaillet, Ph.D., Raymond Liu Chai, Robert E. Ferrell, Ph.D., Beth Zamboni, and Jennifer Hunt, M.D.

University of Pittsburgh Medical Center

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