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University Of Pittsburgh Researchers Uncover Mitochondrial Defect Involved With Inherited Cancers

PITTSBURGH, February 3, 2000 — University of Pittsburgh researchers have uncovered a major new concept of how a certain type of tumor develops by linking a specific defect in mitochondria to a type of inherited tumor.

The Pitt scientists, led by Bora E. Baysal, M.D., Ph.D. and Bernie Devlin, Ph.D., Western Psychiatric Institute and Clinic, found that a defective gene on chromosome 11q23, a region previously implicated in the progression of many solid cancerous tumors, causes a hereditary tumor called hereditary paraganglioma. Paraganglioma tumors most commonly occur in the carotid body, a small organ located in the carotid artery in the neck that senses blood oxygen levels. This discovery is important because for the first time it ties a genetic defect in mitochondria (energy producing organelles inside the cell) to tumor development.

Results of the study appear in today’s issue of the journal Science.

The researchers became interested in families with paraganglioma who show a peculiar inheritance pattern, which can be explained by a process called "genomic imprinting."

While the genetic defect is transmitted through both mothers and fathers, tumors develop only when fathers transmit the defect. The researchers found that a gene named succinate-ubiquinone oxido-reductase (SDHD), that codes for an integral part of mitochondrial complex II, was defective in families with paraganglioma. By the researchers’ reasoning, the defect is likely to cause mitochondria to fail to properly sense the oxygen levels in the cell. And, because of the oxygen-sensing defect, the carotid body is chronically stimulated to compensate for the lack of oxygen. This chronic stimulation eventually leads to cellular proliferation and tumor development. Chronic atmospheric hypoxia (reduced oxygen level) was previously linked to the development of paraganglioma tumors in people living at high altitudes.

It is conceivable, argue the researchers, that defective oxygen sensing is a fundamental process for the progression of many common solid cancers. It is well known that lack of oxygen helps the development of more malignant cell types in common solid tumors.

"This finding is important because we know that hypoxia actually helps some common forms of cancer become more hardy," said Dr. Baysal. "Most cells, and most cancer cells, are harmed by low oxygen. Low oxygen normally causes cells to self-destruct. In some cancer cells, however, the mechanism for cell death is turned off. These cells reproduce under the difficult conditions brought on by low oxygen levels. The result is that the tumor cells are more aggressive and more difficult to treat. The stressful environment of hypoxia creates a stronger tumor."

According to Dr. Baysal, some types of chemotherapy and radiation treatments rely on oxygen as a reagent to destroy cancer cells. In a tumor with low oxygen levels, those therapies cannot be as effective.

If the Pitt research team’s hypothesis is correct, this discovery may lead to more effective cancer treatments, and have important implications for other common diseases where hypoxia is involved, like stroke and heart attack. The discovery of the gene may also reveal novel "genomic imprinting" mechanisms to explain why only fathers transmit this tumor, said Dr. Baysal.

The University of Pittsburgh researchers were Robert E. Ferrell, Ph.D.; Joan E. Willett-Brozick, B.S.; Elizabeth C. Lawrence, B.S.; Wendy S. Rubinstein, M.D., Ph.D.; and Eugene N. Myers, M.D. Collaborating researchers involved were David Myssiorek, M.D., Department of Otolaryngology and Communicative Disorders, Long Island Jewish Medical Center; Anne Bosch, B.S.; Andel van der Mey, M.D.; Peter E.M. Taschner, Ph.D.; Peter Devilee, Ph.D.; and Cees J. Cornelisse, Ph.D. of Leiden University Medical Center, Leiden Netherlands; and Charles W. Richard, III, M.D, Ph.D., of Wyeth-Ayerst Research.

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