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Updated 11:00 AM October 9, 2006
 

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Study helps explain why all moles don't become melanomas

Most of the time moles are nothing but a cosmetic nuisance. But sometimes pigment-producing cells in moles called melanocytes start dividing abnormally to form a deadly form of skin cancer called melanoma. About one in 65 Americans born this year will be diagnosed with melanoma at some point during his or her lifetime.
Normal melanocytes (above) compared to senescent melanocytes with cancer-causing mutations (below). (Photo by Maria Soengas)

Scientists know that 30 percent of all melanomas begin in a mole. They know that 90 percent of moles contain cancer-causing mutations. What scientists didn't know until now is how melanocytes stop these mutations from triggering the development of cancer.

Maria Soengas and other scientists in the Multidisciplinary Melanoma Clinic at the U-M Comprehensive Cancer Center have found the answer to this important question in an unexpected place—a structure inside cells called the endoplasmic reticulum, or ER.

"Our results support the direct role of the endoplasmic reticulum as an important gatekeeper of tumor control," says Soengas, an assistant professor of dermatology in the Medical School. "Until now, no one knew there was a connection between ER stress and the very early stages of tumor initiation."

The endoplasmic reticulum is the cell's protein production factory. The process begins when chains of amino acids are deposited in the ER membrane in response to coded instructions from genes. Chaperone proteins fold these amino acids into specific shapes. When too many of them build up in the membrane, or when something goes wrong with the folding process, the system gets bogged down. This can stress or even kill the cell.

To prevent this, the ER sends out distress signals to activate what scientists call the unfolded protein response (UPR). This slows the protein production process and gets rid of excess incoming amino acids, giving the ER a chance to catch up. If that doesn't work, the UPR causes the cell to destroy itself in a process called apoptosis.

"Traditionally, the ER's role was considered to be limited to protein folding or protein modification," Soengas says. "But scientists like Randal Kaufman, a
U-M professor of biological chemistry and co-author on our paper, have found that the ER can sense changes in glucose, nutrients, oxygen levels and other aspects of cellular physiology associated with diseases like diabetes and Alzheimer's disease."

"In our study, we found that the ER senses the activity of certain oncogenes in the melanocyte and triggers a response that prevents the malignant transformation of these cells," Soengas adds.

The tumor-suppressive mechanism induced by the ER in melanocytes with these cancer-causing mutations is premature senescence—a form of "suspended animation" that stops the cell cycle and keeps cells from dividing, but doesn't kill them, she says.

"The cells are held in check—they don't die, but they don't proliferate either," Soengas explains. "In the case of moles, melanocytes can stay this way for 20 to 40 years or even your whole life. For most of us, just holding cells in an arrested state is sufficient to prevent the development of cancer. That's why so many people have moles, but few have melanoma."

Scientists found that the tumor-suppressive response in melanocytes varied depending on the type of oncogene being expressed in the cell.

"We found that some oncogenes activated the endoplasmic reticulum, while other oncogenes didn't," Soengas says.

In a previous study, Soengas and colleagues found that certain oncogenes use a different senescence mechanism, which doesn't activate the ER, to block the transformation of melanocytes. Both these mechanisms work in addition to or independent from other well-known tumor-suppressor mechanisms involving apoptosis.

Soengas says the results of the study will be important in helping scientists understand all the different mechanisms melanocytes use to protect themselves against oncogenes. But she cautions that there are no immediate clinical applications for the study and additional research will be required.

In future research Soengas will attempt to determine exactly how oncogenes trigger the unfolded protein response in malignant and nonmalignant skin cells.

The study was funded by the la Ligue Contre le Cancer, the Dermatology Foundation, the Elsa U. Pardee Foundation and the National Cancer Institute.

Christophe Denoyelle and George Abou-Rjaily, former and current U-M postdoctoral fellows, were co-first authors on the study, along with Vladimir Bezrookove, a postdoctoral fellow at the University of California, San Francisco.

Additional U-M collaborators were Monique Verhaegen, Timothy M. Johnson, Douglas Fullen, Jenny Pointer, Stephen Gruber, Lyndon Su, Mikhail Nikiforov and Randal Kaufman. Boris Bastian from UCSF also contributed to the study.

Results of the study are being published in the October issue of Nature Cell Biology.

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