Most of the moles seem to be just personal signs. But in determined situations, melanocytes (pigment producing cells) in moles can develop melanoma, a deadly skin cancer, by starting to divide abnormally.

In US, one in 65 people develop melanoma at some point during their lifetime. And 30 % of the melanomas develop from moles, because 90 % of them contain cancer triggering mutations. The unknown issue was how melanocytes impede cancer development.

Researchers at the Multidisciplinary Melanoma Clinic at the University of Michigan Comprehensive Cancer Center have found that the endoplasmic reticulum (ER), an internal structure of the cell, is responsible for this. "Our results support the direct role of the endoplasmic reticulum as an important gatekeeper of tumor control," says Maria S. Soengas, Ph.D. "Until now, no one knew there was a connection between ER stress and the very early stages of tumor initiation."

The endoplasmic reticulum manages the cell protein production. Its membrane is loaded with ribosomes. They decode instruction from nuclear acids (genes) to amino acids that combine to proteins.

Sometimes, too many proteins amass in the membrane or they fold wrongly, and the system get overloaded, fact that could stress or kill the cell. In this case, the ER activates the unfolded protein response (UPR) in order to distress the system. The protein production is slowed down and the excess of amino acids is eliminated. If this solution doesn't work, the UPR causes the apoptosis (cell death). "Traditionally, the ER's role was considered to be limited to protein folding or protein modification," Soengas says.

"But scientists 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 inhibiting mechanism induced by the ER in melanocytes with cancer-causing mutations is a form of "suspended animation" that stops cells from dividing, but doesn't kill them. "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."

The tumor inhibiting response of the ER varied with the type of oncogene expressed in the cell. "We found that some oncogenes activated the endoplasmic reticulum, while other oncogenes didn't," Soengas says.

Previously, the same team discovered that certain oncogenes trigger a different form of "suspended animation" that doesn't activate the ER in order to stop cancer development. These mechanisms work in addition to or independently from apoptosis.

The team wants to see exactly how oncogenes determine the UPR in malignant and non-malignant skin cells. "By comparing what happens in normal melanoctyes with what happens in melanoma, we may be able to come up with events that are specific for tumor cells, which could be used for future drug development," she says.

Photo credit: Maria S. Soengas. Mole tissue with cancer causing mutant melanocytes (stained green) targeted by UPR.