Skin may hold key to predicting cancer risk elsewhere in body

Key Points

Harry Rubin, D.V.M., D.Sc. (hc), professor emeritus in the department of molecular and cell biology at the University of California, Berkeley, reports in the September 2009 issue of the journal Cancer Epidemiology, Biomarkers and Prevention that mutations should be observable in tissue - namely, skin - before cancers develop. And the solution for detecting cancers early might be as simple and inexpensive as culturing a few skin cells.

"What we had discovered some years ago, using a certain permanent line of fibroblastic cell cultures ... (was) that we could imitate a kind of progression of the tumorigenic state by measuring what is called the saturation density. The saturation density means you can grow them up to a certain population density of cells until they stop growing," Dr. Rubin says. "We found ways of enhancing or amplifying the saturation density - making it reach higher and higher concentrations in repeated rounds of selection. After a few of these treatments under defined conditions, they would actually become cancer cells."

Dr. Rubin says research by others a few decades ago showed that individuals with familial adenomatous polyposis, a type of colorectal cancer, carry a familial mutated gene that greatly increases the likelihood that they will develop colorectal cancer at a young age. That gene was later identified as the tumor suppressor gene adenomatous polyposis coli (APC).

"What was discovered back then was that if you take a biopsy of the skin and grow the connective tissue cells - the fibroblasts - in culture, you can measure their saturation density. Cultures of people with this mutated gene will grow to twice the saturation density of fibroblasts from the skin of unaffected people," Dr. Rubin says. "What that means is that even though the fibroblasts are perfectly normal in appearance, every cell in the bodies of these people has the mutation in that one gene and is one step toward making a cancer, but it only becomes fully manifest in the colon and rectum."

Saturation density of skin fibroblasts was also elevated in women actually bearing breast cancer, indicating there is a significant heritable component of this type of tumor, he says.

Saturation density

Dr. Rubin proposes that the amplified saturation density method would be simpler, more quantitative and much less expensive than existing multigenic methods in determining cancer susceptibility. More research, he says, is needed to determine which other heritable neoplastic conditions in humans would be detectable by saturation density testing.

The amplified saturation density method, Dr. Rubin says, might also be successful for doing cancer susceptibility research in the general population. It is proposed that researchers take skin fibroblasts from people in large populations and correlate the saturation density with the incidence of cancer. However, it would be prudent and expedient to precede the work in humans with tests in experimental animals of known cancer susceptibility, according to Dr. Rubin.

Field cancerization

Another research concept that logically follows from Dr. Rubin's recent paper that applies to skin cancer, as much as to any other cancer, is the phenomenon called field cancerization.

"By definition, preclinical aspects of cancer are not detected before you get a tumor. These aspects are called cancerization fields," he says. "Pathologists have found that if you surgically remove a skin or head and neck cancer and examine the edge of the incision where you have also taken out some macroscopically normal tissue, microscopic examination usually reveals that it is not really normal.

"The epithelial cells adjacent to the cancer grow in more layers in the region around the cancer, but are not cancer. Having such hyperplastic field of what appears grossly to be normal epithelial cells increases the danger of developing a second primary tumor," Dr. Rubin explains.

Such cancerization fields have been found around tumors of many organs, especially squamous cell carcinoma of skin and the oral cavity. (See R.A. Willis' classic text, The Pathology of Tumors). Practically nothing is known about the earliest stages of cancerization because they have only been recognized after histological examination of the excised tumor, he says.

Dr. Rubin is preparing a paper on how to study field cancerization in a more fundamental way in cell culture, using the amplified saturation method to fully describe all stages of the process, and what conditions drive it.

"If we could study the dynamics of the whole process in culture, we might find a way to reduce the likelihood of a second primary tumor after removal of the first one. The field cancerization area is still present in the seemingly normal tissue that remains, because it covers an area wider than the tumor itself," he says.

"If possible, the entire cancerization field might be removed, but often it covers too large an area to permit continuing function of the remaining tissue. Alternative local or systemic treatments could be found that would reduce the probability of second primary tumors."

As an emeritus professor who is no longer doing experiments, Dr. Rubin says much of this work will have to be done by others, but he says he would be glad to cooperate with anyone interested in undertaking the studies in cell culture.

Regarding the test for cancer susceptibility in the published paper, "It (is) a great idea, scientifically; the question is, 'Is it there clinically?'" says Douglas Brash, Ph.D., professor of therapeutic radiology, genetics and dermatology, Yale School of Medicine, in a UC Berkeley press release on Dr. Rubin's research. "This is interesting enough that someone should look to see whether it is clinically reliable."

Disclosure: Dr. Rubin reports no relevant financial interests.