Are all moles really tumors?

Some scientists seem to think so. As a multiple malignant melanoma survivor and someone who has many dysplastic nevi, I would seem to think these researchers are correct. Many of the moles on my body date back to when I was very young. The vast majority are harmless but some mutated. Its been almost 13 years since my original melanoma diagnosis and I've been free of disease despite having four removed from my body. Next week I go for my annual cancer checkup with the oncologist.

God bless the Melanoma warriors.

Linked to- Third World County, Planck's Constant,

For those of us with dozens of moles, the spots speckling our skin can seem no more significant than freckles. But it turns out, each mole is a tumor of pigment cells that started on a path to cancer and then stopped. The cells do not divide again. A mole is an incipient cancer that halted in its tracks.

It is a view that has surprised even scientists. Moles, it turns out, are a sort of strange hybrid in the cancer spectrum. They are little benign tumors, meaning they are harmless, with cells that cannot spread through the body like a cancerous tumor and kill a person. But moles start out the same way that malignant tumors start out, with a mutated gene that lets cells proliferate wildly.

“Moles are real tumors,” said Dr. Wolter J. Mooi, a pathologist at the Vrije University Medical Center in the Netherlands. If mole cells did not stop growing, he said, “chances are that by the time we were 10 years old, we would not only have very large moles, but some might well have progressed to fully malignant melanomas.”

And moles may not be the only tumors like that. Some scientists now suspect that the same sort of phenomenon is happening inside the body as well, with tiny tumors heading off on the path to cancer and then halting forever. They usually go unnoticed because they are tiny, no one is looking for them, and they have no pigment, meaning they don’t stand out like moles on the skin.

“I would bet my last penny that our bodies are riddled with these things,” said Dr. David E. Fisher, the director of the melanoma program at the Dana-Farber Cancer Institute in Boston.

It’s an unnerving idea: a cell randomly gets a mutation in a gene that puts it on a path to cancer. As a result, the cell starts to divide. Then, just as suddenly, the whole process stops, and there is a little tumor whose cells may never divide again.

But scientists say the process in which moles and molelike tumors start and then stop may be good news. It seems to be an important way for the body to stop cancers that can easily get going when a random mutation pushes a cell along that path.

“It is a fair guess to say that this mechanism protects us from cancer over and over again,” Dr. Mooi says. “Perhaps on a daily basis.”

It is not the only way to stop a cancer, but it must be a highly effective one given all the moles that many people have. In fact, it is so effective that melanomas very rarely, if ever, come from moles, Dr. Fisher said. Instead, they seem to come from other skin cells.

Of course, few would have predicted that a cell could start along a path to cancer and then stop, and when scientists first suggested it, they were met with skepticism. Many researchers did not believe the effect was real. Most of those doubters have changed their minds, though, because new research shows that the phenomenon explains moles and similar tiny tumors that scientists recently found in human prostate glands. Now, scientists are saying that they want to develop cancer treatments that mimic the process. The goal is to deliberately force cancers back to the stage where their cells stopped dividing.

It’s a prospect that is still very much on the horizon, and it is impossible to predict when, or even if, it will lead to treatments. But at least in the eyes of many scientists, the possibilities are real.

“It is an explosive topic with very important therapeutic implications,” said Dr. Pier Paolo Pandolfi, the head of the molecular and developmental biology laboratory at Memorial Sloan-Kettering Cancer Center.

The story of how and why the process was discovered dates to 1982, when the first human cancer gene, ras, was found in bladder cancers. Like the many other cancer genes that have been found since, it was a normal gene that had been mutated so that it no longer functioned. Ras turned healthy-looking normal cells into cancer cells, with ugly jumbled chromosomes and wild, uncontrolled growth.

There was one glitch, but few paid it much attention. The ras gene did not convert every type of cell into cancer, and in particular, it seemed to work best with one type of cell. Those were so-called immortalized cells.

Unlike ordinary cells, which divide a certain number of times in the laboratory and then stop, immortalized cells have genetic changes that allow them to divide indefinitely. Scientists used them because they were easy to maintain, said Scott Lowe, a Howard Hughes Medical Institute investigator at Cold Spring Harbor Laboratory.

One paper, however, raised questions. Its lead author, H. Earl Ruley, now at Vanderbilt University, pointed out that the ras gene not only failed to produce cancer in cells that were not immortalized, but also seemed to do something else. It seemed to make such cells stop dividing altogether. It let them remain alive but never divide again. In his paper, published in 1988, Dr. Ruley even suggested pursuing the work to develop cancer therapies.

That idea, however, went against the entire cancer gene hypothesis. Why would a cancer gene make a cell stop growing? Cancer genes were supposed to make cells grow out of control, not stop. And no one had any idea how such a process, if it were real, would even work.

“People didn’t get it,” said Dr. Lowe, who was Dr. Ruley’s doctoral student.

But as techniques of molecular biology improved, Dr. Lowe and a few others revisited Dr. Ruley’s idea and untangled the molecular biology.

They discovered that the very cancer gene that makes a cell grow eventually turns on other genes that stop growth. Researchers called the process oncogene-induced cell senescence and said it might be one way to stop a cancer from progressing.

“The cell has a built-in sensor that says ‘shut down proliferation’ and says ‘O.K., that’s enough,’ ” Dr. Lowe said. “Then the cells will never divide again. It’s a terminal event.”

Dr. Mooi recalled his astonishment. “It was an amazing finding,” he said. And it raised an obvious question: Did this happen in humans, or was it an artifact of growing cells in petri dishes?

“There was this conundrum,” Dr. Lowe said. “If you couldn’t see it in animals, maybe it was not relevant.”

But recent research changed all that.

Dr. Mooi and Daniel Peeper of the Netherlands Cancer Institute in Amsterdam showed that the phenomenon explains what happens in moles. Mole cells have a cancer gene, BRAF, that makes them divide. BRAF then turns on another gene, p16, that makes them stop dividing forever.

Dr. Leonard Zon and Elizabeth Patton of Children’s Hospital, Dr. Fisher, and their colleagues produced moles in zebrafish by giving them the BRAF gene. Next they tried the same experiment in zebrafish that lacked a gene, p53, that prevented the BRAF gene from activating the cell’s brakes on cell division. The result was a malignant cancer, moles that quickly turned into deadly melanomas.

The same sort of thing happens in the prostate, Dr. Pandolfi discovered. In prostate glands removed from men with early prostate cancer, he saw cancer cells, of course, but he also saw something else: tumors that were the molecular equivalent of moles, made up of senescent cells.

The investigators began asking why those senescent cells in the prostate glands had stopped dividing. The story was the same as in moles. First the cells lose a normal gene, PTEN, that is often missing in prostate cancer. The effect is the same as knocking out a normal gene with a mutation that creates a cancer gene. Without PTEN, cells grow aberrantly. Then the cells turn on their p53 gene. That halts their division forever.

Dr. Pandolfi and his colleagues reproduced the effect in mouse prostates, creating molelike tumors there. Then they asked what would happen in mouse prostates if cells lost not only PTEN but also p53, the fail-safe gene.

“This tumor was now devastating,” Dr. Pandolfi said. “It was a tremendously aggressive tumor. It would kill the mouse in a few months.”

Now he wants to find treatments that revert cancers back to a molelike state.