Putting the Brakes on Prostate Cancer: Time for “Peter Pan”
  to Grow Up


A cancer cell is a lot like Peter Pan: It doesn’t want to grow up. Normally, cells are supposed
to divide and generate new cells, and then mature into differentiated cells, with well-defined boundries — on a very small scale, the equivalent of settling down and having a fenced-in yard in the suburbs. This maturation is called “terminal differentiation,” and cancer cells don’t do it. They do not complete this process, and “there is abundant evidence that this contributes to their unlimited potential to grow, divide and ultimately causes loss of life,” says pathologist Angelo De Marzo, M.D., Ph.D., the Beth W. and A. Ross Myers Scholar.

What is wrong with these cells? Why don’t they want what the rest of us are supposed to want — to grow up, do their jobs, have a nice, peaceful life, and not cause any trouble?

Something is missing: A key brake to prevent rampant cell division. De Marzo believes he and colleagues have not only identified an important culprit, but they’ve found out why this is happening in men who get prostate cancer.

More than a decade ago, as a postdoctoral fellow working with legendary Hopkins scientist Donald S. Coffey, Ph.D., De Marzo learned that a protein called p27 was decreased in prostate cancer cells. This protein is known as a “cell cycle control gene,” which means it helps put the brakes on out-of-control growth. But p27 was even decreased in prostate cells that hadn’t yet become cancerous; these cells, misfits that are not cancer, but not normal, either, are called prostatic intraepithelial neoplasia (PIN), and they are direct precursors to prostate cancer. In the normal prostate, p27 levels were highest in the most mature, “well-adjusted,” terminally differentiated cells.

Scientists have known, from research in mice, that inactivating p27 in the prostate causes the development of early prostate cancer. Men with low levels of p27 tend to have cancer that is more advanced and difficult
to cure. But no one has figured out how or why p27 is decreased in prostate cancer.
Cheryl Koh, a Ph.D. student working in De Marzo’s laboratory, may have uncovered a possible explanation: a protein called MYC (pronounced “mick”). This work stemmed from a recent finding just published online by Bora Gurel, M.D. (a postdoctoral fellow working with De Marzo) and others, including De Marzo, William B. Isaacs, Ph.D., and Jun Luo, Ph.D., and Chi Dang, M.D., Ph.D., a renowned expert on MYC, of the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins.

What is wrong with these cells? Why don’t they want what the rest of us are supposed to want — to grow up, do their jobs, have a nice, peaceful life, and not cause any trouble?

MYC, which lives in the nucleus of cells, is an administrator type; it regulates cells’ proliferation and growth. In normal cells, MYC makes few public appearances, appearing only briefly, and at low levels. When something goes wrong, when MYC doesn’t function properly and is churned out at abnormally high levels in cells, it can cause cancer; in fact, unregulated MYC has been demonstrated in many types of cancer. This recent work by Gurel and colleagues showed, for the first time, that MYC protein levels are elevated in most human prostate cancers and in PIN lesions. Thus: When MYC goes up, p27 goes down, and this leads to prostate cancer.

In laboratory experiments, Koh knocked down levels of MYC protein in prostate cancer
cells. In four different types of prostate cancer cells, she found that this profoundly inhibited cell division. “These are very exiting results,” says De Marzo, who had worried
that advanced cancer cells — such as those tested by Koh — might have figured out how to bypass MYC, and to grow on their own. “These studies suggest that prostate cancer cells remain addicted to MYC, in that they still need it to divide.”

Looking at samples of prostate cancer tissue under the microscope, De Marzo observed that cells which expressed high levels of MYC “appeared to be the identical cells that contained low levels of p27.” Armed with these observations, Koh then discovered that when she decreased the level of MYC in prostate cancer cells, not only did cell proliferation go down, but p27 went up — and this seemed to put the brakes back on cancer cell division. When Koh simultaneously inhibited p27 and MYC, cell proliferation did not go down as much. This revealed that more p27 is required to stop prostate cancer cell proliferation when MYC is reduced.

The next step, De Marzo says, is to determine precisely how MYC is regulating p27. “We will harness the expertise of all our collaborators, including Dr. Dang, to help us uncover these mechanisms.” Even more exciting, he adds: “This new work suggests that methods to decrease the activity of MYC in cancer cells — which are already under development in other laboratories — may be useful in treating prostate cancer in the clinic.”

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