Science Editor

Three men out of four who reach 75 years of age will acquire a disease called BPH - benign prostatic hyperplasia. Its symptoms are bothersome, but not dire.

Unwelcome urination is the main bane of BPH. It takes the form of two primary symptoms - frequency and urgency. Frequency means waking often at night to visit the bathroom. Urgency, whether by night or day, insists on answering nature's bladder-voiding call right now, without delay.

Roughly the size and shape of a walnut, the prostate gland wraps around the urethra - the canal by which the bladder empties through the penis. "The human prostate gland," observed research urologist Robert Getzenberg at the University of Pittsburgh, "has a couple of different zones. Its transition zone is the central area in the prostate, where the urethra runs through. That's where the symptoms in BPH arise, because that zone grows in BPH and constricts the urethra."

Getzenberg is senior author of a paper in the Proceedings of the National Academy of Sciences (PNAS), released online today, May 21, 2002, but dated May 28. Its title: "Symptomatic and asymptomatic benign prostatic hyperplasia: Molecular differentiation by using microarrays." (Hyperplasia means overgrowth.)

"The principal finding in this paper is the fact that we can first of all identify two distinct groups of people with BPH," Getzenberg told BioWorld Today. "They comprise patients who have severe symptoms that require aggressive surgery and other types of aggressive therapy, to people who have BPH in their prostate but which may or may not cause symptoms. Prior to our PNAS manuscript," he continued, "all BPH was thought to be one disease. Some people happened to be worse, and others weren't, but it was never thought to be more than a single malady. Clearly, we can now show that it's two different diseases, from a form of BPH that's severe to one that does not cause severe symptoms, if any.

"I think this will henceforth allow us to approach BPH differently at a clinical level," Getzenberg opined. "I think it's given us some new targets in regulating prostate growth that have not yet been previously elucidated."

Symptom Caused By Squeezing Urinary Canal

"Prostate cancer typically happens in the transitional or outer zone of the prostate gland," he pointed out. "And we also looked at BPH in people who had prostate cancer [PC]. Although these PC patients didn't have symptoms, they had BPH. We found out that their BPH is very closely related to the people who have the severest BPH symptoms. So we saw an underlying relationship between prostate cancer and severe BPH that had not been identified to date.

"The reason these people were picked up with PC was not urination symptoms but because they had PSA levels that were elevated, or digital rectal exams that would be abnormal, and therefore they would be biopsied, so they had biopsy-proven cancer. Then the urologist went in and took out the prostate gland. They were removed for PC, and the BPH was found only as we pathologically analyzed the prostates."

To analyze the continuum of BPH tissue from asymptomatic through to PC via microarray gene chips, Getzenberg and his co-authors garnered four types of samples:

"First is the normal prostate that doesn't have any BPH in it," he enumerated. "These came from transplant donors who had passed on, and we were able to get their normal prostates via the university organ donation network, and do studies on them.

"We also got asymptomatic BPH, because some of those donors, although they died from car crashes, also had BPH in their prostates. Others who died from violent causes did not have BPH.

"The third group had BPH with symptoms so severe they had to undergo surgery to remove part of their prostate.

"The fourth and last cohort consisted of patients with prostate cancer, who had BPH in their prostate glands.

"For the microarray screening," Getzenberg recounted, "we used the Affymetrix [Inc.] 42k chips, which contain 42,843 genes that are out there. Some of them were known, some not. We were able to compare these from one of those patient groups to another. We did this across all the relatively large samples that we looked at. And we were able to show which genes were overexpressed and which underexpressed - in patients in one group compared to another. Of the entire analysis we came up with only 511 genes that were differentially expressed - ones that we wanted to study more and prioritize on the basis of their over- and underexpression - relative from one group to another.

"For example," Getzenberg pointed out, "we found one gene, JM27, that we talk about in the PNAS paper. This gene was 17-fold increased in expression in the BPH with symptoms compared to the BPH people who didn't have symptoms. We were able to confirm even higher expression at the protein level. These were expressed at much, much higher read-outs in the BPH with symptoms than the asymptomatic patients."

JM27, A Known Gene, Gets Hot New Gig

"JM27," he observed, "has been known to be a member of a large gene family. It's in the Affymetrix database. No one has shown an association between that gene and prostatic growth and prostate regulation. We're trying to figure out its product right now. It's a member of a family called mage proteins, which are known to be very good antigens for cancer. Mage stands for melanoma antigen. They appear to be membrane-bound proteins, but we have some evidence now that they are found as well in the nucleus - certainly in the prostate."

Getzenberg foresees the first putative clinical application as "a diagnostic or prognostic indication, to differentiate BPH into its two different types. That will put patients onto two tracks for treatment. I think the next stage after that will come up with new agents based upon these new pathways. JM27, for example, might prove to be an agent to inhibit the growth of BPH as well as, potentially, PC. I think that's relatively imminent. Actually we're doing it now on an experimental level. Scaling it up to being used on a national level will take maybe the next couple of years - not three to five years. We're also trying to see if we can pick JM27 up in the blood, but I think first," he concluded, "it will become available for a tissue-based test."