Cancer doesn't kill.

This silly-sounding statement is true _ particularly of prostatecancer (PC). Most of the 244,000 American men diagnosed each yearwith cancer of the prostate will not die of it. The 40,000 who losetheir lives each year to the malignancy succumb, not to the primaryprostatic tumor, but to its deadly spread in the body.

Metastasis is cancer's cruelest, most lethal, manifestation, in nearlyall forms of malignancy, not just the prostatic. When the Romansgave cancer its name, they called it "the crab," because both movesideways.

When a primary prostatic cancer moves sideways out of its glandularsheath into the circulation, it changes from a safely encapsulatedgrowth into a bloodborne messenger of certain death. There is nocure for metastatic prostate cancer.

There isn't even a way for a doctor to tell whether or not a patientnewly diagnosed with the localized disease is among the sevenpercent predestined to suffer fatal metastasis.

With no way of knowing in advance which fate awaits which patient,urologists tend to play it safe by going for risky, life-degradingsurgical removal of the gland before the tumor has broken loose andspread to distant sites. (See BioWorld Today, April 21, 1995, p. 1.)

Now molecular oncologists have discovered ametastasis-suppressing gene that blocks tumor spread in malignantprostate cells. It has the potential of signaling whether or not a givencancer cell is programmed to metastasize. What's more, at least inconcept, the gene's discovery could lead to compounds capable ofcuring, or at least curbing, metastatic prostatic cancer.

Today's Science tells the story in an article titled: "KAI1, aMetastatic Suppressor Gene for Prostate Cancer on HumanChromosome 11p11.2." Its first author, Jin-Tang Dong, did thisresearch at the National Institute of Environmental Health Sciences(NIEHS) in Research Triangle Park, N.C. (He has since relocated tothe Johns Hopkins Oncology Center in Baltimore.)

Dong and his co-authors knew that the short arm of humanchromosome 11 is home to a number of tumor suppressor genes,notably the one that blocks Wilm's tumor. So they reasoned that thesame row of loci might harbor a DNA sequence designed to nipmetastases in the bud.

"In the first place," Dong told BioWorld Today, "we identified thatregion on chromosome 11." To do so, by chemical manipulation,they broke open human cells, isolated their chromosome 11, wrappedeach one-chromosome package in a membrane and inserted these"microcells" into rat genomes.

Gene Found Among Five Candidates

"We found that if prostate cancer cells had that region," Dongcontinued, "then they were not metastatic. Cells that didn't, were. Sowe concluded that the gene in that region must be a metastasissuppressor." Dong christened it "KAI1," after kang ai, Chinese for"anti-cancer."

Polymerase chain reaction (PCR) amplifications gave them probes toscreen a cDNA library. "We wound up with five candidate genesfrom that chromosomal region," Dong continued, "which should betumor suppressors."

One of the five, when sequenced, had very high expression in cellscontaining human chromosome 11, Dong said, "and did suppressmetastases."

To the team's surprise, when they compared their prize sequence withgene-bank data bases, "we found that our sequence had already beenidentified from human lymphocytes by three other groups, in Europeand Japan."

The gene encoded a product that turned out to be a 267-amino-acidtrans-membrane protein, which crisscrossed the cell membrane fourtimes, back and forth. "Because metastasis is a problem between acell's interactions with the extracellular matrix," Dong and colleaguesreasoned, "if the gene is on the cellular membrane, it is veryreasonable to think it might be the correct one we were looking for."

To test this supposition, they inoculated the rat metastatic cellscontaining the KAI1 gene into nude mice to see if the metastasis wassuppressed or not.

It was.

"KAI1 suppressed a significant number of lung metastases permouse," their Science paper reported, "but did not affect growth ofthe primary tumor." Also, in human metastatic PC cell lines, thegene's expression was lower than its level in normal prostate tissue.

Male rats have prostate glands, of course, but they don't as a rule getprostate cancer. Back in 1963, a biologist in the Netherlands screened3,327 of the rodents to find one with spontaneous PC. That led toestablishment of the cell line that the co-authors hybridized withhuman chromosome 11 to test their putative metastasis-suppressorgene.

"Other groups have cloned that gene sequence," Dong said, "and oneof them sent us antibodies. These can detect the encoded protein inour transfectant."

He added, "The most important thing we are doing now is looking forexpression of KAI1 in human normal prostate, primary tumor andmetastatic prostate cancers. We want to see if there is a correlationbetween reduced expression of the gene and the patient's metastaticpotential."

Dong observed that such a correlation "could be very useful, becausewe might be able to use this PC marker to predict which patients aregoing to metastasize. Treatment for them would be different than forthose with localized cancer."

As a separate goal, he suggested that once the structure of KAI1 isknown, "probably we can find some pockets for drug development toprevent or even cure metastasis."

`A Big Market' Awaits Genes That Suppress Metastasis

At the National Cancer Institute's Division of Cancer Prevention andControl, medical oncologist Otis Brawley is enrolling 18,000 men at208 clinical centers in the U.S. and Canada for a seven-year PCprevention study.

"Of course," Brawley told BioWorld Today, "we will incorporate thisnew metastasis-suppressing marker as one of our trial's endpoints."

First of all, Brawley observed, "is that clinical trials come forthdemonstrating that this gene or marker is good for predicting tumorsthat metastasize versus those that are indolent and stay in the prostategland. Then it is going to be utilized by virtually everyone who isscreened, and diagnosed with localized PC."

He foresees "a big market for it."

Ultimately, Brawley envisages gene therapy "to treat men who havemetastatic or regional disease, by actually infecting them with avector that would transfer this gene into their cancer."

He acclaims the discovery as "in the world of baseball, a solid hit; inthe world of science, a great clue."

For a three-base hit, Brawley suggests that "the next group of studiesdefinitely look at mammary cancer, which is very similar to prostatecancer. We need to look for a gene like this _ if not this particulargene _ in some of our more indolent breast cancers." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.

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