Of all the bizarre things that can happen in the
genetic structure of men with prostate cancer, this may be one
of the most bizarre—unstable chromosomes, which break apart and
patch themselves together with completely different chromosomes.
Groundbreaking genetic work at the Brady Urological Institute,
building on decades of pioneering research by a handful of scientists
including Don Coffey, William Isaacs, William Nelson, Alan Partin
and others, has shown that the more vicious the prostate cancer,
the crazier this chromosomal mix-up becomes.
Coffey, whose legendary work on the architecture
of cancer cells laid the foundation for this most recent discovery,
thinks he knows what makes this happen, and he even has two key
culprits—and maybe, two new pathways for blocking the very worst
kinds of prostate cancer.
In this case, the architecture of cancer cells
is a bit different from the structural landmarks pathologists
use to determine the Gleason grade and stage of cancer. If we
were talking about buildings—say, a medieval cathedral—what the
pathologists make note of would be things like apses, arches,
naves, and buttresses. What Coffey and colleagues are investigating
would be the stones and mortar.
a Funhouse Mirror
To backtrack two and a half decades: Coffey helped create a new
subspecialty of cell biology when he discovered how DNA— the body’s
genetic material—is organized within a cell’s nucleus. Scientists
had long known that the nucleus of a cancer cell is odd-looking;
it’s distorted, like someone’s reflection in a funhouse mirror.
When this happens, the chromosomes often lose their normal shapes,
as well. Coffey discovered that there is a scaffolding inside
each nucleus, a skeleton that determines its shape. He called
this the nuclear matrix. He found that the DNA was attached to
this matrix in countless loops (actually, about 50,000 little
loops), each locked at its base to the scaffolding. Coffey and
colleagues also showed that those loops are a genetic hot spot,
where DNA replicates itself. They named the loops “replicons,”
and found that DNA reproduces itself in little pieces—the loops—instead
of as one very long string of information.
Several years ago, William Nelson discovered a
key enzyme, called topoisomerase II (topo II for short) at the
base of those loops, and Alan Partin found that the composition
of the nuclear matrix was different in normal and in cancer cells.
Then Coffey and colleagues noticed that in cancer cells, the loops
were unwinding —because topo II was unwinding them. Another strange
thing: The composition of the proteins in the nucleus was changing—and
another scientific subspecialty, called proteomics, the study
of proteins expressed by various genes, was born.
Coffey likens what’s happening here to the working
of an audio cassette player. “The tape is the DNA, the cassette
is the nucleus, and the cell is the whole tape recorder,” he explains.
“The messenger RNA is the electricity coming off the tape, and
the protein is the sound the tape recorder is making. The transient
material is the electricity, and the product is sound. What we
want to know is the sound that’s coming off the tape recorder—what
protein is the cell making? That pattern is proteomics.” There’s
also plenty of static. “About 95 percent of the DNA in a chromosome
never makes sound, or protein. We used to call it ‘junk DNA,’
but now we find it’s this silent, repetitive DNA that makes up
the distance between letters, words, and paragraphs.” (Some of
these spaces are now called introns.)
Bad Patchwork Quilt
At the ends of the chromosomes are little pieces of repetitive
DNA—small caps, like the aglet at the tip of a shoelace—called
telomeres. “If you look at your shoe lace, as long as the aglet’s
there, it’s pretty stable,” says Coffey. “But when the aglet wears
away, the lace starts fraying, and the chromosome starts getting
in trouble. When that happens, the cell is unhappy; the DNA is
not doing well.”
Losing the telomeres is one cause of the spooky
chromosomal rearrangement. Another culprit is a protein at the
base of those loops on the matrix, with the alphabet- soup name
of HMGI(Y). “It’s like a railroad switch that can make the train
go down a different track,” says Coffey. “The train is attached
to the matrix, the railroad track, but this little protein can
flip the switch, and get the trains mixed up.” HMGI(Y)’s close
buddy, genetically speaking, is topo II, and they work together.
HMGI(Y) puts the railroad tracks in a dangerous situation, and
topo II is the miscreant hammering the boards together.
One suspicious fact about HMGI(Y) is that it’s
not found in normal adult cells. It’s usually a part of embryonic
cells, but as we mature, it disappears. It reappears in cancer.
“So cancer is a lot like developmental tissue,” notes Coffey,
“and it picks up a lot of embryonic properties—like a stem cell
for the cancer.” Coincidentally, telomerase (which makes telomeres)
is also in stem cells, and in cancer cells, too.
When HMGI(Y) is added to DNA, it causes it to form
four-way junctions (think of any awful exit of I-95)—and makes
“a perfect place for DNA rearrangement to occur,” says Coffey.
“HMGI(Y) is in the right position at the base of those loops,
it can form a four-way junction, and we know that topo II is sitting
there, flipping the DNA open and closed. It’s the ideal place
to mess it up, especially if the matrix isn’t normal. So rather
than two train tracks going left and right, they now cross over,
and the cars begin to pile up.”
Coffey and colleagues have a way of painting the
chromosomes to make each appear as a different color under a microscope.
“Imagine yourself standing in front of a white wall, and you pick
up a brush and paint the first chromosome as a red stripe, all
the way down the wall,” explains Coffey. “The longest by size
is chromosome 1; the smallest is number 22. Next, you paint the
2 chromosome blue, and make it a little shorter. By the time you
get to the end of the wall, you have a picket fence that goes
down, and gets shorter and shorter, 22 different colors.” When
the scientists painted the chromosomes of prostate cancer cells
in this way, they were shocked at the result. “Holy mackerel!
There’s a piece of red on top of a piece of blue, with a piece
of green at the bottom. Or a piece of yellow, a piece of blue,
and a piece of green. Then two that look okay, but the fence has
too many pickets—instead of 22, it’s got 37. This thing is messed
The scientists looked for this crazy patchwork
effect in three well-known strains of prostate cancer. Like the
porridge that Goldilocks taste-tested, two are extreme— one notoriously
vicious, (Coffey calls it a “mean sucker that grows like crazy”),
one pretty mild, and one right in the middle. In rat tumors, the
worse the cancer, the more metastatic and aggressive it is—the
more HMGI(Y) it has. In humans, the higher the Gleason grade,
the more HMGI(Y) there is. In Coffey’s recent experiments to study
chromosomal rearrangement, the most benign cell line had some
rearrangement, but—this is important—it was balanced rearrangement.
“If you took a deck of cards, and put the top half of the two
red queens on the bottom half of the two black jacks, you would
see two other new cards made, with the bottom half of the red
queens and the top half of the black jacks.” This is called a
“reciprocal translocation,” and it is balanced.
But the very worst cell line resembled
a train wreck—“31 unbalanced chromosomes. It looked like a trash
dump, all parts combined in unbalanced translocations, colors mixed
up in every way you could imagine.”
When the Brady scientists inserted
a piece of HMGI(Y) into the tamest cancer, the one with the balanced
rearrangements, it became unhinged—and made the unbalanced matches
found in the worst form of cancer. The extent of the damage matched
the level of HMGI(Y).
Now, what to make of all this? “We
can cure some cancers—such as leukemias, lymphomas—easily,” says
Coffey. “They are the kinds of cancers that have balanced rearrangements
of chromosomes.” One such cancer, Burkett’s lymphoma, has an “8-14
translocation”—an even mix-andmatch of chromosomes 8 and 14. This
form of cancer affects children in Africa, and it’s horrible: “The
whole face is distorted, like the most severe mumps ever,” says
Coffey. “It looks like the person has elephantitis of the face;
the lymph glands are growing like a house afire. But if you treat
this person with cytoxan, he goes home. He’s cured!” Another example
is advanced testicular cancer, which struck American cyclist Lance
Armstrong. “Some of these men have so many metastases in their lungs,
it looks like they’re drowning in tumor; they’re spitting up blood,
they can’t get enough oxygen. Lance Armstrong had three metastases
in his brain the size of golf balls. But he was treated, his cancer
went away, and he wins the Tour de France. I want to know why that’s
Coffey’s latest research has found
that the cancers most difficult to cure are the kinds—like prostate
cancer—prone to unbalanced rearrangements. “We know that the reason
it’s so hard to cure advanced prostate cancer is because of its
genetic instability. It spins off such a variety of cells that it’s
almost impossible to beat it.” The latest piece of the puzzle, the
subject of some of the cutting-edge research at the Brady right
now, is the telomeres— the tips of the shoelaces, or chromosomes.
Knocking out telomerase—getting rid of the telomeres—causes unbalanced
chromosomal rearrangement, too. “So we’ve got two ways to cause
unbalanced rearrangement—HMGI(Y), and losing telomerase. Both of
these can happen in a man with prostate cancer. Can we make a target
out of this? Maybe we can go after HMGI(Y) and telomerase, and somehow
stop this mismatched rearrangement. Currently, we’re trying to figure
out the best way to take this to the patient.”