A team of molecular biologists have located a genetic switch in
prostate cancer cells that may play a role in triggering a quiescent
tumor to erupt into an invasive, deadly cancer.
The discovery of this single genetic switch could open a research
pathway that might lead to a road map of the complex changes prostate
cancer cells undergo as they progress to a deadly form, according to
the scientists. Such a road map not only would yield molecular
markers that would allow physicians to better pinpoint the stage of a
prostate cancer but also could lead to new drugs to kill cancer cells
at earlier stages, they said.
The scientists, Russ Carstens, MD and Mariano Garcia-Blanco, MD, PhD,
of Duke University Medical Center, department of pharmacology and
cancer biology, and Wallace McKeehan of Texas A&M published their
findings in the April issue of Molecular and Cellular Biology.
Working with rat prostate cancer cells, the researchers discovered
the molecular basis of a genetic switch that governs whether a cancer
cell generates one or another form of a protein receptor molecule
called fibroblast growth factor receptor-2 (FGF-R2). These receptors
are molecular locks, secreted by another cell in the prostate, into
which a protein called a growth factor fits.
As long as the FGF-R2 receptor is of one type--called IIIb--the
cancer cell is relatively well-behaved. But when the cancer cell
abruptly switches over to making another receptor type, called IIIc,
it needs no outside stimulation to grow, and grows uncontrollably.
This phenomenon was originally observed by Dr. McKeehan. The Duke
researchers subsequently began exploring its molecular mechanism.
They discovered the switch has a short stretch of RNA nestled in the
string of messenger RNA, a molecule which constitutes the blueprint
for the receptor and which moves out of the cells nucleus to
the protein-making machinery, where it governs production of FGF-R2.
The scientists found that this string of messenger RNA actually
includes the code for producing both receptor IIIb and IIIc, with the
genetic switch sitting between the two lengths of RNA code. That
switch acts as a molecular "scissors" to activate one form
of FGF-R2, while suppressing another.
The phenomenon is called "alternative splicing," said Dr.
Garcia-Blanco, an associate professor. "Alternative splicing is
quite similar to the process of editing film," continued Dr.
Garcia-Blanco. "An editor, starting from the raw footage, can
decide to cut one scene and not another, possibly producing two very
He emphasized that "we dont know yet for a fact whether
this switch in the receptor is critical for either
androgen-independence or metastasis, or whether its just a
marker. But even if it is a marker, it could still be useful as a
very early signal of tumor progression." However, he asserted
that this mechanism "has a very good chance of being an
important enabling component in the progression to metastasis and/or
"The stages in prostate cancer that lead to the development of
very highly metastatic and androgen-independent tumors are not well
characterized," he added. "So, this finding can help us to
better understand what other genetic lesions are necessary for the
cancer to progress." The finding is unique, said Dr.
Garcia-Blanco, because aberrant gene expression in cancer usually
occurs as a result of genetic mistakes in producing messenger RNA in
the nucleus and not because of alternative splicing of the RNA into
one form or another.
Future Research to Focus on How the RNA Switch Is Controlled
The researchers next goal is to expand on this initial clue to
understand how the RNA switch itself is controlled and, ultimately,
to use this information to broadly map the deadly machinery of
"While we think this switch has tremendous physiological
consequences, because it affects this fundamental receptor, we now
want to know why the switch is being tripped," said Dr. Garcia-Blanco.
"And whatever protein is triggering this switch, we believe,
could affect many other parts of the cell machinery that go awry as
the tumor progresses."