June 26, 2003
Distinctive Genetic Program Guides Breast Cancer’s Deadly Spread
Researchers have peered inside breast cancer's toolbox and
identified a set of rogue genes that accelerates the spread of cancer
from its primary site in the breast to a secondary location in bone
marrow. The genes identified by the scientists are distinct from those
that spawn the initial tumor, which invites speculation about whether
different cancers bear unique “gene expression signatures”
that increase the probability that a cancer will spread in a process
called metastasis.
Metastasis occurs when cells from a primary tumor break off and
invade another organ. It is the deadliest transformation that a cancer
can undergo, and therefore researchers have been looking for specific
genes that propel metastasis. If they can identify distinctive
metastatic gene programs for different cancers, it may be possible to
slow or halt metastases by targeting the proteins produced by those
genes.
“Our finding is that above and beyond the genetic signature that has created this tumor, there is a toolbox of overexpressed genes that the cancer cell will need.”
Joan Massague
In the June 2003 issue of the journal Cancer Cell,
researchers led by Howard Hughes Medical Institute investigator Joan
Massagué at Memorial Sloan-Kettering Cancer Center,
published a report showing that breast cancer metastasis to bone is
mediated by a specific set of genes. Massagué collaborated on
the studies with colleagues from the University of Texas Health Science
Center.
“There has been a raging controversy in the cancer research
field between two hypotheses,” said Massagué. “One
is the classical view that says that only a few cells in a tumor
acquire alterations that render them increasingly metastatic. And of
the millions of tumor cells that enter the circulation, the patient
only gets a handful of metastases from these cells.
“By contrast, there has been recent evidence that primary
tumors that go on to develop metastases already possess a `poor
prognosis signature' involving a group of genes whose high level of
activity is indicative of the potential for metastasis,” he
said.
To attempt to distinguish between these two models, Massagué
and his colleagues used a precise technique to isolate specific cells
from cultures of cells from a breast cancer patient who had died from
metastatic disease. The researchers explored whether some of these
types of isolated cells were better than others at metastasizing to
bone - a major site of breast-cancer metastasis.
“Indeed, we did find that certain of these cells were more
adept at metastasizing to bone when injected into mice,” said
Massagué. “And when we analyzed the gene expression in
these cells, we found a set of genes whose activity was specifically
associated with this enhanced metastatic ability.”
These overexpressed genes enabled tumor cells to home in on bone, to
trigger growth of blood vessels, and to recruit bone cells in the
metastatic process, said Massagué. Furthermore, he said, the
bone-metastasis genes were distinct from those in cells that
metastasize to the adrenal gland.
“We also asked the question of whether these bone-metastasis
genes were among the genes previously identified as part of the `poor
prognosis signature,' and the answer was zero, not a one,” said
Massagué.
“This means that the metastatic gene signature defines and
forms a violent society — a large group of cells in a tumor that are
competent to become metastatic cells.” However, said
Massagué, discovery of these metastatic genes does not
invalidate the classical model that tumor cells require additional
genetic mutations to metastasize.
“In and of themselves, these genes may not be mediators of
metastases,” he said. “Our finding is that above and beyond
the genetic signature that has created this tumor, there is a toolbox
of overexpressed genes that the cancer cell will need; that will be the
mediators for the cell to thrive in the bone marrow. So the
poor-prognosis signature is bad news, but that signature is not
enough.”
Massagué and his colleagues conducted two types of
experiments to demonstrate that the metastatic-related genes were,
indeed, causative in triggering cancer spread to the bone. In one
series, they engineered poorly metastatic cells to overexpress
different numbers of the genes they had identified as being necessary
for metastasis to bone. They found that cells in which more of the
genes were overexpressed showed more aggressive metastasis in mice.
In the second set of experiments, the researchers analyzed existing
cultured breast cancer cells to determine which ones had more of the
overexpressed genes they had found associated with metastasis. When
they injected those cells into mice, the researchers found that that
the more of the mutant genes the cells possessed, the more aggressively
metastatic they were.
Massagué said the findings indicate “we have basically
identified a Darwinian process of selection at work. These cells just
happen to accumulate the `winning combination' of hyperactive genes
that enables them to thrive in bone marrow. And once the traveling
tumor cells pass through bone marrow, they are incredibly successful at
attaching to and invading bone.”
According to Massagué, additional studies will be required to
understand whether distinct collections of “metastatic
genes” exist in other metastatic tumors, including breast
cancers.
While the presence of these telltale proteins in the blood of cancer
patients could give clues to the specific identities of the cancers,
“I cannot be sure that such analyses will have major value in
diagnosis,” said Massagué. “Imaging technologies for
metastases are already very effective at detecting them. Nevertheless,
some of these factors might be expressed at such high level by
micro-metastases that they might become a first line of diagnosis.
“The much more conceivable possibility is that we could
determine precisely what particular combination of genes is driving a
patient's metastasis. And with that profile, we might be able to use
specific blockers to attack and silence enough of these proteins to
render the `metastatic toolbox' ineffective, and to ameliorate
metastatic growth.”
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