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Genetic mutation makes cancers
aggressive, resistant to chemotherapy drugs
NEW YORK, N.Y, -- Jan. 18, 2001 -- What makes
one patient's cancer more aggressive than another? Why does a
patient's cancer develop resistance to a previously effective
chemotherapy drug? A genetic mutation of a key cell-division
protein may provide the answer to both of these questions.
Researchers at Memorial Sloan-Kettering Cancer
Center in New York have genetically engineered a mutation in
the MAD2 gene in human cancer cells that eliminates a checkpoint
essential to normal cell division. The resulting mutation made
the tumor cells genetically unstable, a characteristic long associated
with more aggressive cancers.
The result of the study, published in the
Jan. 18 issue of Nature, has implications for drug development
and may provide a new marker for diagnosing the potential aggressiveness
of tumors, Dr. Loren Michel, the study's lead author, said in
a statement
"When we took a particularly stable human
colon carcinoma cell line and genetically engineered the loss
of one copy of the MAD2 gene, we were able to visualize the cell's
chromosomes falling apart prematurely during cell division by
using a simple test," Michel said.
In 1996, Drs. Robert Benezra and Yong Li of
Memorial Sloan-Kettering Cancer Center first identified MAD2,
a member of a class of proteins referred to as mitotic checkpoint
proteins. These are a series of proteins that act as quality
control checks as cells duplicate their chromosomes before dividing.
The loss of checkpoint proteins has been thought
to produce a form of chromosome instability in which whole chromosomes
can be lost or gained. Cancers that exhibit this type of chromosome
instability are usually more aggressive and have a poor prognosis.
Correlations between chromosome instability and the loss of the
mitotic checkpoint have been identified in human colon cancer
cell lines.
There was previously no evidence, however,
providing a direct relationship between these two phenomena.
Now, Benezra's team has found that the loss of MAD2 in a genetically
stable cancer cell line created chromosome instability.
"Although the loss of one copy of MAD2
caused only subtle decreases in the amount of MAD2 protein levels,
it had a great impact on the cell's genetic behavior," Michel
said.
"The tumor's genome became highly unstable
and continued to grow even in the presence of chemotherapy drugs
in the taxane family. Our results suggest that developing a similar
test to detect the changes in this genetic pathway in human cancers
could be used to predict disease progression," he said.
Taking the findings one step further, the
researchers found that the identical genetic mutation that had
such a dramatic effect on a pre-existing tumor cells could also
contribute to the initiation of cancerous tumors in mice.
"Mice with complete absence of MAD2 protein
die during embryonic development. We introduced a mutation that
inactivated just one copy of the MAD2 gene in mice and this resulted
in cancer," says study co-author Vasco Liberal.
"Uniquely, this mutation resulted in
a high frequency of lung carcinomas despite the fact that these
genes are found in every cell of the body and the disease is
extremely rare in most mice. Why the lung tissue is specifically
affected is unknown but it does show that disruption of this
process participates in the development of cancer. Interestingly
in humans, low levels of MAD2 have been observed in breast tumor
cell lines," Liberal said.
The researchers also found that small changes
in the MAD2 protein level result in a partial loss of the mitotic
checkpoint.
"When the cell was missing half the normal
amount of MAD2, it became resistant to taxane drugs. This was
a surprise since similar experiments in yeast suggested the exact
opposite," said Benezra, who heads the Molecular Mechanisms
of Differentiation Laboratory at Memorial Sloan-Kettering.
"This could have implications as to why
a cancer cell suddenly develops drug resistance and needs further
investigation," he said.
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