April 02, 2002
Gene Alteration Spurs Growth of Colon Cancer
Researchers have discovered a novel gene alteration that causes an
abnormal cellular “off-switch” that contributes to the
growth of colon cancer. Identification of the gene alteration, which
appears to contribute to tumor malignancy in about 40 percent of
patients with colon cancer, may permit researchers to better understand
how tumors become malignant and invasive.
Howard Hughes Medical Institute investigator Sanford
D. Markowitz and colleagues at Case Western Reserve University,
University Hospitals of Cleveland, and four other institutions have
shown that inactivation of the helicase-like transcription
factor (HLTF) gene contributes to transforming normal colon
cells into cancer cells. The gene is a member of a family of genes that
removes the proteins that coil around DNA, thus exposing individual
genes to the cell’s gene-expression machinery. HLTF proteins help
stabilize DNA and regulate the production of other proteins in the
cell.
“Understanding what this gene does in the cell will help us comprehend how colon cancer gets started and could be a new target for drug intervention.”
Sanford Markowitz
“HLTF belongs to a pathway that is just beginning to be
appreciated in the development of cancer,” said Markowitz.
“This is the first time a protein in this family has been
implicated as a participant in a major, common form of cancer.”
Markowitz and his colleagues reported their findings in the April 2,
2002, edition of the Proceedings of the National Academy of
Sciences.
“This is a new colon cancer suppressor gene whose inactivation
appears to contribute to malignancy in about 40 percent of
cases,” said Markowitz. “Understanding what this gene does
in the cell will help us comprehend how colon cancer gets started and
could be a new target for drug intervention.”
In the study, the scientists examined colon cancer cells and normal
cells from 63 colon cancer patients and 34 colon cancer cell lines
grown in the laboratory. They discovered that production of the HLTF
protein had been shut down by a mechanism called DNA methylation.
“This type of methylation produces an abnormal ‘off
switch’ that in this case inappropriately shuts down production
of a tumor suppressor protein,” said Markowitz. The methylation
process has also been implicated in turning off other tumor suppressor
genes and is recognized as a contributor to the development of
cancer.
When the scientists introduced a functional copy of the HLTF
gene into the colon cancer cell lines that lacked the gene, the cells
stopped growing. This finding suggests that the HLTF gene is
itself a tumor suppressor gene that can stop tumors from growing.
Markowitz said that the studies also hint that drugs that reverse
methylation may be a new type of cancer treatment. These drugs are now
in the early stages of development. In the short term, however,
Markowitz believes the finding may help doctors diagnose colon cancer
and perhaps differentiate aggressive, invasive tumors from less
aggressive forms of colon cancer.
When Markowitz and his colleagues looked in lung and breast cancer
cells, they found the HLTF gene was normal. Based on this
result, they concluded that the HLTF gene may be involved
specifically in colon cancer progression. Furthermore, the scientists
had previously detected abnormal methylated DNA in the blood of some
colon cancer patients, suggesting that if the findings hold for the
commonly methylated HLTF gene, it could be a target for a new
diagnostic test for colon cancer. Markowitz cautioned that the result
needs to be duplicated and other cancer cells need to be tested.
Markowitz is optimistic, and he cites recent work by HHMI
investigator Bert
Vogelstein at The Johns Hopkins University School of Medicine that
demonstrates a new targeted, non-invasive test for finding about half
of colon cancers using the APC tumor suppressor gene.
“What has limited the development of a simple diagnostic test
for colon cancer previously has been finding the right target that can
catch close to all the cases,” said Markowitz. “What we
describe in this paper is a test that can catch 40 percent of colon
cancers. A screen that searches for APC and HLTF
mutations may be able to catch more than 90 percent of cancers, making
blood or stool sampling practical.”
The development of a simple, non-invasive colon cancer diagnostic
test could greatly increase early detection of the second leading cause
of cancer death among adult Americans, said Markowitz. A blood or stool
test is seen as a way of significantly increasing the number of people
whose colon cancer is detected in the early stages of growth when the
prognosis for full recovery is good. By contrast, colonoscopy, the
current standard for detection, is invasive, so people tend to put off
or avoid having the test.
The scientists also found that those tumors with the silenced
HLTF gene were actually less likely to spread to adjacent
tissues. The results suggest that tumors with HLTF turned off may grow
more slowly than other tumors.
“In the patient group we studied, the patients with abnormal
HLTF seemed to do somewhat better,” he said. “This suggests
testing for HLTF mutations may have some prognostic value in
determining how aggressive the cancers are.”
Markowitz added that the combination of applying modern molecular
techniques and identifying key targets such as HTLF should make colon
cancer diagnosis and treatment easier, as well as providing more
information about the severity of the disease.
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