They say you can't judge a book by its cover, but you
may be able to judge how resilient certain cancer cells
are based on their cover — or rather DNA packaging.
According to a study published in the April edition of
the American Journal of Pathology, DNA in cancer
cells is tightly packed away in protein complexes, making
it less susceptible to getting chewed up by restriction
enzymes, proteins that cut DNA at specific sites. In fact,
the more invasive the cancer, the better its DNA is protected
from restriction enzyme cleavage.
"What our findings suggest is that
it is precisely the most malignant cells that will be
the most resistant to most current forms of chemotherapy
— most of which were designed to interfere with
DNA metabolism," explains Dr Andrew Maniotis, study
author and Program Director of Cell and Developmental
Biology of Cancer at the University of Illinois in Chicago.
"These approaches do not target,
and will never target the most malignant cells whose
DNA is largely protected through what we have identified
as a cytoarchitectural resistance mechanism deep within
the malignant cell." Enhanced DNA protection was observed
in many different types of cancer, suggesting that DNA
re-arrangements may be a universal feature of malignant
cells. Dr Maniotis' lab is developing diagnostic tests
to take advantage of this characteristic.
LET'S
GET PHYSICAL
"In effect, we've developed a physical marker that may
be useful in many if not all types of cancer detection,
rather than elaborate on current methods which detect
chemical markers that are highly variable from tumour
to tumour and from patient to patient, or which are
highly specific for certain types of tumours," says
Dr Maniotis.
Unravelling the mystery of DNA
packaging or sequestration is leading researchers to
realize that there are more ways to influence which
genes are turned on, or expressed, than previously assumed.
They've discovered that seemingly innocuous proteins,
both outside and within the cell, can almost instantaneously
affect the arrangement of DNA within the cell's nucleus.
Tighter DNA packaging is triggered
by the cell's cytoskeleton — the scaffolding of
proteins that gives each cell its shape and keeps its
internal components organized. Interestingly, proteins
lurking in the area outside of the cell can somehow
interact with the cell's cytoskeleton to provoke DNA
sequestration. Exposure of even one edge of a cell to
certain extracellular proteins can kick DNA sequestration
into gear.
The American Journal of Pathology
study revealed that oncogenes are at least partially
responsible for this mechanism. Inserting three oncogenes
into previously normal cells caused them to go into
DNA protection mode in an identical manner to that seen
in malignant cell cultures.
Despite the bad news for chemotherapy,
this study shows that by 'thinking outside of the cell'
and understanding how cancer cells manipulate and respond
to their extracellular environment, physicians might
acquire a whole new set of weapons against cancer.
Am J Pathol Apr 2005;166(4):1187-203
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