Cancer's
penchant for developing drug resistance is a result of chromosome
reassortment, UC Berkeley scientist proposes
24
Jan 2001
By
Robert Sanders, Media Relations
Berkeley
- A heretical theory about the origins of cancer could explain
a longstanding medical mystery - why cancers often become
resistant to the drugs used to treat them.
The controversial
theory, if correct, also suggests a possible way to treat
cancer to restore its sensitivity to drugs.
The theory,
espoused by Peter Duesberg, professor of molecular and cell
biology in the College of Letters & Science at the University
of California, Berkeley, disputes the common assumption that
cancer results from a series of genetic mutations that kick
a cell into uncontrolled growth.
Instead,
Duesberg argues, cancer results from a wrench thrown into
the machinery - the spindle apparatus - controlling chromosome
splitting when a cell divides. This leads to an abnormal number
of chromosomes that unbalances hundreds to thousands of genes
and proteins in the cell and generates the many odd characteristics
of cancer cells.
Cells with
the wrong number of chromosomes are called aneuploid cells,
and scientists have known for a long time that essentially
all solid tumors are aneuploid. This was thought to be the
result of the genetic mutations leading to cancer, however,
not the cause of cancer.
One consequence
of this aneuploidy is that the sensitive balance of proteins
in the spindle apparatus also is upset, destabilizing the
machinery that normally divides the chromosomes evenly between
two daughter cells. As a result, each time a cell with an
abnormal balance of chromosomes divides, it makes new mistakes
in chromosome division, creating a snowball effect that keeps
changing cellular properties, particularly in cancer cells
with highly abnormal chromosome numbers.
In the
Dec. 19, 2000, issue of the Proceedings of the National Academy
of Sciences, Duesberg and his colleagues, UC Berkeley researcher
Reinhard Stindl and Ruediger Hehlmann of the University of
Heidelberg at Mannheim, Germany, reported the results of a
simple experiment that bolsters their argument that aneuploidy,
not genetic mutation, causes cancer.
The experiment
showed that cells with an abnormal number of chromosomes respond
very differently to chemotherapeutic drugs than do cells with
a normal number. Aneuploid cells with 50 percent more chromosomes
than normal developed drug resistance after as few as nine
days of drug treatment, whereas no normal cells developed
resistance. Thus, aneuploid cells respond to chemotherapeutic
drugs just like cancer cells.
The researchers
concluded that continuous chromosome reassortment facilitated
by aneuploidy is a likely mechanism to explain the high mutation
rates of cancer cells and the frequent development of drug
resistance.
"People
have been working on drug resistance for 60 years, and the
question still remains - why the huge discrepancy between
mutation to drug resistance in cancer cells and everything
that is known about mutations in normal cells," Duesberg said.
"Our cancer hypothesis offers a unifying explanation for the
high mutation rates in aneuploid cancer cells and the generation
of drug resistance."
An analysis
of Duesberg's paper appearing in the January 2001 issue of
Nature Biotechnology concluded that "he and his co-workers
have provided compelling evidence that the high mutation rates
of cancer cells are due to an aneuploidy-based continuous
chromosome reassortment."
The author,
Harvey Bialy, resident scholar in the Institute of Biotechnology
at the National Autonomous University of Mexico in Cuernavaca,
also endorsed Duesberg's theory that aneupolidy is the basis
of cancer.
"The best
tests of any theory are its accuracy at making experimental
predictions ... and its ability to explain previously inexplicable
findings," Bialy wrote. "In the latest PNAS paper, aneuploidy
as the functional genetic basis of cancer passes both these
tests in ways that should be of interest to biotechnologists
of a variety of stripes."
Previous
researchers looking at the development of drug resistance
have failed to consider chromosome reassortments catalyzed
by aneuploidy as a mechanism of mutation to drug resistance,
Duesberg said. In his experiments, he compared mutation rates
to drug resistance of aneuploid cells that typically develop
into tumors with mutation rates of normal diploid cells.
Every one
of the cultures of highly aneuploid cells developed drug resistance
after repeated treatment with one of a variety of cancer drugs,
such as methotrexate. None of the normal cell cultures developed
drug resistance. The mutation rates of aneuploid cancer cells
to drug resistance fell between one in a thousand and one
in a million cells. By contrast, the mutation rates of normal,
diploid cells to drug resistance were too low to be detected
under the conditions used.
Duesberg,
Stindl and Hehlmann found that cells with highly abnormal
chromosome numbers have a one to two percent chance of gaining
or losing a chromosome each time they divide. In a colony
of a million cells, that provides lots of opportunity for
one or more cells to mutate and gain the ability to disarm
a drug, probably through activation of a new biochemical pathway.
By contrast, the odds for a normal cell to lose or gain a
chromosome during mitosis are undetectably low under most
conditions.
Duesberg
also noticed that his aneuploid cells exhibited something
else common in cancer cells - multidrug resistance. Frequently,
when a cancer becomes resistant to one drug, it proves to
be resistant to others that are structurally different. Scientists
have had a hard time explaining this as the result of genetic
mutation and have suggested various hypothetical scenarios,
including mutator genes and multidrug resistance (MDR) genes
that somehow become mutated in cancer cells.
Duesberg
dismisses this as improbable. "If there are mutator or multidrug
resistance genes, why do only cancer cells, but not normal
cells, benefit from such genes in the face of chemotherapeutic
drugs?" Duesberg said. "Resistance of normal cells is never
seen in chemotherapy."
Based on
their experiment, Duesberg and his colleagues concluded that
aneuploidy best explains the development of multidrug resistance.
Chromosome reassortment is capable of activating numerous
biochemical pathways that could disarm a variety of drugs.
The results suggest, however, that the cause of drug resistance
is not the loss of drug-sensitive genes when a chromosome
is lost.
One possible
way to force a cancer to revert from drug-resistant to drug-sensitive
is to exploit the instability of aneuploid cells. By treating
cancer cells with an agent such as a phorbol ester, which
promotes the reassortment of chromosomes without causing cancer
by itself, it may be possible to force aneuploid cancer cells
to rearrange their chromosomes enough to lose the ability
to resist chemotherapeutic drugs.
"Phorbol
esters catalyze the reassortment of chromosomes and could
cause the phenotype to change and lose drug resistance," Duesberg
suggested.
Cancerous
tumors that have become drug resistant sometimes spontaneously
revert and again become sensitive to drugs, something expected
from the unstable nature of aneuploidy, he said.
The research,
most of it conducted at the University of Heidelberg in Mannheim,
was supported by grants from various sources, including San
Francisco philanthropist Robert Leppo.
###
Links:
Proceedings
of the National Academy of Sciences
.
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