On
The Origin of Cancer Cells
Dr. Otto Warburg
SCIENCE, (FEB. 24, 1956) Volume 123, Number 3191, pp. 309-314.
Professor Warburg was director of the Max Planck
Institute for Cell Physiology, Berlin-Dahlem, Germany. This article
is based on a lecture delivered at Stuttgart on 25 May 1955 before
the German Central Committee for Cancer Control.
The era in which the fermentation of the cancer cells or its importance
in carcinogenesis could be disputed is over, and no one today
can doubt that we understand the origin of cancer cells from damaged
respiration and the excessive fermentation of cancer cells.
We now understand the chemical mechanism of respiration and fermentation
almost completely. We know that cancer cells can obtain approximately
the same amount of energy from fermentation as from respiration,
whereas the normal body cells obtain much more energy from respiration
than from fermentation. For example, the liver and the kidney
of an adult animal obtain about 100 times as much energy from
respiration as from fermentation.
Injuring of Respiration
Since the respiration of all cancer cells is damaged, the question
is, 'How can the respiration of body cells be injured?' Of this
damage to respiration, it can be said at the outset that it must
be irreversible, since the respiration of cancer cells can never
return to normal. Second, the injury to respiration must not be
so great that the cells are killed, for then no cancer cells could
result.
One method for the destruction of the respiration of body cells
is removal of oxygen. If, for example, embryos are exposed to
an oxygen deficiency for some hours and then placed in oxygen
again, 50 percent more or more of the respiration in destroyed.
The cause of this destruction of respiration is lack of energy.
The cells need their respiratory energy to preserve their structure,
and if respiration is inhibited, both structure and respiration
disappear.
Another method for destroying respiration is respiratory poisons.
From the standpoint of energy, this method comes to the same result
as the first method. No matter whether oxygen is withdrawn from
the cell or whether the oxygen is prevented from reacting in the
cell by a poison, the result is the same in both cases - namely,
impairment of respiration from lack of energy.
The first notable experimental induction of cancer by oxygen deficiency
was described by Goldblatt and Cameron (3), who exposed heart
fibroblasts in tissue culture to intermittent oxygen deficiency
for long periods and finally obtained transplantable cancer cells.
Clinical experiences along these lines are innumerable: the production
of cancer by intermittent irritation of the outer skin and of
the mucosa of internal organs, by the plugging of the excretory
ducts of glands, by cirrhoses of tissues, and so forth. In all
these cases, the intermittent irritations lead to intermittent
circulatory disturbances. Probably chronic intermittent oxygen
deficiency plays a greater role in the formation of cancer in
the body than does the chronic administration of respiratory poisons.
Any respiratory injury due to lack of energy, however, whether
it is produced by oxygen deficiency or by respiratory poisons,
must be cumulative, since it is irreversible. Frequent small doses
of respiratory poisons are therefore more dangerous than a single
large dose, where there is always the chance that the cells will
be killed rather than that they will become carcinogenic. If an
injury of respiration is to produce cancer, this injury must be
irreversible. We understand by this not only that the inhibition
of respiration remains after removal of the respiratory poison
but, even more, that the inhibition of respiration also continues
through all the following cell divisions, for measurements of
metabolism in transplanted tumors have shown that cancer cells
cannot regain normal respiration, even in the course of many decades,
once they have lost it.
Increase of Fermentation
When the respiration of body cells has been irreversibly damaged,
cancer cells by no means immediately result. For cancer formation
there is necessary not only an irreversible damaging of the respiration
but also an increase in the fermentation of great enough magnitude
that it compensates energetically. But how does this increase
of fermentation come about?
There is no physical or chemical agent with which the fermentation
of cells in the body can be increased directly. For an increase
in fermentation, a long time and a great many cell divisions are
always necessary. The mysterious latency period of the production
of cancer is, therefore nothing more than the time in which the
fermentation increases after a damaging of the respiration due
to oxygen deprivation. This time is long in man and often amounts
to several decades, as can be determined by the cases in which
the time of the respiratory damage is known -- for example, in
cancer due to radiation.
The driving force of the increase of fermentation is the energy
deficiency under which the cells operate after destruction of
their respiration, which forces the cells to replace the lost
respiration energy in some way. They are able to do this by a
selective process that makes use of the fermentation by the normal
body cells. The more weakly fermenting body cells perish, but
the more strongly fermenting ones remain alive, and this selective
process continues until the lowered energy level due to respiratory
failure is compensated for by the increase in fermentation. Only
then has a cancer cell resulted from the normal body cell.
Dedifferentiation
Why are the body cells dedifferentiated when their respiration
energy is replaced by fermentation energy? At first, one would
think that it is immaterial to the cells whether they obtain their
energy from respiration or from fermentation, since the energy
of both reactions is transformed into the energy of adenosine
triphosphate, and ATP = ATP. This equation is certainly correct
chemically and energetically, but it is incorrect morphologically,
because the ATP synthesized by respiration involves more structure
than the ATP synthesized by fermentation.
It is as if one exposed the same amount of silver on a photographic
plate with the same amount of light, but in one case with diffused
light and in the other with patterned light. In the first case,
a diffuse blackening appears on the plate, but in the second case,
a picture appears; however, the same thing happens chemically
and energetically in both cases. Just as one type of light energy
involves more structure than the other type, the adenosine triphosphate
energy involves more structure when it is formed by respiration
than it does when it is formed by fermentation.
It has been known for a long time that fermentation -- the energy
supplying reaction of the lower organisms -- is morphologically
inferior to respiration. Not even yeast, which is one of the lowest
forms of life, can maintain its structure permanently by fermentation
alone; it degenerates to bizarre forms. However, as Pasteur showed
in 1876, it is rejuvenated in a wonderful manner, if it comes
in contact with oxygen for a short time. The explanation is the
strong connection of respiration with structure and the weak connection
of fermentation with structure.
This, therefore, is the physiochemical explanation of the dedifferentiation
of cancer cells. If the structure of yeast cannot be maintained
by fermentation alone, one need not wonder that highly differentiated
body cells lose their differentiation upon continuous replacement
of their respiration with fermentation.
When one irradiates a tissue that contains cancer cells as well
as normal cells, the respiration of the cancer cells, already
too low, will decline further. If the respiration falls below
a certain minimum that the cells need unconditionally, despite
their increased fermentation, they die; whereas the normal cells,
where respiration may be harmed by the same amount, will survive
because, with a greater initial respiration, they will still possess
a higher residual respiration after irradiation. This explains
the selective killing action of x-rays on cancer cells. But the
descendants of the surviving normal cells may, in the course of
time, compensate for the decrease of respiration by the increase
of fermentation and, thence, become cancer cells. Thus it happens
that radiation which kills cancer cells can also at the same time
produce cancer.
Sleeping Cancer Cells
Since the increase in fermentation in the development of cancer
cells takes place gradually, there must be a transitional phase
between normal body cells and fully formed cancer cells. Thus,
for example, when fermentation has become so great that dedifferentiation
has commenced, but not so great that the respiration defect has
been fully compensated for energetically by fermentation, we may
have cells which indeed look like cancer cells but are still energetically
insufficient. Such cells, which are clinically not cancer cells,
have lately been found, not only in the prostate, but also in
the lungs, kidney, and stomach of elderly persons. Such cells
have been referred to as "sleeping cancer cells."
Aerobic Fermentation
Aerobic fermentation is a property of growing cancer cells, but
aerobic fermentation without growth is a property of all damaged
body cells - for example, embryos that have been transferred from
amniotic fluid to Ringer's solution. Since it is always easy to
detect aerobic fermentation but generally difficult to detect
growth of body cells, aerobic fermentation should not be used
as a test for cancer cells, as I made clear in 1928.
Summary
Cancer cells originate from normal body cells in two phases. The
first phase is the irreversible injuring of respiration. There
are a great many secondary causes of cancer -- tar, X-rays, arsenic,
urethane -- but there is only one common cause into which all
other causes of cancer merge, the irreversible injuring of respiration.
The irreversible injuring of respiration is followed, as the second
phase of cancer formation, by a long struggle for existence by
the injured cells to maintain their structure, in which a part
of the cells perish from lack of energy, while another part succeeds
in replacing the lost respiration energy by fermentation energy.
Because of the morphological inferiority of fermentation energy,
the highly differentiated body cells are converted by this into
undifferentiated cells that grow wildly -- the cancer cells.
The other theories of cancer origin (mutation and carcinogen)
are not viable alternatives, but empty words. Even more harmful
in the struggle against cancer is the continual uncovering of
miscellaneous cancer agents and cancer viruses, which, by obscuring
the true cause, lack of oxygen, may hinder necessary preventive
measures and thereby become responsible for cancer cases.
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