STUDIES ON, THE NATURE OF THE GROWTH
STIMULUS I N CANCER
MONTROSE T. BURROWS
(From the Research Laboratories of the Barnard Free Skin and Cancer Hospital, and
the Department of Surgery, Washington University School of Medicine,
Saint Louis, Missouri)
Our general studies of growth as seen by the tissue culture and
an analysis of the conditions which induce and cause the growth
of the cells in cancer have indicated quite clearly that cancer is
not a reversion of the cells to an embryonic type, but evidently
the freeing of them from those general forces which hold them
together to make the organism a unit structure or, in other
words, a return of them to their most primitive unicellular
existence. Cancer does not deal with questions of embryology,
but those much more general evolutionary forces which came
into existence and led to the development of metazoan forms
of plants and animals.
The facts which have forced this generalization were derived
by finding certain very definite similarities between cancerous
tissue and cultures of unicellular organisms which show these
tissues and cells to be living under very different conditions
than the cells in the normal organism. These facts are the
outcome of an analysis of the processes of growth, differentiation
and function of body cells, as they exist in the tissue culture,
in the normal organism and cancer.
Many of the earlier students of botany and general biology
had fully appreciated that the cell is not the dominating agent
in the development of the body. Its growth, differentiation and
function as they occur in the body are initiated and regulated
by other much more general formative forces in the organism.
This idea is found in the works of the botanists, Hoffmeister,
Sachs and DeBary and also in the studies of Driesch, Whitman,
Hertwig and other students of animal life and development (1).
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MONTROSE T. BURROWS
Ribbert had also appreciated this general fact in his studies of
cancer.
Others in biology and medicine have taken a different view.
They have looked at the cell as the dominating agent. The
cycle of change peculiar to the cell in the body is controlled by it.
Those clinging to the first view looked a t cancer as merely the
freeing of the cell from the dominance of these general forces or
the result of changes in the environment about the cells. The
others looked at the cancer cell as a different cell type.
Before the solution of the problem of cancer could proceed it
was necessary that this controversy be settled. It remained
for the tissue culture to give the facts necessary for the decision.
As noted in 1915 (2) the author had found that, whether an
embryonic heart muscle cell is to grow, to differentiate or to
function depends entirely on its immediate environment in the
tissue culture. The heart muscle cell can be changed from one
state of activity into the other at will, by changing the environment about it. It was also interesting to note that these cells
when they grow in a tissue culture do not grow to form organs.
Their growth is not followed by differentiation. They grow as
cancer cells grow in the organism and as bacteria grow to
invade the medium and degenerate in cultures and in nature.
It became evident, therefore, from these early observations
that the growth of the cells in the body, their differentiation
and function is something guided absolutely by other general
forces in the organism and that these cells in their simplicity
are not fundamentally different from other simple unicellular
organisms. When isolated under conditions suitable for their
growth they grow as these simple unicellular organisms grow.
Cancer in the light of these facts cannot be a reversion of the
cell to an embryonal type, but rather a return of the cell to its
more primitive state or a release of it from those forces dominating it in the organism.
The questions that these studies then presented were the
nature of the dominating forces in the organism and the conditions which freed the cells from them and allowed them to
grow independently as in cancer. The solution lay in the
NATURE OF THE GROWTH STIMULUS IN CANCER
241
more complete analysis of the conditions in the environment
controlling each of these changes, growth, differentiation and
function.
I n a previous paper (3) the author had already shown that
the cells of young embryos from 60 hours to 10 or 11 days old
grow most readily in tissue culture. In studying the growth
of cells of these embryos it was shown that it takes place in
normal blood plasma and simple synthetic medium only when
these cells are crowded into narrow stagnant confines which are
supplied with an ample amount of oxygen. This growth can
be slowed or stopped by washing these cells with a stream of
serum or salt solution. It can be stopped by separating the
cells or increasing relatively the amount of plasma or other
media about them without disturbing their oxygen supply.
When too few mesenchyme cells are placed in a drop of
plasma for growth to take place, they migrate apart and show
changes peculiar to their differentiation in the body. As these
cells separate more and more their movements slow. Finally,
they come to rest and then lie inactive for an indefinite time.
These inactive cells are physiologically dead, but fully intact.
When collected together again and placed in fresh plasma, they
show activity as before. Single mesenchyme cells placed in a
layer of plasma, may stretch out to a stellate or spindle shape
and then come to rest. For these cells to show any great
activity they must be crowded with other cells.
Function maintains in these body cells when one end of the
cell is placed against a dense stagnant mass of cells and the
other end is in contact with the open medium into which any
products liberated by the cells in its metabolism may escape.
This fact was deduced by the study of heart muscle cells of
chick-embryos in the tissue culture. When these cells are
crowded together, they revert to simple growing mesenchyme
cells. When they are less crowded they differentiate into
fibroblasts. When one end is placed against a dense mass of
cells or is bathed with products diffusing from such a dense
mass of cells and the other end is in contact with the open
medium into which any products of the metabolism of these
16
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MONTROSE T. BURROWS
cells may escape they contract rhythmically. .Any type of
muscle cells may be made at will, to contract rhythmically, to
change into a simple mesenchyme-like cell capable of forming
intercellular fibrils or to grow and divide.
These particular environmental conditions are important not
only for the growth, differentiation and function of muscle cells,
but for all types of cells in the body. The type of function is
not determined by the environment, but by the cell. Isolated
heart muscle and striated muscle cells contract at a rate of 90
per minute. Their contractions are quick and snappy. Single
smooth muscle cells on the other hand have the same slow
contractions peculiar to them in the body.
In the body all functioning cells have a similar polarity. The
nerve fibrils are stretched between the dense brain tissue and
an end organ. The gland cells are stretched between a stagnant
duct and a rich vascular supply without.
From these observations it became evident, therefore, that
the conditions suitable for the growth of body cells are not
different from those of unicellular organisms. It is in the
stagnant pool and not in the running stream that such life
abounds. Wilders had shown that a few yeast cells will not
grow in a wine cast. Either many or an extract of yeast must
be added before growth takes place. The same has been shown
to be true for many bacteria.
Differentiation and function as noted above in the case of
body cells are changes which take place under conditions not
suitable for growth. They are the result of less crowding on
the one hand and a localization of stagnant conditions on the
other.
In analyzing for the significance of these facts it has been
found that stagnation and cell crowding are important for the
growth of these cells because this growth depends on the
accumulation about the cells of a certain concentration of a
substance or substances formed by them. This substance or
substances has been called the archuaia (8). It cannot be
retained by the cells. It is soluble in the circulating fluids of
the body, in salt solution, in serum and in plasma. It can
NATURE OF THE GROWTH STIMULUS IN CANCER
243
reach the concentration necessary for growth only when there
are a sufficient number of cells forming it in a small quantity
of medium from which it cannot escape.
This substance can be readily extracted from growing systems
and added to medium containing isolated and inactive cells.
From these studies it was learned that it acts not only to produce
growth, but every act of the cell. When a fragment of cellular
tissue is placed in a culture medium the cells first show migration,
then growth, and finally self digestion as the archusia gradually
accumulates about them. A study of the effect of the archusia
on isolated cells has shown that it has no effect in low concentrations (Sl). In medium concentrations (S2)it causes the
cells to migrate into plasma clots, to engorge themselves with
fat droplets and protein particles. Extracellular fibrils of connective tissue are laid down under these conditions. Function
takes place when this concentration of the archusia is maintained
at one end of the cell. Growth and division never maintained
under these conditions. It is in concentration (S3)that the
cell digests the fat and protein in its cytoplasm and the medium
about it, grows and divides. I n all higher concentrations (R4)
it suffers a self-digestion. This self-digestion although similar
morphologically to autolysis is not the same. Toxic products
are liberated in the autolysis of cells from the absence of oxygen.
No such toxic products are liberated in this self digestion of
the cell. It is similar to the degeneration seen in the center of
malignant tumors.
It was in the light of these facts that the author assumed that
cancer may be nothing more than the result of a local crowding
of cells in the organism and a relative reduction in the blood
supply to the mass thus formed. In proof for such a contention
it was found that those conditions which lead to cancer act only
in this capacity. Recent careful work on the cause of cancer
has shown very definitely that it may be produced by any one
of a number of conditions and substances; such as coal tar,
X-ray, radium, animal parasites, bacteria, etc. I n man it arises
most frequently on old inflammatory processes and in congenital
tumors and defects.
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MONTROSE T. BURROWS
There was no evidence from these same studies that any
one of these substances act otherwise than to induce this
disease. Coal tar applied repeatedly to the skin produces
cancer. Cancers thus produced then proceed independently of
the tar. The same is true for cancers produced by animal
parasites, X-rays and radium.
These studies alone have shown that cancer is not the result
of any specific external agent, but merely the result of some
change in the tissues or the cell which may be produced by any
one of a number of different substances and conditions.
In previous studies (4)the author had shown that body cells
have no mechanism for migration such as is seen in the cilia of
paramoecium or many bacteria or in the internal mechanism of
the amoeba. They migrate by liberating a substance which is
readily absorbed by proteins and fats. This decreases the
surface tension of the cells in the presence of proteins and fats.
Body cells cannot migrate into liquids, but only into masses of
protein and towards large fat droplets. Smaller particles of
protein and small fat droplets are drawn into the cell by the
same mechanism. This substance is a lipoid and has been
called the ergusia ( L ) . It is soluble in coal tar and many other
lipoid solvents. Jorstad ( 5 ) has found that drops of coal tar
placed in the tissue dissolve this substance and drag the tissue
cells to them away from their intercellular substance and blood
vessels. The cells are thus accumulated in masses about the
peripheries of these droplets. This substance acts to produce
the cancerous organization by thus drawing the scattered cells
of the organism into dense stagnant masses. These drops act
only until they become saturated with the ergusia. If too great
an amount of ergusia is taken away from the individual cells
they degenerate. If this degeneration fails and sufficient
number of cells are accumulated they can grow in this stagnant
area in that they can form and retain suffieient archusia for
growth. X-ray, radium, bacteria and animal parasites produce
the same stagnant organization in that they liberate growth
stimulus in the tissue. Any cells affected by this stimulus
grow to form a dense mass of cells free from blood vessels.
NATURE OF THE GROWTH STIMULUS IN CANCER
245
I n other studies (6) it has been shown that such a dense mass
of independently growing cells once established in the organism
may continue to reproduce itself through the fact that it can
destroy the normal tissues and blood vessels about it. Metastases as they occur in cancer can also be explained in the same
terms (7). While the cells under ordinary conditions in the
body cannot migrate excepting into proteins and fats unsaturated with the ergusia, under conditions of stagnation and
crowding such as is seen in cancer conditions are different.
The cells in the center of such masses are digested by an excess
of the archusia. A soap-like substance is liberated under these
conditions which can flow readily over the surface of water
solutions, plasma and differentiated cellular tissues in the body.
In the films of this soap the cells can migrate readily and grow.
I n further proof that these mechanical changes in the arrangement of cells explain cancer, it is well known that cancerous
tissue is a dense mass of stagnant cells. The blood vessels in all
cancers are few per unit cell area. They are also constantly
being destroyed in this tissue. The author as well as many
other students of the tissue culture have shown that all cancerous tissue contains large quantities of the growth stimulus, the
archusia (8).
CONDITIONS REUULATING, GROWTH IN THE NORMAL ORGANISM
I n applying these conditions suitable for growth, differentiation and function in the culture to the body the mechanisms
at work in the general development of the organism takes on
much simpler aspects. It is in the early periods of development
that growth is most active. This growth wanes and ceases and
differentiation and function makes its appearance with the
development of the blood vascular system. The development
of the active circulation not only removes these conditions
suitable for growth, but establishes the polarity necessary for
function.
It became evident then that the dominating forces in the
organism which leads to its development and function are
associated with the development of the blood vascular system.
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MONTROSE T. BURROWS
There is no evidence that the endothelial cells are possessed with
any property of independently growing and forming these
structures. The question that presented itself in the further
development of cancer was the conditions con trolling and
regulating this vascular development. It is the dominance of
the crowded masses of cells in the cancer over those forces
which maintained the blood vascular system which allowed the
cancer to grow and destroy the organism.
In studying more carefully the conditions of growth in normal
organisms it soon became evident that a t no time in the life
of these organisms are conditions favorable for an independent
growth of the cells as in cancer. At no time is the stagnation
and cell density sufficient to allow the cells to grow independently
except in the earliest periods of development. At this period
the blastomeres are filled with yolk. The simple crowding
together of such yolk laden cells in the culture is not ample
for their growth. To make them grow the yolk must be
removed or a considerable amount of archusia extracted from
an actively growing tissue must be added to the medium about
them. At a later period after the yolk has disappeared these
cells respond by growth when removed from their circulation
in the body to the stagnant culture medium. In the embryonic
body on the other hand the circulation is too great for them to
form and retain ample archusia for their growth. I n later life
dense masses of cells fail to respond when placed in the plasma
clot. Lambert (8) has shown, however, that if fragments of
cellular adult tissues are transplanted repeatedly into drops of
fresh plasma that they will eventually grow actively in the
plasmatic medium. These same tissues can also be made to
grow in the first plasma clot by adding an extract of an actively
growing tissue or archusia to the medium about them.
The question arose then is the growth of the body dependent
on conditions different from those found suitable for growth in
the cultures and in cancer, or is it controlled by a supply of
stimulus or archusia from without. I n previous work (9) the
author had shown that archusia introduced into an area of the
skin of a rat whose circulation has been disturbed, causes the
NATURE OF THE GROWTH STIMULUS IN CANCER
247
cells to grow actively and form a dense mass of cells largely
free from blood vessels or a cancerous organization. It became
evident, therefore, that this same stimulus acting on the egg
cell may force channels to develop into the mass of forming
blastomeres. These channels may become the blood vascular
system (10). Such a stimulus continuing to enter by way of
the blood vessels must be in greatest concentration about the
endothelial cells of these vessels. This must cause these cells
to grow in excess of the cells without. A vascular functioning
tissue must, therefore, result. The further proof of this deduction lay in showing that such a stimulus exists in the universe
and acts to so build these metazoan forms.
I n other studies it has been shown that the storage of fat in
the cells, the building of extracellular fibrils, migration and
function in cells is the result of their liberating a lipoid-like
substance, the ergusia. In studying these various acts in the
cultures it became evident that the cells cannot form the ergusia
under the conditions suitable for the building of extracellular
fibrils by connective tissue, for the absorption of fat, function
and migration. Only actively growing cells can maintain their
activity indefinitely (11). Connective tissue cells forming extracellular fibrils in the cultures, migrating and taking in fat and
heart muscle cells contracting become exhausted of this substance in a few hours or two or three days. In the body this is not
true. The heart continues activity for years. The connective
tissue cells build large masses of bone and intercellular material
over many years in the organism. It was wondered, therefore,
whether the ergusia might not also be supplied to these cells
from without .
It is now known that higher animal life cannot exist on
protein, fat, carbohydrates, salts and water alone. Other
accessory food substances are also necessary. These have been
called vitamins. The most important of these vitamins are A
and B. In comparing the properties of the archusia and
ergusia with these vitamins, it became evident that they
correspond exactly to vitamins B and A respectively.
Previous authors had already noted that vitamin A inhibits
248
MONTROSE T. BURROWS
the growth of cells. In previous studies the author had noted
that the plasma clot induces migration in cells in that it dissolves the ergusia. It was possible that the failure for the
blastomeres to grow when crowded in the cultures was due to
the ergusia or vitamin A dissolved in the fat and proteins of the
yolk. In previous papers the author has given direct proof
that the fat droplets and proteins of the yolk are taken into the
cell only as they dissolve the ergusia of the cell. The failure
for response of older tissues until after they have been replanted
several times into fresh plasma may be due again to the presence
of the ergusia or vitamin A in the cells, or intercellular substances of the organism at this period. In proof for this contention it is known that coal tar produces cancer. The author
was unable to induce growth in adult tissues by washing them
in salt solution. Growth is induced by washing them with or
exposing them to fats or ether, but not by substances incapable
of dissolving the ergusia.
According to these general deductions the ergusia does not
inhibit growth as a foreign toxic substance, but as any product
of any incomplete reaction may inhibit this reaction when
added in excess to the reacting system. The ergusia is a
product of the growth reaction, while the archusia is merely
the energy necessary for this reaction to take place. Vitamins
A and B in the light of these facts are merely products of other
growing systems in nature.
I n proof of these deductions it has become of interest to test
solutions rich in archusia for their vitamin activity, to see if the
ergusia removed from the body can be replaced by vitamin A,
to ascertain directly if the vitamin A content of the normal
organism goes up and down with the ability of the cells to
react in the cultures, to test for the vitamin content of malignant
tumors and to determine directly if vitamin A is a product of
inorganic nature or of growing systems.
It has been these later studies which have given a definition
for vitamins, cancer and a clue to the conditions which have
lead to the development of metazoan life in the universe.
Careful studies of the archusia content of chick embryos have
NATURE OF THE GROWTH STIMULUS IN CANCER
249
shown it highest in 5-day-old chick embryos. It decreasea with
the age of the embryos. In the same manner it has been found
that the vitamin B content of these embryos is greatest at 5 days
and decreases in the same proportion as the archusia decreases
(10).
The five-day-old embryonic tissue responds at once when
placed in the cultures. As tissues age they demand more and
more washing with plasma for them t o grow. When these
embryos are fed to animals the younger are found to contain
little or no vitamin A. This A value increases in these embryos
with age and their ability to respond in the cultures. The
blastomeres again contain very large quantities of vitamin A.
This disappears with the yolk granules. Cancerous tissues on
the other hand contain no vitamin A but very large quantities
of vitamin B (10).
I n all of these studies we found that the vitamin I3 values
vary exactly as the archusia (S) values. In further proof that
these substances are identical, Wright (12) has recently shown
that the archusia is dialysable as vitamin B is dialysable.
Wright (13) has also shown that the yolk of hen’s eggs contains
large quantities of this growth stimulus. The quantity in the
yolk of a 7-day-old chick embryo is much greater than in the
embryo itself.
I n the studies of the action of coal tar on the organism
Jorstad (14) has noticed that rats are readily killed by an overdose of this substance. He has also found that this toxicity
can be overcome by feeding the animals larger quantities of
vitamin A.
I n the studies of the bacterial cultures it has been found that
during their active growth they liberate only vitamin B (lo),
(15). When they are allowed to overgrow the medium as they
do in stagnant pools and in decaying animal and vegetable
matter, they suffer a self-digestion as the cells degenerate in
cancer. With the breaking up of their protoplasm vitamin A
is liberated by them. It is liberated when the protoplasm of
these cells break down (11). There is no evidence, therefore,
that vitamin A is a product of sun light. It is a product of
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MONTROSE T. BURROWS
living things degenerating in an excess of archusia or vitamin B.
Light acts, as shown from the study of X-rays (16), to increase
the production of vitamin B in living things. This acts in
turn to liberate vitamin A in the tissues (11).
The final analysis of the conditions leading to cancer reduces it,
therefore, to very definite and practical terms. Cancerous
tissue is a simple-growing cellular system. It is identical to a
growing culture of bacteria in that it contains no vitamin A
and a high value of vitamin B. The normal organism differs
from these systems in that it contains a high value of vitamin A.
This value decreases in certain periods of embryonic life. The
cells at this period resemble the cancer cells in many ways.
It was this resemblance which led to the mistaken notion that
cancer cells may be growing embryonal cells.
In the light of these facts it has become evident that metazoan
forms may owe their existence in the universe to the presence
of vitamins A and B. Cancer is only the result of a local
vitamin imbalance in the organism (17). It may be produced
by anything which removes the vitamin A or increases the
vitamin B content in the tissues. In the presence of a high B
the cell grows and the free A becomes incorporated in the
protoplasm, since it is only a product of protoplasmic matter.
Coal tar acts to produce cancer in that it removes the vitamin
A from the tissues and crowds the cells together in a nonvascular zone so they can produce and retain an excess of
archusia (8)or vitamin B. X-rays, radium, anirnal parasites,
bacteria, produce cancer in that they increase the vitamin B
and disturb the vascular supply to a part so that the vitamin A
cannot be supplied to it. The normal actively diffusible
stimulus in the organism can then act to stimulate the cells in
these parts to grow and form a cancerous organization.
Previous authors have given ample evidence to show that
metazoan life has come from unicellular forms. How this
change was brought about remained obscure. The above observations indicate that it may be due to two things, to the development of a cell capable of absorbing vitamin A and the appearance
of this vitamin in the universe. Cancer is a disease which
NATURE OF THE GROWTH STIMULUS IN CANCER
251
must be prevalent in an undernourished race and one which
suffers from substances and conditions capable of removing
vitamin A from their tissues. It must disappear when the
nutrition of this race is improved, they cease to be slaves of
fashion, have protected themselves against improper drugs,
abuses of certain trades and freed themselves from diseases,
such as syphilis, which cause undernutrition.
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1. WILSON,E. B.: 1906, “The Cell in Development and Inheritance,” New York
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2. BURROWS,
M. T.: Sec. Pan. Am. Sci. Cong. Washington, D. C., 1915, Sect. vii,
pt. 2, 494.
3. BURROWS,
M. T., AND JOHNSTON,
C. G.: Arch. Int. Med., 1925, xxxvi, 293.
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M. T.: Energy Production and Transformation in Protoplasm as
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L. H.: J. Cancer Res., 1925, ix, 232.
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M. T.: J. Med. Res., 1924, xliv, 615.
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R. A.: J. Exp. Med., 1913, xvii, 499.
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M. T.: J . Mo. State Med. ASSOC.,1923, xx, 145.
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M. T., .AND JORSTAD,
L. H.: On the Source of Vitamin B in Nature.
Am. J. Physiol., 1926, lxxvii, 24.
M. T., AND JORSTAD,
L. H.: On the Source of Vitamin A in Nature.
11. BURROWS,
Am. J. Physiol., 1926, lxxvii, 38.
12. WRIQJ~T,
G. P.: On the Dialysability of the Growth Activating Principle Contained in Extracts of Embryonic Tissues. J. Exp. Med., 1926, xliii, 591.
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Yolk of Incubated Hen’s Eggs. Proc. SOC.Exp. Biol. and Med.,1926, Xxiii,
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L. H.: J. Exp. Med., 1925, xlii, 224.
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M. T.: Proc. SOC.Exp. Biol. and Med., 1925, xxii, 241.
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M. T., JORBTAD,
L. H., AND ERNST,
E. C.: The Effects of X-rays on
the Vitamin Needs of the Organism and Cancer. To appear in Radiology.
Previous communication read before Int. Radiological Congreae, London,
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M. T.: Studies on the Cause, Prevention and Treatment of Cancer.
17. BURROWS,
To appear in South. Med. Journal.