THE HYPERPLASTIC REACTION OF THE SKIN TO
SULPHYDRYL AND ITS SIGNIFICANCE IN
NEOPLASIA
STANLEY P. REIMANN
(Froll! the Lankenau Hospital Research Institute, Philadelphia)
Recognition of the significant role played by the sulphydryl
group places a powerful tool in the hands of experimenters in cell
proliferation, be they biologists, physiologists, pathologists, or
others interested in this field.
There are two fundamentals which must be appreciated, viz.,
first, -SH is the naturally occurring chemical group in cell division,
as actually discovered in dividing cells; second, cell proliferation
is regulated by an equilibrium between chemical compounds in
which -SH is the key group. Chemically speaking, this equilibrium is, in many respects, unique, inasmuch as it depends on
changes of valence, oxidation, reduction, and hydrolysis of extremely labile chemical groups revolving around the one element,
sulphur. The directions in which this equilibrium may shift in
living organisms have been charted in principle by Hammett (1).
It is obvious that many circumstances alter the levels of the
equilibrium in respect to the different stages of oxidation, etc., of
the sulphur, and this must be rigidly controlled in experiment;
knowledge of sulphur metabolism in mammals is only in its beginnings (2).
Since the -SH group has been demonstrated to occur under
natural conditions within the nuclei of dividing cells, it follows
that offering -SH-containing compounds to proliferating cells will
increase their rate of division unless their nuclei contain as much
sulphur as they can use for this purpose. Abundant experimental
evidence has been provided (first by Hammett) that cell division
rate is increased by appropriate -SH compounds in a number of
different organisms, both plant and animal, and in a number of
different expressions of cell division. The later work of Voegtlin
and Chalkley (3), using the -SH compound, glutathione, shows
that even the lowly ameba responds. The effects of sulphydryl
2149
2150
STANLEY P. REIMANN
on cell division, as established at the Lankenau Hospital Research
Institute, have been practically applied in the Lankenau Hospital
in accelerating the healing of stubborn ulcers, bed sores, and the
like (4).
Among its many other uses, this tool-sulphydryl-forces cells
in a localized area to divide more rapidly than they normally do (5).
Again, practical advantage is taken of this principle in thickening
the new, thin skin over recently healed burns, etc. (6).
The fact, stated above, that it is a naturally occurring stimulus
which does the forcing, not one foreign to the organism, as, for
example, scarlet red, tar, and x-rays, gives a high theoretical value
to the pictures obtained.
Hammett (7), using as material the skin of rats and mice, found
the following:
(1) The normal skin of the adult mouse is one to three cells in thickness, without stratification or regularity in distribution. There is no
stratum germinativum. Very few cells have protoplasmic brid~es.
There is no definite basal membrane. The stratum granulosum is
discontinuous. There is an occasional mitosis, but always in an epithelial
cell resting on the connective tissue layer; always in a plane vertical to
the skin surface. This results in a few scattered groups of two or three
columnar cells vertically oriented and resting on the connective tissue
layer. Since division takes place only in cells of the lowest layer, it is
assumed that these are the younger, incompletely differentiated cells
from which normal replacement occurs analogous to the columnar cells
in the basal layer of human skin.
After the application of sulphydryl:
(2) The number of cells and follicles, the thickness of both' epithelial
and connective tissue layers, and the length of the follicles are increased.
(3) Practically all epithelial cells resting on the connective tissue
layer are vertical and parallel; mitoses are numerous and only in the
same layer as in normal untreated skin; the number of cells in this basal
layer is greater per unit length. A definite basement membrane appears.
The basal cells and those immediately above are connected by protoplasmic bridges. A stratum granulosum appears.
(4) There is a definite increase in the elastica and the white fibrous
connective tissue beneath the skin.
(5) In some animals the proliferation is differentially much greater
in the connective tissue, in some it is about equal in epithelium and
connective tissue. In the majority it is the epithelium which is chiefly
influenced.
(6) There is no exudative process, i,e" inflammation, except to
minimum degrees in a few cases.
(7) Deviations from the normal occurred in upward proliferations
FIG.
1.
MOUSE EARS, RIGHT EAR TREATED WITH THIOCRESOL, I,EFT EAR TREATED
WITH CRESOL: EXPERIMENT TO VISUALIZE THE GROSS CHANGES.
The treated skin of the animals becomes palpably thickened, as the ears.
cresol is somewhat of an irritant, whereas benzyl mercaptan is not.
Thio-
REACTION OF SKIN TO SULPHYDRYL
2151
producing papilloma-like growths, and downward growth in fan-like
projections. The basement membrane was absent in the latter.
From these findings, Hammett drew the following conclusions:
(1) The source of the increased number of epithelial cells is always
the younger, incompletely differentiated cells. Adult, fully differentiated
epithelial cells of the skin are incapable of division.
(2) Stimulation to active division results in expansion in rate and in
degree of the differentiating powers of the stimulated cells. This is
secondary to the increase in number of cells and involves both epithelium
and connective tissue.
(3) Since the stimulated mouse skin resembles the normal skin of an
animal belonging to a higher order, mouse epithelium is a stage in the
evolution of this general type of tissue.
(4) Mouse epithelium has a lower natural level of stimulation to
division than that of man. This can be attributed to a lower equilibrium
level of the -SH regulatory mechanism.
(5) There is a connective tissue and an epithelial type of reaction in
different animals. This is determined by constitutional differences.
(6) A tendency to structurally abnormal growth is manifested by
some individual animals.
(7) Since these structural abnormalities occurred mostly in the
animals treated with an alcohol solution and not in those treated with a
mineral oil solution, the irritants (alcohol and glycerin) may have
played some part in the reaction.
The same material will now be used in an attempt to interpret
these pictures in terms of malignancy. The same photomicrographs are used to illustrate the changes. The technic of preparation of animals and specimens is given in detail by Hammett (7).
Briefly, the hair was carefully clipped from the region between
the scapulae of mice and the area gently rubbed with 5 per cent
benzyl mercaptan in 3 parts of 95 per cent ethyl alcohol and one
part of glycerin for one set of animals, and in liquid petrolatum for
another set. Specimens of skin were removed from this region so
that a series was obtained showing the changes at weekly intervals
for six months. But one specimen was taken from each mouse.
A total of 219 mice was used. Controls came from untreated
mice, since the use of the analogous non-sulphur compound and
the solvents was unnecessary (5). The sexes were kept separate;
control and treated animals were kept separate. The animals,
bred in the Institute, were from a strain inbred for the elimination
of spontaneous tumors. The specimens were fixed in Susa's
solution, embedded in paraffin, and cut at 3 micra. The sections
were stained with hematoxylin and eosin and with iron hematoxylin.
2152
STANLEY P. REIMANN
RESULTS AND DISCUSSION
Under what may be termed normal circumstances, cells divide
to produce an adult from a fertilized ovum, to replace wear and
tear, to produce more cells for certain purposes (e.g., muscle cells
in the pregnant uterus), to allow of rhythmic growth in certain
organs (e.g., endometrium, breast, in the menstrual cycle). Pathologically, cells divide to accomplish repair of wounds and injuries,
produce hyperplasias, produce the cells in exudates both acute
and chronic, and, finally, to produce tumors of all sorts.
In the first of these two groups of division activity the cells are
fulfilling their normal destiny; in the second, they are forced to
divide by reasons outside their normal destiny of producing and
reproducing an individual organism.
As stated, we can now experimentally add to, and thus supply
at a higher level, the natural chemical stimulus of cells to division.
Bearing in mind the results and implications of this type of
"forcing" on normal skin, as summarized above, let us examine
its possible relation to tumor formation. Can normal cells be
forced by a normal stimulus to become cancer cells?
As a basis of discussion, I will use a favorite example, the
rhythmic growth and regression of the epithelial and connective
tissues, alternately, of the female breast, "forced" by the menstrual
impulses. Suppose the epithelial cells do not stop at the proper
time. The result will be, if the growth is general, (a) an enlarged
normal breast or (b) a carcinoma of the entire organ, as in carcinoma en cuirasse; if the stimulation to growth is local, (c) one or
more enlarged lobules or (d) a local carcinoma of the usual kind.
In all four cases, cell division produces the growth. In all four
cases cells have been "forced" to divide. Wherein lie the differences'?
One way of examining the differences is to study the parts.
The parts consist of (a) cell division, (b) differentiation, (c) organization. '
(a) A review of the literature shows there is no difference
anatomically in the mitotic figures of the healthy cells of a malignant
tumor and those of cells dividing for other reasons. l Hammett
has shown that the same chemical group, -SH, stimulates cell
division in seven different expressions of this function, tumor
formation included (1). Whatever variations them are in the
1
For data, discussions and reviews, see Levine (8).
2153
REACTION OF SKIN TO SULPHYDRYL
function of cell division as carried on for different end-results
would, therefore, seem to be quantitative, not qualitative. The
quantitative aspect discloses itself in varying rates of cell division
in various processes. The relative rate is progressively slowed as
the fertilized ovum becomes the adult individual. But the rate
can be enormously speeded when cell division begins locally, even
in an adult. Hammett finds, for example, that a hermit crab can
regenerate an entire claw in ten days (9). Compared with this,
the rate at which cell division produces the same relative mass of
malignant tumor (i.e., relative to the body weight) is slow indeed.
FIG.
2.
NORMAL MOUSE SKIN, THICKNESS OF A FEW CELLS.
X 930
There are no spinous cells and no continuous stratum granulosum. Mitoses are
few and far between, vertical to the plane of the skin. Protoplasmic bridges are rare.
Another instance of rapid growth is the formation of new tissue
in breasts during pregnancy.
But in these instances, cell division begins in many cells at
once. For example, all the cells in the quiescent breast are stimulated when conception occurs. According to our present knowledge, most tumors begin from a few cells. Why do the other
morphologically similar cells in the immediate vicinity refrain
from dividing in the majority of instances of malignancy? As
framed by Hammett (10), the sulphydryl hypothesis requires that
the chromosomes of certain cells have a lower threshold of response
to this chemical group; this is now experimentally· shown. There
2154
STANLEY P. REIMANN
is also a biological reason why certain cells should divide under
less provocation than others. The covering of the body and its
cavities is constantly subject to desquamation by wear and tear;
for this and other reasons there is more necessity for division of
epithelial cells than of the protected underlying connective-tissue
cells. And it is a fact that carcinomas are much more frequent
than sarcomas.
(b) Differentiation is the name given to the process whereby
cells, as they become mature, take on the special characteristics
of epithelial cells, connective-tissue cells, etc. The cells of malignant tumors differentiate to all degrees except perfection, i.e., to
form normal adult cells. It is not necessary to publish photomicrographs to show this. To everyone experienced in the
microscopy of tumors, it is the commonest of observations that
in a series, or even in one carcinoma-for example, of the rectumall pictures are encountered from absence of differentiation (so
that the cells can scarcely be recognized as epithelial) to definitely
formed, mucus-producing gland cells, architecturally almost, even
if not quite, as perfect as normal rectal gland cells. Differentiation is, therefore, measurable in degrees as a quantitative change,
and qualitatively as to structure and function.
(c) Organization may be defined as the orderly, mutually
considerate growth of two or more tissues to form a part. I know
of no evidence determining whether any tissue takes the lead over
the others in the growth of a part, sayan arm; but in a carcinoma,
it is the epithelial tissue which determines the growth of the stroma,
or, to use the previous terminology, "forces" the growth of the
stroma. If this "forcing" is interrupted, the stroma stops its
growth and shrinks to a scar or disappears completely. This also
is perfectly familiar, as in the following example: radiation can be
so applied to a poorly differentiated carcinoma that it destroys the
carcinoma and not the stroma, whereupon the stroma stops
growing and regresses.
But it must be remembered that the stroma which grows along
with a carcinoma is composed of two parts, one which grows as a
result of the stimulus to organization, and one which grows as a
result of stimulation by products of degeneration, i.e., as an inflammatory reaction (some think it is a sort of specific immune
reaction to the invasion of the cells!). Except that the (we believe
non-specific) inflammatory stimulus is accompanied by more or
less exudation of cells, it is impossible in any given case to separate
REACTION OF SKIN TO SULPHYDRYL
2155
the connective tissue due to inflammation from that due to the
attempt at organization. That the organization in malignancy is
changed not only quantitatively, but also qualitatively, is apparent
from the fact that only connective tissue grows, not muscle,
nerves, etc., as would be the case if an intestine or a stomach were
to be produced. The bone production and the rarer muscle
production occurring with certain tumors are probably not due
FIG. 3.
MOUSE SKIN AFTER TREATMENT WITH 5 PER CENT BENZYL MERCAPTAN IN
LIQUID PETROLATUM.
X 950
Basal layer of cells all vertically oriented, cells larger; continuous layer of prickle
cells; continuous stratum granulosumj very distinct basement membrane.
to a specific organization stimulus, but are secondary to injury of
bone or muscle. The quantitative aspect is brought out by the
fact, mentioned above, that fairly good (though not perfect)
organization is encountered, for example, in some rectal carcinomas with well developed acini, vessels, and stroma (but not
muscle); or, even better, in the so-called malignant adenomas of
the thyroid, in which thyroid tissue is imitated excellently, though
2156
STANLEY P. REIMANN
not perfectly. Thus differences in organization between the
growth of. normal parts and of tumors (benign or malignant) are
like those of differentiation, viz., both quantitative and qualitative.
Considered from another angle, cell division is a non-specific
process. All living things, animals and plants, increase the number
of their units (cells) by a process of mitosis which is similar in all,
not only in principle, but in detail. Exactly half of the essential
substance of the nucleus of the mother cell is distributed to each
of the two daughter cells. Thus any quantitative or qualitative
change in the chromosomes will be equally distributed in the
daughter cells. Since the chromosomes are the structures which
transmit qualitative characteristics to the succeeding generations,
it is through them that the specificity of tissues and of organisms
as a whole is maintained. But the specificity of organisms as a
whole is far more fixed than the specificity of tissues-which is
merely stating that a giraffe is quite a different organism from a
human being, but both human beings and giraffes have, for example, epithelial tissues which resemble each other much more
closely than do the completed organisms. In other words, organization is much more of a specific process than differentiation, and
this in turn is more specific than cell division. On a priori grounds,
when the growth processes deviate from the normal, the expectation is that organization, the most highly developed process, will
be most interfered with and cell division least, and differentiation
will occupy a mid position. This is exactly what occurs not only
in that disturbance of growth known as malignancy, but also in
other familiar examples of growth interference; e.g., in monsters,
cell division and differentiation occur, but organization is deviated.
As to the quantitative aspects, newly produced daughter cells
have less material in their nuclei than the mother cell, but the
quantity is soon increased. Hammett has found that cells can
quantitatively increase their degrees of differentiation when they
are stimulated to division by -SH (7).
Examining now the evidence from the skin sections, when
normal epithelial cells are" forced" to divide by sulphydryl applied
without irritation and without provoking inflammatory reaction,
the result is both greater differentiation and higher organization.
Hence, forcing division of cells with normal (for the species)
chromosome constitution results in the opposite of malignancy.
Tumors cannot, therefore, arise from completely differentiated
adult cells; because if normal division takes place in a completely
REACTION OF SKIN TO SULPHYDRYL
2157
differentiated cell, the qualitative composition of the chromosomes
is quantitatively equally divided among the two resulting daughter
cells. These daughter cells, therefore, inherit a perfect chromosome complex from the mother cell which had perfect chromosomes,
or it could not have differentiated perfectly. Therefore, malignant
tumors must arise from young, incompletely differentiated cells,
the chromosome complex of which is qualitatively altered as to
FIG. 4.
MOUSE SKIN TREATED WITH 5 PER CENT BENZYL MERCAPTAN IN LIQUID
PETROLATUM.
X 950
Numerous mitoses all vertically oriented.
resting on the connective tissue.
diff~rentiation
No mitosis in any other cells than those
and organization factors. Hammett now finds that
only young, incompletely differentiated cells can divide at all in the
skin. Consequently, there is no such thing as" de-differentiation"
in respect to a cell, because the cell, erroneously so called, never was
differentiated.
Chromosomes are composed of chemical molecules, which
react among themselves and with those in the cytoplasm and in
2158
STANLEY P. REIMANN
the surroundings. The failure of a cell to differentiate properly is,
therefore, resident in a qualitative chemical change in its chromosomes. Likewise, the failure to organize properly is due to a
chemical change in the nucleus; but in this case (unlike differentiation, which is the business primarily only of the cells), the
change involves its neighbors and probably also the fluid media.
There is not the proper interaction of chemical molecules to
produce the co-ordinated growth which normally results in the
right organ or part.
Hence such studies as are directed to changes in the cytoplasm
of cancer cells can have bearing on the causes of malignancy only
in so far as cytoplasmic changes influence the chemistry of the
chromosomes. But it should be borne in mind that the latter
also influences the cytoplasm and may well be the cause of cytoplasmic chl:+nges found, as by Warburg 2 (11).
Qualitative changes in the chemistry of the chromosomes may
be (a) hereditary or (b) acquired.
No other conclusion can be reached from the work of Loeb
(12), Slye (13), Little (14), and others, than that the predisposition
to tumors is an inherited, constitutional characteristic. The
sulphydryl hypothesis demands that certain cells have a lowered
threshold to the cell-dividing stimulation of this chemical group
(10).
According to the above biologically minded statements, the
cell-dividing stimulus should be non-specific. That it is, has been
demonstrated experimentally in seven types of cell division in
numerous plants and animals (1). Several of the reasons, among
others, for believing that there is a varying sensitivity to cell
division are given above. Since most malignant tumors begin
from one or a few cells, it is these cells which have chromosomes
hypersensitive to sulphydryl for the division, and qualitatively
altered for the imperfect differentiation and organization. Perhaps the qualitative changes to differentiation and organization
are sufficient to produce the hypersensitivity; the reverse does not
seem to occur.
Furthermore, the final qualitative changes in the chromosomes
which lead to malignancy cannot be present in the fertilized ovum,
2 Note in Warburg's communication (Biochem. Ztschr. 228: 257,1930) that tumors
can originate only when the injury to the oxidative mechanism is transmitted from cell
to cell. Immune reactions, also, must be due primarily to altered chromosome chemistry. See Lumsden, T.: Tumor immunity, Am. J. Cancer 15: 563-640, 1931.
REACTION OF SKIN TO SULPHYDRYL
2159
nor in the fetus, nor in the child, nor in the young adult in the great
majority of cases, for most malignancies begin later in life. It is
the exceptional case that presents a congenital tumor or a malignancy in youth. In other words, during the period when cell
division is occurring most actively, and when faults in the chemistry of the chromosomes are most likely to be apparent, these faults
are not manifested. This" latent" period is not exactly paralleled
by, but can be compared (for the differences) with the" latent"
period observed in so many recurrences of malignancy after oper-
FIG. 5.
MOUSE SKIN TREATED WITH 5 I'ER CENT BENZYL MERCAPTAN IN LIQUID
PETROLATUM: DETAIL OF PROTOPLASMIC BRIDGES.
X 950
ative removal of the main growth. For example, the surgeon
performs the radical operation for carcinoma of the breast, but is
unable to remove a few particles of the tumor beyond the lines of
his incision. Nothing occurs for eight, ten, or more years, when
the particles begin to grow with the inevitable result. The cells
have remained "latent" and refrained from dividing for years,
until conditions again stimulated division. 3
In the former case, the division is normal and the faults of
differentiation and organization develop later; in the latter case of
3
This, unfortunately, is also only too well known. See case report in reference 17.
2160
STANLEY P. REIMANN
"latency," i.e., after operative removal (and also in some tumors
which grow in spurts), the faults of differentiation and organization
are already present and manifested, but division is not stimulated.
In terms of the sulphydryl hypothesis, it is consistent to postulate
shifts of the equilibrium (by as yet unknown factors) which are
capable of investigation in the test tube and in vivo, during periods
of latency and of actual malignancy, etc. (20).
The conclusions are, therefore, that certain strains of cells by
heredity contain chromosomes of chemical composition less stable than
others. This instability is followed finally by a change in the chemical
composition sufficient to result in an increased susceptibility to the
stimulus to cell division (sulphydryl), and to altered differentiation
and organization. This latter acquired characteristic is then transmitted to the succeeding generations of cells.
Malignancy, indeed practically all tumor formation, is, therefore, an example of the inheritance by cells of acquired characteristics of a qualitative (not quantitative) kind. With these and
other complications, it is small wonder that geneticists are unable
to agree in detail! (13, 14).
In considering acquired qualitative changes in the chromosomes, it must be stated that in no case in which carcinoma has
arisen from a known exciting cause, as from irritation, can a constitutional factor be excluded. Not all tarred animals develop
carcinoma. Probably in those in which tars (and many other substances) produce overgrowths which regress with cessation of
application of the stimulant, this constitutional factor is absent
(10). That there is also a quantitative aspect to the situation is
apparent from the facts (a) that it requires different times in
different individuals to change the chemistry of the chromosomes
to the point of malignancy (two to thirty years for tar workers to
develop carcinoma) (15), and (b) that the carcinogenic factor can
be concentrated (16, 17).
To return to the sections of mouse skins: when benzyl mercaptan was applied in an irritant solvent (alcohol 95 per cent, 3 parts;
glycerin, 1 part), abnormalities in differentiation and organization
soon appeared in a number of the animals. The longest periods of
application were of six months' duration (3 times weekly). No
actual malignancy developed at the time, or later (six months
more). The photomicrographs (Figs. 6 and 7) show the upward
overgrowths as flat or raised, thick or slender, papilloma-like
projections. When they developed, they grew fairly uniformly
FIGs. 6 AND 7. MOUSE SKIN TREATED WITH 5 PER CENT BENZYL MERCAPTAN IN
THREE PARTS 95 PER CENT ALCOHOL AND ONE PART GLYCERIN: PAPILLOMA-LIKE UpWARD GROWTHS,
X 265
2161
2162
STANLEY P. REIMANN
over the surface treated. Conversely, when the growth was
downward~i.e., in those parts in which the basement membrane
was lost, in which the cells were streaming downward, in which
the cells had lost their strict epithelial morphology and had become
spindle-shaped, had lost their polarity and orientation~the deviation occurred in but a relatively small part of the total area
treated (Fig. 8). Thus, the change in chromosomes which led to
FlO. 8. MOUSE SKIN TREATED WITH 5 PER CENT BENZYL MERCAPTAN IN THREE
PARTS 95 PER CENT ALCOHOL AND ONE PART GLYCERIN: FAN-LIKE DOWN-GROWTH WITH
Loss OF BASEMENT MEMBRANE. X 115
upward growth was more widely distributed than that leading to
downward growth, which would indicate. apparently, that the
chemical groups of the chromosomes of more cells are sensitive to
upward growth change (a lesser deviation) than to down-growth
change, which is a more radical deviation. In both cases the
epithelium remaining around papillomas and down-growths showed
the same phenomena as detailed by Hammett.
The non-occurrence of actual malignancies may be explained
by the facts that the animals were inbred for the elimination of
spontaneous tumors, the irritant used was mild, and the time of
application was relatively short. In terms of the present thesis,
REACTION OF SKIN TO SULPHYDRYL
2163
the differentiating and organizing chemical groups were not sufficiently changed to allow of the inheritance of this acquired
characteristic by the succeeding generations of cells.
To apply the sulphydryl hypothesis to the example of the
breast previously quoted (page 2152): in (a) and (c), when the
growths are normally differentiated and organized but differ by
being general or local, the reduced-oxidized sulphur equilibrium is
FIG. 9.
MOUSE SKIN TREATED WITH 5 PER CENT BENZYL MERCAPTAN IN LIQUID
PETROLATUM: EPITHELIAL TYPE OF REACTION.
X 115
shifted to the -SH side generally throughout the breast, or locally
in the part. Evidence that the -SH groups can be liberated locally
is quoted by Hammett (10). Chemical knowledge of the equilibrium gives adequate basis for the belief that many other physical
and chemical agents can liberate the group.
The breast epithelial cells, when" forced" to divide, continue
to differentiation and organization because they contain normally
constituted chromosomes, just as the mouse skin in the experiments reported. The malignancies, (b) and (d), local or general,
04
2164
STANLEY P. REIMANN
also arise from cells stimulated to divide by sulphydryl, but these
cells fail to differentiate and organize by reason of a qualitative
chemical change in their chromosomes.
Modification of certain statements regarding cell division in
my paper on tumor grading (18) becomes necessary in view of
Hammett's results and the discussion here. 4 At the time it was
written, there was no knowledge of what happens when cells are
stimulated to divide by sulphydryl.
A speculation on inhibition of cell division may be permitted.
As stated above, differentiation is the cell's own business, whereas
organization is its neighbor's business as well. In the example of
the breast, when the connective tissue regresses, sulphydryl is
liberated to stimulate the epithelium (19). The chemical groups
for organization, now active in the nuclei of the epithelial cells,
interact with the chemicals for the same purpose in the nuclei of
the connective-tissue cells. The sulphydryl equilibrium in the
epithelial cells is finally brought to the inhibiting side of the
equation by the influx of chemicals from the connective tissue.
This loss may conceivably tilt the -S equilibrium in the connective
tissue cells to the mitosis level, when the direction of flow of organizing molecules is reversed, until again the epithelial cells are
driven to proliferation. Since there is unequivocable evidence
that ovarian secretion is the activator of the breast epithelial
proliferation, its mode of action can be conceived as that of a
"trigger" effect, starting the shift of equilibrium to the ~SH side
in the epithelial nuclei. Or, biologically speaking, the epithelial
cells may be more sensitive to the effects of sulphydryl, since in
any demand for increased numbers of specifically functioning cells
in any active organ of the body, it is often epithelial cells which are
called upon to perform this function, e.g., in the thyroid gland and
the liver. The organization chemicals thus may determine shifts
in the equilibrium to start and stop cell division, and, biologically
speaking, organization is the stimulus and inhibitor of cell division.
Since the organization chemicals obviously differ not only from
species to species, but also from area to area in the same individual,
it follows that different parts of any organism show different levels
of equilibrium at different times. At all events, the reverse occurs,
i.e., mitosis has been shown experimentally to have a decided
effect on differentiation and organization (7).
4 The main thesis, of course, stands; tumors can not be graded for the individual
patient.
REACTION OF SKIN TO SULPHYDRYL
2165
The fact that a certain few animals react by more connectivetissue proliferation than epithelial is but another experimental
demonstration of Virchow's "connective-tissue type individual,"
which tends to develop heavy scars, abundant adhesions, and,
perchance, sarcomas rather than carcinomas. To obtain some
concrete figures on the number of humans possibly belonging to
this type, scars of two hundred operative patients were examined.
The scars were of McBurney incisions for appendectomy and of
FIG. 10.
MOUSE SKIN TREATED WITH 5 PER CENT BENZYL MERCAPTAN IN LIQUID
PETROLATUM: CONNECTIVE-TISSUE TYPE OF REACTION.
X 115
herniotomy incisions. All were examined nine months after
operation; the ages were between twenty-five and forty years; the
operative sites were" clean," and all the wounds had healed rapidly
and normally by first intention. Apparently the same procedures
were followed in all patients, by the same surgeon. Of the 200,
11 (5.5 per cent) were heavy raised scars, 110 (55 per cent) were
thin lines, and the remainder showed varying degrees between.
Among the specimens of malignant tumors collected by the Tumor
Bureau of the city of Philadelphia, 64 per cent are carcinomas and
8.5 per cent are sarcomas. That the connective-tissue cells of
2166
STANLEY P. REIMANN
some individuals are more prone to division than those of others,
is undeniable.
Since, in treating the mice, the sulphydryl group was gently
applied to the surface of the skin, it, or its influence, had to traverse
the epithelial cells to reach the connective tissue. In certain mice
the epithelial cells responded relatively and absolutely less than
the connective tissue, from which two conclusions are to be drawn:
(1) that their connective tissue was more sensitive than that of
other mice to the sulphydryl group, and (2) that their connective
tissue was more sensitive to this group than their epithelial cells.
SUMMARY
The -SH-S03 equilibrium regulates cell proliferation. This
equilibrium is chemically unique, and due attention must be given
to this fact in experiments.
It forces cells to divide beyond their normal division levels.
The pictures so produced are important, because -SH is the
naturally occurring stimulus, not an artificial one.
The skins of mice (and rats) were treated with the -SH compound, benzyl mercaptan, in a bland and in a mildly irritating
solvent.
The proliferations so produced are discussed in relation to
their pathological significance.
In the bland solvent, the -SH produced increased cell division,
differentiation, and organization, architecturally manifested as in
an organism higher in the evolutionary scale (as described by
Hammett).
In the irritant solvent, the -SH not only produced the same
result, but also, in a number of animals, such deviations of pathological significance as upward growths into papillomas and downward growths with loss of basement membrane and of differentiation (anatomically) of the cells.
An experimental example of "connective-tissue type" individual is given.
CONCLUSIONS
1. The experimental forcing of cell division with a natural
chemical stimulus-sulphydryl-results not in diminished but in
increased differentiation and organization of the cells so forced.
2. Increased rate of cell division alone can never lead to malignancy.
REACTION OF SKIN TO SULPHYDRYL
2167
3. A qualitative alteration of those chemical groups in the
chromosomes which control differentiation and organization must
occur before malignancy can be produced.
4. The chemical groups of the chromosomes controlling differentiation and organization of certain lines of cells are by inheritance
less stable in those individuals who later develop malignancy.
5. The actual qualitative chemical alterations in the chromosomes leading to malignancy are usually not developed until later
in life.
6. This qualitative alteration is transmitted from mother cells
to daughter cells as an acquired inherited characteristic.
7. The instability of the potentially altered chemical groups
of the chromosomes can be pictured as one of degree, requiring in
some individuals a slight, in others a greater impetus (irritation)
to produce the actual change, and in some individuals perchance
none at all applied externally.
8. Certain cells are more sensitive to stimulation to divide (and
to sulphydryl) than others, sometimes reaching to the development
of an actual type, as the" connective-tissue type" individual.
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