Morphological and Chemical Investigation of Dermal
Elastic, and Collagenic Tissue During
1@' .1
1I'@'i
Jipiaermai
@arcinogenesis
CHUNG
(From the Department
of Anatomy,
Washington
K.
Univerrity School of Medicine, St. Louis 10, Missouri)
Before cancer develops in mouse epidermis in
fluenced by methylcholanthrene,
generations of
epidermal cells live for months in a strangely a!
tered kind of existence. Their lives are in a sense
askew for they carry on despite many marked de
ficiencies and some excesses in essential materials.
The features of their manner of life have been re
cently summarized (1).
Investigation of these epidermal cells is now be
ing supplemented
by study of accompanying
changes in the underlying dermis. Thus, a new
method for staining nerve endings and fibers has
been devised (2, 3) and will be used. Sebaceous
glands andhair follicles (4, 5), lodged in the der
mis, undergo interesting modifications. The lipase
activity of sebaceous glands and of dermal fatty
tissues, as revealed by the Gomori reaction, is
lost (6). Alterations observed in the number and
fluorescence of mast cells (7) suggested operation
of the spreading factor (hyaluronidase)
in the
breaking down of resistance to invading cancer
cells possibly offered by hyaluronic acid in the
dermal tissue fluid. Preliminary
experiments in
volving injections of hyaluronidase in the vicinity
of cancer transplants seem to indicate that metas
tasis is thereby
promoted
(8). On the theory
S Aided
by
grants
from
the
C. F. Kettering Foundation,
Club of St. Louis.
National
Cancer
Institute,
University.
zones. The first is the zone of tumor
growth
next to the
second that
cancer and a more distant
increase,
the conditions
described
were those
after cancer development. There is apparently no
account in the literature of the sequence of altera
tions in dermal
elastic
and collagenic
tissue
during
epidermal carcinogenesis except one which was re
ported by Bierich (12) who made a study of mouse
skin at 5 minute, 6 hour, 24 hour, and 5 day inter
vals after x-ray irradiation.
But some useful infor
mation
genic
is available
tissue
concerning
on nonmalignant
elastic and colla
conditions
of the
skin (13 to 24). I am grateful to Dr. E. V. Cowdry
for suggestions.
MATERIAL
AND
METHODS
histological data.—Female Swiss mice 4 weeks old
were employed: (1) Five served as normal controls.
(2) Others
received
applications
of 0.6 per cent methyl
cholanthrene
in benzene delivered
No.
three
4 brush
times
a week
to their backs by a
in exactly
the
same
manner that is regularly done in work by others in this
group. Of these 30 mice, 5 were killed after 10, @0,30,
40, 50, and 60 days. (3) Still others received similar ap
plications
of pure
killed at 10 and
benzene.
Of these
10 mice,
5 were
@0days.
Excised samples of skin were placed on thick paper
and fixed in fresh Helly's fluid. Some tissues were em
bedded in tissuemat and sections, cut @2,5thick, were
stained in alcoholic orcein or in Weigert's resorcin
fuchsin. Others were embedded in hard paraffin and
the
and the Women's Advertising
f In part fulfillmentfor the degreeof Doctor of Philosophy,
Washington
three
devoid of elastic tissue; the second is the zone of
cellular infiltration with decreased elastic tissue;
while the third is the zone of pressure character
ized by increased elastic tissue. Turning to the
skins of mice, tTlesco-Stroganowa (11) induced can
cer by applications of coal tar and found in the re
gion of epithelial hyperplasia a marked increase in
elastic tissue and in mast cells while about the
cancer elastic tissue was absent. It is to be noted
first that in both these tissues of humans and mice
the investigators reported decrease in elastic tissue
that
dermal mast cells may play some part in the pro
duction of the hyaluronic acid other experiments
are being made (9). Thus, data are being gathered
on dermal modifications with a view to building up
a comprehensive picture of what happens.
In this paper morphological and chemical modi
fications in dermal, elastic, and collagenic tissue
are reported in the hope that they will supply clues
to the changing physical and chemical properties
of the dermal ground substance. The literature on
this subject is scanty. It has been reported (10)
that human skin with carcinoma is divisible into
@
MAt
sections, cut 8 ,.t thick, were colored by Mallory's stain,
the quad stain, or by Foot's method. The direction of
481
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Cancer Research
482
sections
was transverse
to the long axis of the body
in
some instances and longitudinal in others.
Attempts
were made quantitatively
to measure
alterations observed in the elastic tissue (25). A disc,
ruled in large and small squares, inserted in the ocular
was
calibrated
by
reference
to
a micrometer
slide.
At
the magnification employed one of the small squares
@
covers
square
microns
of tissue.
Twenty-five
of these
small squares were included in each square.
Chemical
data.—Female
Swiss
mice
of the same
age
(4 weeks)wereusedandthemethylcholanthrene
was
applied
in the same manner.
For elastin,
chemical
analyses
were made of 90 mice killed in lots of 18 on 0,
10,
@0,30, and 60 days; for collagen,
analyses
were
made of 108 mice killed in lots of 18 on 0, 10, @0,30, 40,
and @0
days from the initiation of application. Six deter
minations
were
made
at each
stage
and
the
averages
are given in the tables.
For normal mice, the skin was removed from almost
the entire back, while from the treated mice it was only
taken
from
the area painted
with
carcinogen.
Pannicu
lus carnosus was carefully removed from both with a
scalpel. Epidermis was separated from dermis by the
heat method of Baumberger,
Suntzeff, and Cowdry
(@6).
to the slope of the hair, that is longitudinally to the
long axis of the body and likewise to the hair fol
licles. Part of the erector muscle is located to the
right of the hair follicle in the obtuse angle formed
between it and the epidermis. Elastic fibers en
circle the distal portions of the hair follicles,
stretch
muscles.
between
them
and along
the erector
Some fibers are concentrated
just be
neath the epidermis, especially at the attachments
of these muscles, and seem, as so-catted Herx
heimer's
fibers,
to be attached
to the epidermis.
Individual fibers are approximately
1.2js in thick
ness.
But the actual orientation and arrangement of
elastic tissue in living skin is undoubtedly
some
what different. When still living skin is freshly cx
cised, it can be seen to shrink noticeably
when flattened out on a piece of stiff paper
so that
for fixa
tion it occupies a smaller area than it did originally
in the
animal.
been measured
skin by Evans,
The
extent
of this
shrinkage
has
in biopsy specimens of antecubital
Cowdry,
and
Nielson
(29). Skins
of young persons in their thirties lost 38 to .50 per
cent of their original areas. In mice this shrinkage
is more difficult to determine accurately because of
The elastin content of dermis for normal mice and
mice of 10, @0,30, and 60 days, and the collagen con
tent of dermis for normal mice and mice of 10, @0,30,
extreme
hairiness.
There
is also a further
shrinkage
40, and 50 days after the first application of carcinogen
were determined exactly as described by Lowry,
@il1i- of at least 10 per cent owing to fixation and other
steps in the preparation
of sections. Consequently
gan, and Katersky (@7). Since the water content in the
dermis was markedly
samples
were frozen
affected by carcinogen,
and dried for 48 hours
all dermis
before ex
traction with alkali in order that the results could be
calculated on a uniform dry weight basis.
The percentages thus obtained sufficed to show the
relative amounts of elastin and collagen. To compare
the elastin
carcinogenesis,
and collagen content
an absolute
collagen is necessary.
in various
measurement
Hence, further
stages of
of elastin
and
work was done by
the elastic
tissue
of the living animal
up of thinner
out, made
greater
It is
sented
usually
tension than Figure 1 indicates.
also to be noted that if the sections repre
in Figures 1 to 4 were of the thickness
employed in histopathological
examina
tions, say 10 ;s, instead
elastic tissue contained
fibers,
is more
spread
and under
of 25 @,the amount
of
in them would be much
less. The advantage of these thick sections is that
with a binocular microscope the arrangement
of
Unit area of dermis was taken by means of a quadri
fibers in depth can be better studied. Individual
lateral razor-blade device which covers an area of @275 fibers can be traced through longer distances and
square mm. (1 1 mm. X@25 mm.). The skin sample was
alterations
in their girth can be detected. The
obtained directly from the carcass of the shaved mouse
photomicrographs
give only an artificial, flattened
by using this instrument in as uniform a manner as pos
out
picture
in
one
plane of the fibers.
sible to minimize distortion. The dry weight of the
By
counting
the
elastic fibers in many 25 square
dermis of a unit area of dermis was thus determined,
and by multiplying it by the percentage of either elastin micra areas a rough measure was obtained of the
or collagen of the corresponding stage, the absolute
number of elastic fibers. The dermis selected for
taking
unit
areas
of dermis
and
weighing
both
before
and after being dried at a temperature of 110°
C. (23).
weight of elastin or collagen of that special stage was
obtained.
To separate the dermal part from the epithelial part
of the cancer is impossible; consequently, the elastin and
collagen content of the cancer were compared with that
of fresh normal skin, that is, of dermis plus epidermis and
the results
were calculated
on a wet weight
basis.
OBSERVATIONS
Figure 1 illustrates
sue in a section
that
the appearance
of normal
mouse
such determinations
of elastic tis
skin cut parallel
waslocated
between
hair fol
licles and at some distance from them so as to
avoid the concentrations
of elastic tissue in their
immediate vicinity. Also, in making the counts the
upper margin of the large square in the ocular as
nearly as possible was superposed on the distal cx
tremities of the layer of basal epidermal cells so
in each specimen
fibers
in an equal
depth
of
dermis covered by the small squares were counted.
These counts showed a gradual and progressive
Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1949 American Association for Cancer Research.
Fio. 1.—Skinof normal mouse, cut parallel to the hair cur
rent to show the elastic fibers and their relation to the hair
shown.
follicles and erector pill. Mag. X 850.
sue, (the so-called “elasticamimica―). X 350.
Fm. 2.—Skinof mouse 40 days after initial application of
carcinogen.
Increase
of elastic
fibers cut
longitudinally
is
X 350.
FIG. 8.—Skin
of mouse
after
60 days.
Islands
of elastic
tis
Fm. 4.—Skin of mouse likewise after 60 days. Masses of
cancer cells with no elastic fibers. X 350.
Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1949 American Association for Cancer Research.
Cancer Research
484
increase of elastic fibers in specimens examined
@0,and
30 days
after
the beginning
10,
of applications
of the skin of 0.6 per cent methyicholanthrene
in
benzene. After 10 days individual fibers became
thickened to about 1.5 @s
and retained this thick
ness to the stage
shown
in Figure
3. The peak
found in the stroma of the resulting cancer is
shown by Figure 4.
Figure 5 shows the dermis of normal mouse. It
in
number seemed to be at 30 days for at 40 days
there was a noticeable decrease which became very
much greater at 50 days. The fibers became so
closely bound together at 60 days that counting
was impossible.
This increase in elastic fibers to a maximum at
30 days
in the
specimens
examined
is definite
but
some individual variations may exist. The vertical
thickness of the dermis in preparations
of the
skins of normal untreated mice ranged from 60 to
@
90
This
repeated
thickness
rapidly
applications
increased
with
of the carcinogen.
the
In the 30
and 40 day specimens,
thicknesses
of @00and 400
@z
were measured.
If the dermis had, on the con
trary, decreased
tic fibers might
in thickness,
have
of approximately
sheet of dermis.
the increase in elas
been attributed
to crowding
the same number
into a thinner
is composed
TABLE
PERCENTAGE
OF ELASTIN
o days
1.75±0.22
Elastin
Collagen
31.2
10 days
1.57±0.06
±1.17 17.5
mass,
in which
±0.57 12.8
individual
collagenic
IN FROZEN
AND DRIED
30 days
fibers
fibers
DERMIs
40 days
30 days
60 days
1.88±0.14 3.06±0.16
±0.98 24.5
The appearance of elastic tissue at 40 days is in
dicated in Figure 3. The elastic tissue immediately
beneath the epidermis is reduced but the amount
stretching in a band between remnants of hair fol
licles is certainly increased. Some of the fibers are
also of larger girth. Careful study showed a little
irregularity in thickness of individual fibers. A few
detached or broken ends were slightly swollen. No
change could be detected in their affinity for spe
cific stains.
At 60 days entangled masses not unlike the so
called elastica mimica in facial skin (15, 16, 17, 30)
were found and are shown in Figure
@.A large
mass made of deeply staining degenerated fibers is
to be seen a little to the left of center. A larger and
less dense
arranged
1
AND COLLAGEN
10 days
of densely
and a few connective cells, the cytoplasm of which
is not easily seen and the identification of which is
only marked by smaller, darker nuclei.
Figures 6 and 7 are pictures from mice 30 days
after treatment
with carcinogen. Though there
seems a little difference between these two one
thing is common, that is they become more cellular.
The connective tissue cells are larger, irregular in
shape, with abundant
granular cytoplasm
and
large nuclei. The collagenic fibers appear to be
fragmented
in comparison with the long wavy
course of that of normal dermis.
The stroma of cancer is composed of loosely ar
ranged collagenic fibers and is much diminished in
bulk in comparison with the invading epithelial
cells. This is shown in Figure 8.
The results of chemical analysis together with
the standard errors of the mean are shown in the
following tables:
2. 23±0. 11
±0.72 16.9±1.03
15.2±0.51
TABLE
2
PERCENTAGE OF ELASTIN AND
COLLAGEN
Elastin
Collagen
IN FRESH
SAMPLES
Fresh dermis
Cancer
1.46±0.09
0.38±0.03
10.4 ±0.55 1.47±0.20
TABLE
S
DIFFERENCE IN WEIGHT OF A UNIT AREA (275 MM.)
OF MOUSE DERMIS, BEFORE AND AFTER ThEAT
MENT WITH METHYLCHOLANTHRENE
dryMeanweight
Mean of wetMean
of
dermiswaterin
of dermisweight
gramscontentUntreated
gramsin
of
skin
71.3%
0.0508±0.001751.4%
0.171@±0.0320.0246±0.0040
MCtreatedskin0.0496±0.0089
can
more clearly be distinguished, is further to the left.
In the course of epidermal carcinogenesis, the
elastic fibers lose their attachments
to the epider
mis as this tissue becomes hyperplastic. As the hair
detachment
is advanced so that these islands of
elastic tissue appear to lose form and become
Dry weight of unit area dermis was determined
on the thirtieth day. Table S shows a 40 per cent
relative increase in water cofitent. The weight of
formed elements is doubled. Therefore in absolute
weight the dermis on the thirtieth day contains a!
most four times as much elastin and over 60 per
cent more collagen than that of normal dermis. If
granular,
a curve
were plotted,
similar
though
follicles
degenerate
fibrous
and disappear
this process
of
vestiges.
That elastic tissue fades out and can hardly be
the elastin
it would
not
content
quite
would be
coincide
with
Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1949 American Association for Cancer Research.
@
-
FIG. 5.—Dermis
of normal,
numerous densely arranged
nective tissue cells. X 350.
uiitreated
collagenous
mouse.
i'@
There
are
fibers but few con
Fia. 6.—Dermis of mouse 30 days after application of car
cinogen. Connectivetissue cellsare much increasedin sizeand
in number. X 350.
@. :
Fm. 7.—Mousedermis SOdays after application of carcino
gen, to illustrate
the dominant
FIG. 8.—Illustrating
diminished
cancer.
that
connective
the
in bulk in comparison
connective
tissue cells.
tissue
with the epithelial
stroma
is
cells in
Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1949 American Association for Cancer Research.
Cancer Research
486
that obtained by plotting the fiber counts. In both
there would be a rise followed by a fall. Fiber
counts are impossible in collagen fibers.
DISCUSSION
of methyicholanthrene-induced
Study
mal
carcinogenesis
stressed
tions
by
the chemical
of the
dermis.
this
spreading
epider
has
largely
and morphological
altera
This
group
report
has
considered
quantitative
shifts in some of the connective tissue
elements of the dermis under the standardized con
ditions
employed
here.
An initial increase in amount of dermal elastic
and collagenic fibers after exposure to methyl
cholanthrene
has been described; this is followed
by a loss of fibers. Little significance is attached
to
the time scale of alterations
in fiber content since
samples for analysis were taken at 10-day inter
vals. Thus, the increase in elastic fibers first noted
in the 10-day sample may actually reflect a situa
tion existing several days earlier, and the peak in
elastic fiber content of the dermis described at 30
days
may
occur
some
time
between
21 and
39
days. The essential point is that application of
methyicholanthrene
to the skin of the mouse re
sults in a transient increase in both elastic and col
lagenic fibers followed by a pronounced drop in the
content of these fibers.
In view of the fact that so little is known of the
physiology
of connective
tissue fibers,
it is difficult
to attempt to evaluate the significance of the
changes here reported. Three clear possibilities
seem to exist. Variations in connective tissue fibers
reflect alterations in the behavior of the ubiquitous
fibroblasts,
and in surface
adsorptive
capacities
of
the fibers. Third, and perhaps most significant,
loss of a network of fibers from the dermis may
facilitate metastatic
activities of the squamous
cancer cells.
Some information
tions of fibroblasts
is available
on the interrela
and connective
tissue fibers.
Morrione (31) induced liver cirrhosis with carbon
tetrachloride
and p-dimethylaminoazobenzene
in
albino rats. In the course of fibrosis he noted a pro
liferation of fibroblasts. After stopping application
of hepatotoxic substances, the fibrous tissue under
went resorption. He attributed the latter to the ac
tivity of liver cells, the function of which is in turn
dependent upon diet. Recovery from cirrhosis is
impaired
by a high fat, low protein
Hass and MacDonald
in tissue
cultures
that
diet.
(3@) have demonstrated
depression
hyaluronic
acid and chondroitin
sulphuric acid
. content amount to
@4.5±5.7 and
@6;@
±4.7
mgm. per 100 gui. of fresh tissue, respectively. In
jection of hylauronidase
seems to facilitate the
of pH restricts
collagen fiber deposition
and enhances
This has been discussed
by Cowdry
resorption.
(33).
In 1949, Pearce and Watson (34) analyzed hu
man skin and concluded that, in fresh samples, the
of cancer
(8). Some
change
may
there
fore occur in dermal hyaluronic acid after applica
tion with carcinogen. But data are still lacking.
The thickening of dermis referred to is probably
accompanied by edema, the possible relationship
of which to changes in elastic fibers has been dis
cussed by Dick (14) ; but it is not clarified by these
experiments.
The chemical procedures of Lowry (27) for
preparation of elastin and collagen paved the way
for analysis of connective tissue fiber changes in
carcinogenesis. The method for elastin is simple
and depends upon the relative insolubility of this
material in dilute alkali. It is to be expected that
any other materials insoluble in dilute alkali will
be concentrated with elastin. As yet we have de
vised no procedure for separation of the mucopro
tein of elastic tissue from the alkali resistant
residue .
SUMMARY
Marked changes take place in dermal elastic tis
sue during epidermal carcinogenesis induced by
cutaneous applications
of 0.6 per cent methyl
cholanthrene
in benzene.
The
number
of elastic
fibers is increased 10 days after the first applica
tion. Through %0 day specimens this increase is
progressive and attains a maximum at 30 days.
After 10 days individual fibers thicken to a diame
ter of about 1.5 s. Some become rather irregular
in.girth at about 40 days but in general they retain
this diameter to approximately
60 days. From 30
days
onward
the number
of fibers
decreases.
Fol
lowing loss of their epithelial anchorages a few fi
hers exhibit slightly swollen ends and at 60 days
all elastic tissue is reduced to fibrous islands of
material in dermis otherwise free of elastic fibers.
In primary cancers 60 days and more after the
first application of methylcholanthrene
the dermis
is almost
devoid
of elastic
fibers.
This primary
in
crease and later decrease in elastic fibers was sup
plemented by direct chemical analysis of elastin by
Lowry's method which revealed a similar primary
increase and later decrease.
Other dermal changes are those of collagenic
fibers and connective tissue cells. As carcinogenesis
is in progress,
the dermis
tends
to become
more
cellular. With chemical analysis of collagen by
Lowry's method, first a slight increase and then a
decrease were found. Factors possibly effecting the
increase and decrease of elastic and collagenic fi
bers were discussed
mechanism
involved,
but for elucidation
further
study
of the real
is necessary.
Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1949 American Association for Cancer Research.
MA—Chemistry of Epidermal
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Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1949 American Association for Cancer Research.
Morphological and Chemical Investigation of Dermal Elastic,
and Collagenic Tissue During Epidermal Carcinogenesis
Chung K. Ma
Cancer Res 1949;9:481-487.
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