On the Role of Stickiness of Tumor Cells in the Formation
of Metastases
KIYOHIDE
KOJIMA
AND ISAO SAKAI
(Department of Pathology, Nagoya City University Medical School, Nagoya, Japan)
SUMMARY
A comparative study of stickiness of tumor cells to glass surfaces was undertaken
with the use of three strains of rat ascites hepatoma, All 13, All 130, and All 7974.
Stickiness was measured by calculating the percentage of cells clinging to a glass surface
of the calculating plate after it was washed with salt solution.
A significant difference was observed in the cell stickiness among these three strains.
All 13 showed the most active stickiness, All 130 moderate, and All 7974 the least
active. These results indicate that cell stickiness is inversely correlated with the ad
hesiveness between cells in the above tumors.
When these three tumor strains were inoculated intravenously, the most active
strain with respect to cell stickiness caused the largest number of metastatic nodules
in the lung. The same result in frequency of lung metastasis was also obtained with
intraperitoneal inoculation of each tumor. Such a correlation between metastatic
frequency and cell stickiness suggests that the cell stickiness may be an important
property of the cell surface responsible for metastatic spread of tumor cells via blood
vessels.
In order to study the nature of stickiness, chemical treatments
of tumor cells in
vitro were undertaken with the use of Ehrlich ascites carcinoma, All 13, and Yoshida
sarcoma. It was found that the stickiness of tumor cells was decreased by treatment
with protamine sulfate and trypsin, whereas stickiness was increased by treatment
with Tween-80.
Significant effects on stickiness could not be observed with polyvinyl
sulfate, sodium deoxycholate, calcium chloride, and disodium versenate.
Further
more, in acid medium, cell stickiness was significantly decreased, while in alkaline me
dium it was increased.
Based on these results, stickiness of tumor cells to glass was
discussed.
From this point of view, a comparative study on sticki
Surface properties of tumor cells have been considered
as an important factor responsible for malignant trans@ ness was performed
formation
(1).
The
observations
(9,
15)
ascites hepatoma
concerning
with the use of three strains of the
of the rat (8, 12, 13) which are different
passages of circulating tumor cells through capillaries in their mutual adhesiveness. Furthermore, the bio.
suggested that the properties of tumor cells or their logical significance of stickiness for metastatic spread of
tumor cells was also investigated.
reported in this paper.
Recently, Coman (6) reported that the “adhesiveness―
surface may be responsible
for metastatic spread.
MATERIALS AND METHODS
of cells to one another and their “stickiness―
to a foreign
substrate are independent
phenomena,
and that tumor
cells are extremely sticky but poorly adhesive, whereas
normal cells are strongly adhesive but not very sticky.
It may be reasonable to assume that there ii a difference
not only in adhesiveness but also in stickiness, depending
upon tumor strain. To test this possibility, use of tumor
strains of the same origin and of different biological
characteristics
as experimental
material
is desirable,
since
these properties might depend upon those of the normal
ancestral
These results are
for the difference in response
cells.
Tumor
strains
of the ascites
hepa
Yoshida (12), were used for studies on stickiness and
intravenous
transplantation.
In the ascites
hepatoma,
the tumor cells, being epithelial in nature, make cell
associations, forming “islands,―
and individually isolated
cells are also present.
The number of these isolated cells
differs depending upon the hepatoma strain; i.e., All 13
consists
AH
Received for publication March 23, 1964.
rnalerials,—Three
toma, AU 13, AH 130, and AH 7974, established by
130,
of almost
of
abundant
entirely
isolated
single isolated
cells
and
a
tumor
few
cells;
small
“is
lands―; and AU 7974, of isolated cells and “islands.―
1887
Downloaded from cancerres.aacrjournals.org on June 15, 2017. © 1964 American Association for Cancer Research.
Cancer Research
1888
For chemical treatments
tumor
of the
free
All 13, and Yoshida
In
the
present
Moriyama
in vitro, three strains of ascites
cell type,
Ehrlich
sarcoma,
studies,
Psychiatric
ascites
of the
Hospital,
closed
colony
weighing about
in
100 gm.,
and dd/N mice, offered from the animal supply center of
Nagoya University, weighing about 20 gm., were used.
They were highly susceptible to these tumors.
Observation technic on stickiness of tumor cells.—Tumor
suspensions were prepared by adding 0.1 ml. of tumor
ascites to 5 ml. of phosphate-buffered saline at pH 7.2.
Stickiness
was measured
into the calculating
by settling
plate, which was made of a clean glass
A cover slip (50 X 22
mm.) was fixed to the plastic tapes with Vaseline, and
then pressed with care to keep a constant
0.10—0.13 mm.
between
the glass slide and the cover
from one side. A 5-min. period was allowed
while the cells settled on the glass surface.
to elapse
A longer
did not give any change in the number of
stuck cells.
Then the cells within the square were counted.
Subsequently the calculating plate was placed on a stand
slanted at angle of 30°from the horizontal, and the tumor
was washed
medium for each
reagent used, but without the reagent.
As alkaline and acid media, borate
Na@B4O7 . 1OH2O in 0.1 M NaOll
buffer
added
NaCl),
and
0.1
M NaHCO3
pH 9.5; citrate-llCl
M sodium
citrate
added
added
buffer
to 0.85
(0.05 M
to 0.85 per cent
NaCl), pH 9.5; carbonate-bicarbonate-CO2
M Na@CO3
acetate
to
buffer (0.1
0.85
per
cent
(0.1 N HC1 and 0.1
per
cent
NaC1),
pll
4.6;
added to 0.85 per cent NaC1), pH 4.6, were used.
Phosphate-buffered
Ascites tumor
saline, pH 7.2, was used as a control.
(0.1 ml.) was incubated
these buffers for 10 mm. at 37°C.
in 5 ml. of each of
Then the stickiness
of the treated cells was directly observed in these buffers
without resuspension in phosphate-buffered
slip.
incubation
in the plate
media consisted of the appropriate
saline.
space or slit of
The tumor suspension was put into the calculating plate
suspension
of 5 X 10@ M in phosphate
and acetate buffer (0.2 M acetic acid and 0.2 M sodium
the cell suspension
slide (75 X 26 mm.). At the center of this slide, a
square, 2 X 2 mm., was cut in. Thin plastic tapes (about
50 @3
in thickness), 4 mm. wide, were stuck to the two
longer edges of the glass slide.
used at a concentration
1964
buffered
saline.
The trypsin,
CaCl2 , and versenate
suspensions
each were incubated
for 1 hr.
Control
carcinoma,
were used.
rats
Vol. 24, December
by allowing
1 ml. of
RESULTS
Stickinese of the ascites hepatoma cells.—Tumor cells, 5
days after inoculation into the peritoneal cavity, were
used for this study in each tumor strain.
As shown in
Table 1, All 13, a free cell type of tumor, was most
active in stickiness of the tumor cells to the glass surface
(88.9 per cent), and All 7974, containing
abundant
“hepatoma islands― @ndfree cells, was least (57.6 per
on which the tumor suspension had not been inserted.
cent). All 130, consisting of a few “islands―
and abun
dant free cells, was intermediate (75.0 per cent) in sticki
Drops
ness
buffered
ifiter
saline to flow through
of fluid on the latter
paper.
Thereafter,
the thin slit from a side
side were drained
the
cells
that
to the glass surface were counted.
off with
remained
lated.
treatments
of tumor cells in vitro.—Ascites
centrifugally
and resuspended
All
7974.
The
differences
A. STICKINESSOF YOSHIDAASCITESHEPATOMACELLS
TO GLASS SURFACE
Tumor
cellsAllstrainCharacter
of tumor
13
±2.2k
75.0 ±2.9
all cells free
A few “islands―
and abun
All 130
dant free cells
in 5
All 7974Almost
“Islands―
4.7B. and free cells88.9
ml. of phosphate-buffered saline. Thereafter, the sticki
ness of the treated cells was compared with that of sixth
larly treated controls.
The test media and incubation
13 and
TABLE 1
tumor (0.1 ml.) was added to 5 ml. of test medium ad
justed to pH 7.2, and the suspension thus prepared was
incubated at 37°C. After the incubation, the treated
cells were gathered
All
Small “hepatoma
islands― composed of two to four cells were counted as
one, whereas the large “islands―
were not counted at all,
and the percentage of cells clinging to the glass was calcu
Chemical
between
stuck
57.6 ±
VARIANCEs.s.d.f.ms.Among
ANALYSISOF
time were as follows.
Protamine sulfate (L. Light & Co., Ltd.) and polyvinyl
potassium
were
sulfate (Wako Pure Chemical
used
at
concentrations
of 0.2 per
Industries,
cent
Ltd.)
in 0.25
M
sucrose solution adjusted to pH 7.2 with a small volume
of 0.1 N llCl
or NaOll.
The
tumor
suspension
was
incubated in each of these media for 15 mm. Tween-80
was used at a concentration of 0.5 per cent in phos
phate-buffered saline, and the suspension was incubated
for 45 mm. Sodium deoxycholate was used at a con
centration of 0.02 per cent in phosphate-buffered
and the suspension was incubated for 30 mm.
saline,
Trypsin
groups
11.45F.
Errors
Total2460.73
12
141230.37
137.50
2598.232
= 107.46 > F122 = 6.93 (a
S Mean
±
standard
deviation.
Five
cells were used with each tumor
errors,
three
specimens
were
rats
strain.
calculated
0.01)
and
5-day-old
To avoid
from
each
tumor
technical
rat.
The
(Difco Laboratories, Inc.) was used at a concentration
of 0.5 per cent in phosphate-buffered saline. Calcium
total number of cell units observed was 8877 in All 13, 8277 in
All 130, and 5163 in All 7974. The difference among the strains
is statistically significant at the 1 per cent level. Abbreviations:
chloride
8.8.
was
used
at
in phosphate-buffered
a concentration
saline.
of 0.05
per
cent
Disodium versenate was
squares;
sum
of squares;
d.f.
=
degree
of freedom;
m.s.
=
F. = ratio of two mean squares.
Downloaded from cancerres.aacrjournals.org on June 15, 2017. © 1964 American Association for Cancer Research.
mean
Ko@m@&AND SA@i—Stickiness of Tumor Cells
1889
TABLE 2
A. LUNGMETASTASESOF ASCITESHEPATOMACELLS
among the three strains are statistically significant at the
INJECTED INTRAVENOUSLY
Pulmonary m@taslasis of the ascites hepatoma.—The 5day-old tumor cells were drained from the peritoneal
1 per
Ten rats were used with each strain.
cavity
of rats with metastatic
Tumor
strainNo.
(range)All
no. of metastatic
nodu es per rat
frequency)Avera@e
nodules in the lung
(metastatic
cent
by the routine
9.3
(0-30)
0.4
(0—2)
8
(80%)
2
(20%)30.4
All797410
OF CILL
To remove the large “hepatoma
islands,―they were
CELL
Small “islands― Large “islands―
consisted of 2-4
consisted of 5
cells
or
UNITSPOPULATION
Free
cells
moreAll
for 5 mm.
at 0°C.
The super
thus prepared
contained
free tumor
cells
were counted
in each rat 15 days after injection.
The
inoculated cell units, their population, and the number
of metastatic nodules per rat are summarized in Table 2.
All 13 was most active in producing lung metastasis, as
revealed in terms of the average number of metastatic
(%)
OF INJZCTED
Timroa sinauiNo.
at 500 r.p.m.
cell suspension
of tumor
UNITS
in phosphate
and smaller “hepatomaislands.― Both a free tumor
cell and a “hepatomaisland― were similarly counted
as one cell unit. Then 10@cell units were injected into
the tail vein of rats. Metastatic nodules in the lung
B. INJECTEDCELL UNITS ANDTHEIR POPULATION
Fifteen days after the intravenous transplantation
cells, the rats were killed and autopsied.
and suspended
natant was centrifuged three times in the same manner.
All three types of hepatoma were treated alike. The
(7-54)
(100%)
All130
method
buffered saline added to 1.0 per cent methylcellulose.
centrifuged
13
level.
nodules per rat (30.4), All 7974 was least active (0.4),
and All 130 was intermediate
(9.3).
A total of 60 rats were given intraperitoneal inoculations
X 10@
13
1.1 X 10'
All 130
77.6
All 79741.4 1.1 X 10'99.669.30.4
TABLE
of 0.1 ml. of undiluted
20.8
1.6
2.8
27.90
the tumor
metastatic
INOCULATED
INTRAPERITONEALLY
IN THE LUNG
rats were used with each strain.
ascites
LUNGNo.
@
in a
IN
(DAYS)METASTASES
four out of twenty
(20 per cent),
to 49.6 per cent by treatment
AH13O
11.3
9
45
All79747.0
19.316
480
20
positively
OF CHEMICAL
TREATMENTS
IN VITRO
mg/cu cm
± 3.1
Tween-80
0.5%
Control
Trypsin
* This
15
100.0 ±4.5
45
107.8 ± 2.5
45
100.0
13.9 ± 3.9
6049.6 100.0 ± 2.1P
value
is
converted
into
t S.D. = standard deviation.
from each animal.
OF “FREE CELL
TYPE― TUMOR
per
cent
against
the
±S.D.P
± 11.2
differenceMean
a
CELLS
<
<0@05
P<0.0167.1
104.6 ± 1.1
100.0
± 2.3
27.6 ± 8.4
100.0 ± 3.4P
* S.D.P
± 1.5
< 0.01
< 0.01
100.0 ± 3.6
100.0 ± 3.1
± 2.4
5 mg/cu cm15 60
Control2
sulfate,
and also to 13.9
13Yoshida
< 0.01
sulfate
@
with protamine
for 15 mm.,
CENTOF REMAINING
sarcomaMean ascites carcinomaAH
tion time
(mm.)Ehrlich
differenceMean
±S.D.tP
Control
polymer,
4
ON STICKINESS
CELLSReagentsConcentrationIncuba.
CHEXICAL
TREATMENTPER
differenceProtamine
charged
per cent by treatment with trypsin for 1 hr., compared
with the stickiness of the respective controls. However,
TABLE
EFFECTS
respectively.
in Table 4, the stickiness of the tumor cells was reduced
of ratsPer
centAH13
caused death and then were autopsied.
The
frequency
of each strain of ascites l*patoma
Effects of chemical reagents on stickiness of tumor cells in
vitro.—Ehrlich ascites carcinoma cells 6 days after inocu
lation were mainly used for this observation.
As shown
SURVIVAL
Ttrxoa STRAINMEAN
in a
130 and All 7974, nine out of twenty (45 per cent) and
Rats were inoculated
intraperitoneally
with 0.1 ml. of undiluted tumor
state of “nearlypure culture― of each strain.
of each strain
in the lung is shown in Table 3. In animals inoculated
with All 13, lung metastases were observed in sixteen out
of twenty animals (80 per cent), and, in those with AH
3
METASTATIC FREQUENCY OF ASCITES HEPATOMA CELLS
Twenty
ascites tumor
state of “nearly
pure culture.― The rats were l@eptuntil
104.7 ± 1.4
0@01< P <0.05 ioo.@ ± 1.8
P<o.0166.6
39.0 ± 6.8
100.0
± 2.6P
0@01< P <0.05
P<0.01
control.
For this observation three animals were used in each treatment and three specimens were calculated
The pH of the test medium
was 7.2 in all cases.
Downloaded from cancerres.aacrjournals.org on June 15, 2017. © 1964 American Association for Cancer Research.
Cancer Research
1890
Vol. 24, December
STICKINESS
@
I
PROTAMINE
Su LFATE
,
@
POLYVINYL
su LFATE
@
TWEEN
@
DE S OXYC KOLATE ‘
TRYP
-.
..
.@ ‘ ‘ (
—
,
VERSENATE
i_
E
:J 107
8
%
1 0 0. 2
%
@@‘:-;
1 .—Stickiness
of Ehrlich
The
same results
ascites
carcinoma
cells
after
various
chemical
treatments
and at the 5
No significant effects on stickiness were observed in
polyvinyl sulfate (a negatively charged polymer), deoxy
CaCl2 , and versenate
compared
with the cor
responding controls (Chart 1).
The effects of the pH of the medium on the stickiness
6-day-old
Ehrlich
ascites
carcinoma
in alkaline
media,
compared
with
that
saline (pH 7.2) controls; in
citrate buffer (pH 4.6) the stickiness was 61.3 per cent,
in acetate buffer (pH 4.6) 48.7 per cent, in borate buffer
(pH 9.5) 114.4 per cent, and in carbonate buffer (pH
9.5), 110.6 per cent.
OF i'll
The difference
between
OF MEDIUM
5
ON STICKINESS
OF EHRLIcH
ASCITES CARCINOMA CELLS
Incubation
time was 10 mm.
TREATMENTSTICKINESS
DIFFERENCEBufferpHCitrate
CELLS
OF
TO GLASS
(MEAN± S.D.)P
PBSt
7.2
± 3.9
100.0 ± 2.5
Acetate
PBS
4.6
7.2
48.7 ± 4.3
100.0 ± 2.5
P < 0.01
Borate
9.5
7.2
114.4± 0.7
100.0 ± 2.0
P < 0.01
< 0.01
cells were
examined.
As shown in Table 5, the stickiness
of these
tumor
cells was decreased
remarkably
in acid media,
in the phosphate-buffered
TABLE
EFFECTS
were also obtained
in the cases of protamine sulfate and trypsin,
per cent level in the case of Tween-80.
increased
I
I;98.9
in 4-day-old cells of All 13 and Yoshida sarcoma. The
difference between the reagent and the corresponding
control is statistically significant at the 1 per cent level
but
— S
%
vitro. Stickiness is indicated by the percentage of cells that remained stuck to the glass
surface. This value is converted into per cent against each control. Dashed line indicates
the control level (100 per cent) . For this observation three animals were used in each treat
ment, and three specimens were observed from each animal.
107.8 per cent.
of the
.., ..‘
1028
13 9 %
the cells treated with Tween-80 for 45 mm. were more
sticky than the control; i.e., their stickiness increased to
cholate,
190
80
o 4.7
SI N
CHART
61d
J496%
‘ /
C A LC I U M
.
S
4@
(%)
.-
80
CIILORID
@
2@0
1964
PBS
9.5
110.6 ± 2.3
7.261.3 100.0 ± 4.4P
Carbonate
PBS4.6
* This
value
S.D. = standard
is
converted
into
per
cent
0.01 < P < 0.05
against
the
control.
deviation.
each acid
t PBS = phosphate-bufferedsaline. For this observation
or alkaline medium and the control is statistically signifi
cant at the 1 per cent level in the cases of citrate buffer,
three animals were used in each treatment and three specimens
acetate buffer, and borate buffer, and at the 5 per cent
level in the case of carbonate buffer.
DISCUSSION
Yoshida (12, 13) reported that each hepatoma is indi
vidual with regard to transplantability, number of chromo
somes, and resistance of the cells to drugs. In the pres
were calculated
from each animal.
ent study, a clear difference was observed in the stickiness
of tumor cells to glass among the three strains of rat
hepatoma. As described above, it is evident that there
was good correlation
between
metastatic
the lung and stickiness of tumor
suggest
that
stickiness
of tumor
cells.
frequency
in
These facts
cells is at least one of
Downloaded from cancerres.aacrjournals.org on June 15, 2017. © 1964 American Association for Cancer Research.
Ko@mi@AND S@x@i—Stickiness
of Tumor Cells
the important factors responsible for the metastatic
spread of tumor cells via blood vessels. These results
seem to support Coman's opinion (6) that stickiness would
favor the chance that tumor cells will lodge at distant
sites in initiating metastases when transported through
vascular channels. Furthermore, it is evident that there
is a parallel correlation between the number of isolated
free tumor cells and their stickiness in ascites hepatoma;
i.e., a tumor strain containing abundant free tumor cells
was more sticky than those containing a small number of
free tumor
cells.
Hirono
(8) has suggested
from results
1891
and its decrease by treatment with trypsin seem also to
support our assumption on the nature of stickiness.
The greater negative surface charge of tumor cells
compared with that of the normal ancestral cells has been
shown by many workers
(1, 3), and it has been discussed
in connection with reduced adhesiveness in tumor cells
(1,
11).
In
this
connection,
it
may
be
reasonable
that
a
parallelism exists between reduced adhesiveness of tumor
cells and their increased
stickiness.
ACKNOWLEDGMENTS
on the motility of tumor cells that a large number of free
tumor cells in the ascites hepatoma was due to a decrease
in their mutual adhesiveness. On the basis of this fact,
The authors are greatly indebted to Drs. I. Hirono of Gifu
Medical College and M. Hoshino of the Nagoya University School
it may
improvement
of the manuscript
before publication.
Further
thanks are due to Dr. T. Yoshida of the Cancer Institute
and the
staff of the Medical Institute
of Sasaki Foundation,
Tokyo, for
be assumed
that
increased
stickiness
of tumor
cells to a foreign substrate is parallel to a decrease in
their mutual adhesiveness. Reduced adhesiveness of
tumor cells would facilitate separation and allow the
motile tumor cells to invade adjacent tissues and vessels
(14). In this connection, the parallelism between re
duced adhesiveness and increased stickiness is very
interesting with regard to metastatic spread via blood
of Medicine
for their helpful
providing
Several workers (5, 7) have reported that lipase, phos
phatase,
marked
elastase, neuraminidase,
and trypsin show a
effect on stickiness of tumor cells. Little is
known about the physical aspects of cell stickiness, how
ever.
Since most of tumor
to the glass surface
within a short time and the time of contact had no detect
able effect on their stickiness,
stickiness
may be due to
simple contact, reflecting the physicochemical affinity
between the surface of the cells and of the substrate.
As shown in the present study, the treatment
mine sulfate, a positively charged polymer,
with prota
reduced the
stickiness of tumor cells to glass, whereas no detectable
changes in stickiness were observed after treatment with
polyvinyl sulfate, a negatively charged polymer. That
and to Dr. M.
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On the Role of Stickiness of Tumor Cells in the Formation of
Metastases
Kiyohide Kojima and Isao Sakai
Cancer Res 1964;24:1887-1891.
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