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Differences in the Peripheries of Walker Cancer Cells Growing in
Different Sites in the RaU
Leonard Weiss2 and James P. Harlos
Department of Experimental Pathology, Roswell Park Memorial Institute, Buffalo, New York 14263
ABSTRACT
Walker 256 cancer cells growing in the ascitic form and
following direct injection in the livers and in s.c. sites in rats
had significantly higher anodic electrophoretic mobilities than
did cells
derived
from
the same
source
but growing
in kidneys
and spleens. Following incubation with neuraminidase, the
cancer cells from the kidneys and spleen lost significantly less
net surface negativity than did cells growing in the other 3
sites. These kidney- and spleen-associated differences were
not demonstrably due to preexisting, electrokinetic subpopu
lations of cancer cells within the original ascites tumor; they
were maintained on organ-to-organ passage and were reversed
on reconversion of the tumors to ascitic form. The evidence
favors site-induced modulation to account for the differences
between primary cancers and their metastases are conceivably
due to site-induced modulation as distinct from preexisting
metastatic subpopulations.
Evidence which will be discussed later suggests that the
cancer cells in some primary tumors are different from those in
their metastases in at least some organs. The nonexcbusive
possibilities arise of whether these organs were selectively
seeded by preexisting subpopulations of cancer cells from
within the primary tumor or whether the seeding was random.
In either case, the cells in the metastases were different be
cause they were located in specific metastatic sites.
isotonic HBSS. Compared with cells treated with isotonic HBSS
alone, hypotonic lysis changes neither the viabilities (32) nor
the electrophoretic mobilities of the W-256 cells.
Cells were suspended in HBSS at a concentration of i O@
trypan blue-excluding cells/mb. By direct injections through
25-gauge needles, anesthetized animals received 106 dye
excluding cancer cells in a total volume of 0.1 ml. Each animal
received an injection into 1 organ (or lobe of the liver) only,
and its abdominal cavity was closed in 2 layers with nylon
sutures.
Cell Preparation. After 7 days, the animalswere exsanguin
ated by decapitation, and the appropriate organs were me
moved. The tumors were measured, trimmed free of necrotic
regions, minced with scissors, and squeezed through 80 mesh
stainless steel gauze. The resulting suspension was washed
once, resuspended in HBSS, and then passed through 200
mesh gauze. The resulting single cell suspensions were used
for injections into fresh animals or were incubated at 37°for
30 mm in T-fbasks,during which time most of the macrophages
present adhered to the T-flask surface. The suspensions were
divided into 2 x 2-mI volumes containing approximately 3 x
10@total cells/mb. To 1 tube was added 1 unit of neumaminidase
(Grand Island Biological Co., Grand Island, N. V.) per 106 cells;
the other tube received an equal volume of Dulbecco's PBS.
After 30 mm incubation at 37°,the cells were washed 3 times
and resuspended in Dulbecco's PBS to give final volumes of
1 0 ml for cell electrophoresis.
INTRODUCTION
In this communication, we describe reversible changes in the
net surface charge of Walker 256 cancer cells growing at
different sites in rats. It will be shown that our observations
support the concept of site-induced modulation of the surfaces
of these cancer cells.
RESULTS
MATERIALS AND METHODS
Animal Inoculation. Ether-anesthetized rats (young, adult
female Sprague-Dawley, weighing 150 to 200 g) received 10@
Walker 256 ‘
‘carcinosarcoma'
‘
(W-256) cells by i.p. injection.
Ascitic fluid was harvested after 7 days and washed once in
calcium-magnesium-free Dulbecco's PBS3(pH 7.2), and eryth
rocytes
were
largely
removed
by hypotonic
lysis.
In this pro
cedure, 1 part of ascitic fluid was added to 3 parts of half
strength HBSS and centrifuged for 1 mm at I 00 x g. The
washing was repeated a total of 4 times in a maximum of 10
mm, and the remaining cells were washed and resuspended in
1 This
work
was
partially
supported
by
Grant
CA-I
be
addressed.
7609-04
from
The
National
3 The
whom
requests
abbreviations
Electrophoretic Mobilities of Cells from Different Sites.
The results are summarized in Table 1. Compared (by means
of Student's t test) with the original ascites form, cells obtained
from all other 4 sites are different at the 1% (or less) level of
significance. This reflects the large numbers of observations.
However, if the more usual criteria are applied, i.e. , that differ
ences of 3% or less are not meaningful, then only the mobilities
of the cancer cells obtained from the kidney and spleen are
different from the parent ascites cells.
Effects of Neuraminidase on Electrophoretic Mobilities.
The neuraminidase-induced changes in electrophoretic mobil
ities of the cells obtained from the 5 different sites and shown
in Table 1, reveal comparatively
Cancer Institute, NIH.
2 To
Cell Electrophoresis. Electrophoreticmobibitieswere meas
ured with the cells suspended in HBSS in a cylindrical tube
apparatus at 37°.A voltage was applied through gray sintered
platinum electrodes and reversed after each cell transit. Human
erythrocytes were used as standard particles (—1.38 @tm@
sec1 V' .cm) in each group of experiments.
for
reprints
used
are:
should
Dulbecco's
PBS,
Dulbecco's
buffered saline; HBSS, Hanks' balanced salt solution.
Received January 18, i 979; accepted March 29. 1979.
phosphate
minor reductions in those from
peritoneal, s.c., and liver sites. The enzyme-induced reductions
in cells from kidneys and spleens were substantially different
from the parent ascites form, whereas those obtained from s.c.
JULY 1979
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2481
L. Weiss and J. P. Har!os
Table1
Electrophoretic
mobilities of cells from a common ascites source, growing in the different sites indicated
The reductionsin mobilitiesbroughtaboutby incubationwith neuraminidaseare shown.
(pm.sec
neuraminidaseAscites
SiteMobilities
.V- ‘
.cm)Neuraminidase
(%)Controls+
(840)—28s.c.
form (% ascites control)—i.20
induced change
±0.016 (868)b
(100%)—0.87
±0.01 (300)
(97%)—0.90
(300)—22Liver
(% ascites control)—i.i6
(250)—25Kidney
(% ascites control)—
i .1 7
± 0.01
±0.01
±0.01
±0.01
(250)
(98%)—0.88
(% ascites control)—
(432)—8Spleen
1 .1 2
± 0.01
(438)
1 .03
± 0.01
(93%)—
(% ascites control)—
1 .06
± 0.01
±0.01 (462)—13
(450)
(88%)—0.92
6 Mean
±. S.
b Numbers
@
E.
in parentheses,
number
of observations.
sites and livers were not. Enzyme treatment reduced the mo
bilities of the cells from the spleens, but not the kidneys, to a
common bevel.Histograms are given in Chart I of the mobilities
of the ascites tumor cells, with and without neuraminidase
treatment. Analysis of these curves reveals that both fall into
Pearson's type IV (16) with unimodal distribution. The distri
butions are also characterized by kurtosis and skew.
Tumor Size. The diametersof individualtumorswhich were
approximately spherical are given in Table 2. The mean diam
eter of all tumors was 0.86 ±0.03 cm (S.E.) for 75 measure
ments. The mean diameter of the tumors in the kidney was not
significantly different from that in the liver (p = 0.5); and the
Table 2
Meandiametersof
7days W-256tumorsgrowingin the sitesindicated
cellsSite
after the injection of 1 @6
cancer
diameters.c.
Mean tumor
O.130(i0)@)Liver
(20)Kidney
(23)Spleen
a Mean
1.14
0.78
0.71
0.97
±
±0.1
±0.07
±0.06 (22)
± SE.
b Numbers in parentheses, number of measurements.
mean for the s.c. tumors was not significantly different for that
of the spleen (p = 0.2).
Stability of Site-associated Changes. The stability of site
associated changes in cancer cells maintained in the kidney
and spleen was studied by organ-to-organ passage as shown
in Table 3. The results show that compared with cells passaged
in the ascites form, the cells passaged in the spleen and
kidneys maintained a lower absolute net surface negativity and
a reduced susceptibility to neuraminidase, as assessed by
electmophoretic mobility measurements.
Reversibility of Site-associated Changes. The results of 2
separate experiments are summarized in Table 4. When W
256 cells growing in the spleen or kidney were transplanted
into the peritoneal cavities of fresh matsafter 1 passage, their
electrophoretic mobilities, with or without neuraminidase treat
ment, were very similar to those of cells maintained continu
ousby in the ascites form and measured during the same ex
periments. These similarities between cells of different imme
diate origin, growing in the ascites form, were maintained after
6 i.p. passages. At this time, the mobilities of spleen and
kidney-derived cells were 97 and 98% of the continuous as
cites values. Thus, site-associated reversibility occurred.
40
NANose
30
20
0
w
D 10
‘I)
w
@
,,,
:@3e
Lu
U
—I-
—
——60
0‘
—CONTROLr‘.--@
0
I.-
z
20
DISCUSSION
LU
U
Lu
A.
Metastasis involves interactions of cancer cells with their
environment; the initial site for these interactions is the cell
periphery. It is therefore reasonable to seek correlation be
tween the physicochemicab nature of the cancer cell periphery
10'
, ,1@0 ‘l's
,
and
. 20
ELECTROPHORE
TIC MOBILITY (pm.sec@1
volt1cm)
Chart 1. Histograms of electrophoretic mobilities of W-256 cells suspended
in HBSS at 37°,with and without neuraminidase (NANase) treatment; measure
ments were made on 840 and 868 cells, respectively. The curves are unimodal
and show skew and kurtosis.
2482
metastasis.
The
suggestion
that
the
cancer
cells
in
metastases
are
in
some way different from those in the primary tumor generating
them is based on 4 main types of experimental data. First,
there is the general observation on animal tumors that large
numbers of injected cancer cells give rise to relatively small
CANCERRESEARCHVOL. 39
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Surface Modulation in Cancer Cells
Table3
Mobilities of Wp256 cells, with and without neuraminidase
treatment, following the indicated site-to-site
passages
Thedifferencesin mobilitiesbetweenthe ascitescells andthosegrowingin the othersitesare maintained.
Mobilities (@m
cm)AscitescontrolNeuraminidase
.sec ‘
‘
v ‘
.
Origin
changeAscites
(432)—8Ascites
(462)—13Ascites
(840)—28Kidney
Site of growth
Control
(%)
Kidney (1)a
Spleen (1)
Ascites control (1)
—1
.12 ±0,01b (438)c
—1.06±0.01 (450)
—1
.20 ±0.01 (868)
93
88
.03 ±0.01
—0.92±0.01
—0.87±0.Oi
(100)—8Spleen
(1)
(80)—16Ascites(1)
(1)
(100)—28Kidney
Kidney (2)
Spleen (2)
Ascites control (2)
—0.96±0.02 (104)
—
1.11 ±0.02 (90)
—1.23±0.03 (102)
78
90
—0.88±0.02
—0.93±0.03
—0.89±0.02
Kidney (3)
Spleen (3)
Ascites control (3)
—0.90±0.02 (88)
—0.92±0.02 (62)
—1
.16 ±0.02 (100)
78
79
—0.86±0.02
—0.77±0.02
—0.87±0.02
@
(104)—4Spleen
(2)
(60)—16Ascites
(2)
(100)—25a
(2)
+ neuraminidaseinduced
Numbers in parentheses, number of sites.
SE.C
b Mean ±
Numbers
in
parentheses,
number
of
observations.Table
4Mobilities
formThe
of W-256 cells, with and without neuraminidase
previous differences are lost.Mobilities
treatment, after return to the ascites
(Rm.sec ‘
.V ‘
.cm)Neuraminidase
controlOrigin
(%)Ascites
Ascites
Site of growth
Ascites
Control
(%)
100
Ascites
99
—0.85±
Ascites
—i.i4 ±0.02
0.02—31(202)
98
—0.79±
(204)
(356)—27Kidney
change
+ Neuraminidaseinduced
—1
.i6 ±001a
(4O2)@'
—1.15±0.02
0.02—26(204)
—0.85±0.01
(160)Spleen
a Mean
± SE.
b Numbers in parentheses,
@
number of observations.
numbers of metastases. Even in people having long histories
of cancer, the numbers of metastases discovered
at autopsy
are quite small. Thus, metastasis appears to be associated with
some degree of cancer cell selection; this may involve random
selection from the parent population and/or selection based
on genotypic or phenotypic traits. The second body of evidence
is provided by observations that, regardless of mechanism,
sensitivity to chemothemapeutic drugs is different in some pri
mary cancers and some of their metastases (4, 8, 22, 25). The
third type of data shows karyotypic (ploidy) differences be
tween cells of primary cancers and their metastases (18, 20,
37); however, in evaluating evidence of this type, the time
dependent karyotypic fluctuation in the individual (e.g. , 19)
must be borne in mind. The fourth type of data shows antigenic
differences between ‘
‘
primary' ‘
tumor transplants and their
metastases (3, 9, 23) or recurrences (17) in rodents. In the
case of the 3LL tumor, differences between s.c. primary lesions
and their metastases were appare@ntlyirreversible, since they
were maintained after retransplantation and growth of the
metastases to s.c. sites (10). These and other data relating to
differences between primary cancers and their metastases are
critically reviewed elsewhere (31).
Although the differences referred to above exist and are of
potential therapeutic importance, the mechanisms underlying
them need clarification (31 ). Thus, in the natural history of
cancer, metastases may arise by means of a random survival
of cells going through all the complex sequence of events in
the metastatic cascade (29). This type of chance survival is
common to many biological
JULY
events and is perhaps best de
scribed in statistical terms. Another mechanism to account for
the differences is the hypothesis that metastases arise from
preexisting subpopubations within primary tumors as discussed
by Greene (1 1), Leighton (14), and Zeidman (38), and as
supported by the evidence from combined in vitro-in vivo
experiments with one or 2 mouse tumors by Fidler (6), Fidlem
and Kripke (7), Nicolson et a!. (15), and Tao and Burger (24).
Another hypothesis is that differences between primary can
cers and their metastases arise after the metastatic event and
are site-induced
(36)
in connection
modulations
with cellular
of the type discussed by Weiss
differentiation
in developmental
systems. One example of such a site-induced change is pro
vided by sarcoma 37 cells in mice, in which morphological
changes between the solid and ascitic forms, which are due to
a change in cells present as distinct from a selective process
(1 3),
are
demonstrably
associated
with
reversible
changes
in
cell ebectrophoretic mobility and neuraminidase sensitivity (2).
In the present work we have examined some physicochemi
cab properties of the surfaces of W-256 cells taken from a
common (ascitic) source and growing at different sites in rats,
and we have tested the hypothesis that differences between
them were due to site-induced modulation.
On the evidence of cellular electrophoretic mobilities, with
and without incubation with neuraminidase (Table 1), the sum
faces of the W-256 cells growing in kidneys and spleens were
different from their ‘
‘parent'
‘
ascites form, whereas those grow
ing in livers and s.c. sites were not.
A number of previous studies have shown that high growth
rate may be associated with increased cell surface negativity
1979
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2483
L. Weiss and J. P. Har!os
(5), which itself is partially due to increased expression of siabic maintain these properties on continous peritoneal transfer. The
acid moieties at the cellular electrophoretic surface (26, 34). It experimental evidence therefore supports the view that cancer
has also been observed that W-256 tumors at different sites cells growing in certain organs are different from those growing
produce different general effects on the host animal (12) and in other organs because of site-induced changes in the original
that the tumors themselves exhibit different matesof prolifema cancer cell population.
tion at different sites (1 ). The question has been raised of
It must be emphasized that we claim only to have demon
whether the differential response of metastases and primary strated reversible, site-induced differences in the peripheries
cancers to chemotherapy is a reflection of differential growth of W-256 cancer cells growing in different organs of rats by
rate (4). In the present experiments, on a size basis (Table 2), measurements of their electrophoretic mobilities before and
tumors in s.c. sites and the spleen grow faster than do those in after neumaminidasetreatment. We are not prepared to spec
the liver or kidney. However, the mean sizes in the s.c. sites ulate on the functional significance of these changes in terms
and spleen were not significantly different, and those in the of metastasis-related cell interactions (27, 28), since even
kidney and liver were also similar. Therefore, the differences in ‘
simple' ‘
cell contact interactions
require a knowledge
of the
the ebectrokinetic properties of cancer cells growing in the spatial distribution of peripheral ionogenic sites (33, 35) which
spleen and kidney on the one hand and those growing s.c. and cannot be derived solely from electrokinetic data of the present
in the liver on the other cannot be directly ascribed to differ
type.
ences in growth rate in the different sites.
It is important to put the present results into perspective in
It is of interest (Table 1) that treatment with neuraminidase relation to metastasis. The growth of cells in an organ following
should have reduced the mobilities of the cancer cells from the direct injection is not a model for the whole metastatic process.
spleen to a common level with those from the ascites, s.c. , and At most, these experiments are relevant to the growth of cancer
hepatic forms. This suggests that one difference between the cells after delivery to an organ; they give no information on the
splenic and latter forms is a comparative lack of neuraminidase
antecedent history of the cancer cell in naturally occurring
sensitive, surface, anionic sites in W-256 cells growing in the metastasis (27). The sequence of events leading to “delivery―
spleen. In contrast, the difference in the electrokinetic surfaces is demonstrably traumatic to cancer cells (21 ), and this prob
ably contributes to the bowoverall efficiency of the metastatic
of kidney-derived cells is not accountable in terms of neura
minidase-susceptible anionic sites because following enzyme process (30). It is conceivable that selection, either at random
treatment, the mobibities of these cells are not reduced to the or by virtue of the metastatic subpopulation described by Fidlem
common level of the cells growing in the other 4 sites. Although et a!., operates at this level. However, on present evidence,
differences at the cell periphery associated with survival and
the technique of electrophoretic mobility permits measure
ments to be made on individual cancer cells within suspensions growth in different organs could be accounted for without
containing other cell types, it is not possible to make meaningful involving the concept of subpopulations but rather in terms of
chemical analyses on such fresh, mixed populations containing environmental interactions. However, although the present
macrophages, erythrocytes, etc. , which can then be related work establishes the feasibility of site-induced, interactive
exclusively to the cancer cells. The present studies, therefore, changes in cancer cells growing in different sites, it neither
do not permit additional comment on the chemical nature of adds to nor detracts from the feasibility of the role of subpop
ulations of cancer cells in the metastatic process.
the cellsurfaces.
If the observed site-associated, ebectrokinetic differences
between the W-256 cells were due to preexisting subpopuia
ACKNOWLEDGMENTS
tions within the ascites form of the tumor, then these might well
Our sincere thanks are due to Alice Holmes and Dorothy Lombardo for their
be revealed in histograms of the mobility measurements, with
assistance in this work.
and/or without neuraminidase treatment. However, the histo
grams shown in Chart 1, based on the individual measurements
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2485
Differences in the Peripheries of Walker Cancer Cells Growing
in Different Sites in the Rat
Leonard Weiss and James P. Harlos
Cancer Res 1979;39:2481-2485.
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