Blood, Vol. 91 No. 2 (January 15), 1998:
pp. 623-629
The Metastatic Characteristics of Murine Lymphoma Cell Lines In
Vivo Are Manifested After Target Organ Invasion
By
Fawzi Aoudjit,
Edouard F. Potworowski, and
Yves St-Pierre
From the Immunology Research Center, Institut Armand-Frappier,
Université du Québec, Québec, Canada.
 |
ABSTRACT |
The ability of a tumor cell to survive is critical for successful
dissemination to sites distant from the primary tumor. Tumor cells must
enter blood circulation, resist hemodynamic shear stress of the blood
circulation, successfully extravasate, and then migrate through dense
tissue stroma to a site favorable for tumor growth. Some tumor cells
must therefore be endowed with peculiar abilities to successfully
metastasize, whereas others, although capable of forming tumor in
specific organs, cannot metastasize. This property has often been
associated with the homing ability of a given tumor cell, likely
through the expression of organ-specific homing receptors that are
critical for the extravasation process. The present work was aimed at
establishing the point at which metastatic and nonmetastatic lymphoma
cells diverge. Although 164T2 and 267T2 lymphoma cell lines can
successfully form thymic lymphoma when injected intrathymically, only
the 164T2 clone can efficiently form tumor in kidneys, spleen, and
liver after intravenous inoculation. Using the Indium-labeling
technique to monitor the homing kinetic of both cell lines, we showed
that the critical step for the successful metastasis of the lymphoma
cell was determined in the final steps of the disseminating process,
namely after homing. These results indicate that, whereas binding of
tumor cells to vascular endothelium through specific adhesion
mechanisms is a prerequisite for dissemination of tumor cells, the
resistance of a tumor cell to the antagonist action of the host
and/or its ability to grow tumor occurs only after homing to
the target organ.
| |
INTRODUCTION |
METASTASIS OR THE formation of secondary
tumors at distant sites from the primary tumor is a major cause of
mortality. The failure of most current therapies to successfully treat
metastases stresses the urgency of understanding the underlying
mechanisms.
Metastasis is a multistep process that includes (1) primary tumor
growth; (2) release of cancer cells into lymphatic and blood vessels;
(3) survival of the tumor cells within the circulation; (4) arrest in
the microvasculature of the target organ that involves tumor
cell-endothelial cell interactions, resulting in (5) extravasation of
tumor cells and (6) invasion of target organs; (7) migration of tumor
cells into tissues; and, finally, (8) growth of the tumor at the
metastatic site.1,2
For efficient malignancy, cancer cells must be able to accomplish each
of these eight steps while escaping surveillance by the immune
system.3 Homing of cancer cells from the circulation into
target organs has been considered as a major rate-limiting step in
hematogenous metastasis. It depends on the capacity of cancer cells to
survive within the circulation and to extravasate into target organs,
and poor survival in the aggressive blood environment resulted in only
few circulating cells able to escape from that
environment.4,5 Only cancer cells that have successfully extravasated into target organs can form secondary
tumors.2,6 Homing of tumor cells and particularly lymphoma
cells shares some similar mechanisms with homing of normal
leukocytes.7 The latter process depends on interactions
between several pairs of adhesion molecules expressed on leukocytes and
endothelial cells.8 Leukocyte transmigration through the
endothelium occurs in three steps, namely cell attachment, rolling, and
shear-resistant adhesion.9 In each of these steps, the
adhesion molecules involved have been defined in vivo.10-13
Similarly, tumor cell homing depends on their interactions with
endothelial cells and require adhesion molecules. Tumor cells express
the same cell adhesion molecules (CAMs) as their normal counterparts
and in vitro adhesion assays have shown that tumor cell-endothelial
cell interactions can be blocked by anti-CAM monoclonal antibodies
(MoAbs), specifically by anti-LFA-1 MoAb.14
This type of interaction has been strongly correlated with the
metastatic potential of several tumor cells such as hepatomas, melanomas, mammary carcinomas, and lymphomas.15-19 The same
is true in vivo, where treatment with anti-LFA-1, -CD44 and -
5
3 MoAbs was shown to block lymphoma metastasis.14,20-22 These
observations establish a link between the metastatic potential of tumor
cells and their ability to home to target organs.
However, some conflicting results suggest a lack of correlation between
the expression of cell adhesion molecule, homing, and the metastatic
potential of tumor cells. Indeed, it has been shown that hematogenous
spreading as well as peripheral node invasion of lymphoma-derived
leukemic cells may occur independently of the expression of the
lymphocyte homing receptor, LFA-1, and intercellular adhesion
molecule-1 (ICAM-1).23 In addition, data from direct observations of metastasis in vivo using the intravital videomicroscopy technology have shown that most tumor cells entering the circulation extravasate efficiently into tissues independently of their metastatic potential.24 In fact, mammary carcinoma and melanoma cell
lines with high and low metastatic potential differ not in
extravasation and homing but in migration through the perivascular
tissue and subsequent tumor growth.25,26 Furthermore,
blocking of integrin function by the disintegrin agent did not affect
the extravasation and homing of melanoma cells in vivo but reduced
tumor growth.27
In the light of these findings, we sought to determine whether the
generally accepted correlation between the extravasation, homing of
lymphoma, and their metastatic potential also exists in vivo. To this
end, we used two murine lymphoma cell lines, the metastatic 164T2 and
the nonmetastatic 267T2 cells. Although both cell lines give rise to a
thymic lymphoid tumor after intrathymic inoculation in histocompatible
mice, only the 164T2 cells induced massive tumor growth in kidneys,
spleen, and liver 6 to 8 weeks postinjection. In vivo migration assays
showed that, when injected intravenously, both lymphoma cell lines
infiltrated the target organs at a similar rate and with a similar
fate, indicating that metastasis formation of these lymphoma cell lines
is determined after their homing.
| |
MATERIALS AND METHODS |
Cell lines.
The mouse thymic lymphoma cell lines 164T2 and 267T2 were established
in vitro from an in vivo radiation-induced thymic lymphoma in
C57BL/Ka mice using the method of Lieberman et al.28
YAC-1 lymphoma cell line was obtained from American Type Culture
Collection (Rockville, MD). The H59 cells (kindly provided
by Dr Daniel Oth, Institut Armand-Frappier, Québec, Canada) were
derived from the Lewis lung carcinoma.29 The cells were
cultured in RPMI 1640 supplemented with 10% fetal calf serum, 2 mmol/L
glutamine, 10 mmol/L HEPES buffer, and antibiotics.
Flow cytometric analysis.
Cells were stained at 4°C and washed in phosphate-buffered saline
(PBS) containing 0.5% bovine serum albumin and 0.2% sodium azide
(PBA). Before staining, cells were incubated with 10 µg/mL of human
IgG (Sigma, St Louis, MO) for 20 minutes to block
nonspecific binding. Fluorochrome- or biotin-labeled MoAbs were then
added at appropriate concentrations and incubated for another 20 minutes. Cells were then washed four times with PBA. For indirect
staining with streptavidin-Red 670, cells were washed three times after staining with the first MoAb and then incubated for 20 minutes on ice
with the fluorescent conjugate. Flow cytometric analysis was performed
on an XL flow cytometer (Coulter Electronics, Hialeah, FL).
Mice.
C57BL/6x129 H-2b histocompatible mice were bred in
our animal facility and were maintained under specific pathogen-free
conditions.
The in vivo model of lymphoma metastasis.
164T2 and 267T2 lymphoma cells were injected intravenously via the tail
vein to histocompatible mice. Animals were observed regularly for
clinical signs of lymphoma development, were killed 6 to 8 weeks
postinoculation, and examined for the presence of lymphoid tumors. Mice
were examined macroscopically, and their kidneys, liver, spleen, and
thymus were harvested, weighed, and fixed in 10% formalin for
histologic examination.
In vivo migration assays.
The migration of 164T2 and 267T2 lymphoma cell lines was analyzed as
previously described.30 Briefly, 10 million cells were labeled with 10 µCi of 111In in 0.5 mL RPMI for 15 minutes at room temperature. The cells were washed four times with RPMI
and resuspended in PBS. Each mouse was injected intravenously with
106 cells labeled at 0.5 to 106 CPM. At various
times, animals were killed, and kidneys, spleen, liver, and thymus as
well as heparinized blood samples were recovered. The total activity in
the entire blood volume of the body was computed by measuring
radioactivity in 400-µL aliquots of blood and assuming a total volume
of 2 mL of blood per mouse. Homing of lymphoma cells was measured by
counting radioactivity in each organ using a 
-counter (Gamma-7000).
| |
RESULTS |
Lymphoma tumor growth in vivo.
We have previously shown that intrathymic inoculation of 164T2 and
267T2 lymphoma cell lines can induce the formation of thymic lymphoma
within 3 to 6 weeks postinjection.31 However, when injected
intravenously, we have found that only 164T2 cells but not 267T2 had
the ability to induce tumors in peripheral organs in histocompatible
C57BL/6 × 129 mice. Tumors were detected in liver, kidneys, and
spleen at 6 to 8 weeks after intravenous injection. When
105 cells were injected, 17 of 32 (53%) mice developed
solid tumors (Table 1). A score of 100%
within the same time interval was obtained when 5 × 105 or 106 164 T2 cells were injected. In
contrast, no tumor was detected in animals injected with 267T2 cells at
any of the above-mentioned doses. In addition, the resistance of
animals to 267T2 cells metastasis was not time-dependent, because no
clinical signs associated with tumor development were detected for up
to 20 weeks. Macroscopic examination of kidneys of mice injected with
164T2 cells showed that the kidneys were significantly enlarged with
atypical pale coloration. Histologic examination showed massive
interlobular infiltration by lymphoma cells in the deep cortical and
outer medulla areas (Fig 1). Infiltration
of the spleen by lymphoma cells induced severe splenomegaly
characterized by massive and diffuse infiltration of lymphoma cells.
Although no macroscopic signs were observed in liver of mice injected
with 164T2 cells, histologic analysis showed massive lymphoma cell
infiltration in perivascular stroma surrounding the central vein of
hepatic lobules (Fig.1). In contrast, no infiltration by lymphoma cells was detected in any of these organs in mice injected with the 267T2
cells. These results established the metastatic potential of 164T2 in
its ability to induce the formation of tumors in kidney, spleen, and
liver and the inability of 267T2 cells to do the same.
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| Fig 1.
Histologic examinations of mice 6 weeks after intravenous
inoculation of 164T2 (right panel) and 267T2 (left panel) lymphoma cells. Representative sections of kidneys and liver of mice injected with both lymphoma cells are shown. In mice injected with 164T2 cells,
massive lymphoma cell infiltration was observed in perivascular stroma
of liver sections, whereas in kidneys, massive infiltration was
observed in the renal cortex. These results are representative of more
than 50 histologic examinations.
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Phenotypic characterization of lymphoma cell lines.
In light of work showing that LFA-1, VLA-4, and VLA-5 play key roles in
lymphoma metastasis,12,18,32,33 the expression of adhesion
molecules on both lymphoma cell lines was determined. Flow cytometric
analysis showed that both lymphoma cell lines expressed similar levels
of LFA-1, ICAM-1, ICAM-2, and 51 but did not express
41 (data not shown). The 164T2 and 267T2 cell lines were
CD3+CD4
CD8 and
CD3+CD4CD8+,
respectively.
In vivo migration assays.
The differential capacity of 164T2 and 267T2 lymphoma cells to
metastasize despite similar adhesion molecule profiles prompted us to
investigate whether it might be caused by a distinct in vivo migration
pattern to target organs. For this purpose, the 164T2 and 267T2
lymphoma cell lines were labeled with 111In and cell
migration was measured after intravenous injection. The results
(Fig 2) indicate that, at 1 hour
postinjection, the majority of both lymphoma cells leave the blood
circulation to migrate to target organs, because only 7% of 164T2 and
9% of 267T2 were detected in the blood. At that time, similar numbers
of 164T2 and 267T2 were detected in the liver, spleen, and kidneys.
However, 25.7% of 164T2 cells and only 9.1% of 267T2 were detected in
the lungs. At 3 hours postinjection, similar numbers of 164T2 and 267T2
cells were detected in liver, kidney, and spleen. The accumulation of
164T2 and 267T2 cells into the lungs that was observed at 1 hour
appears to be transient, because at 3 hours only 9.6% of 164T2 and
1.44% of 267T2 cells were still detected. By 24 hours, the totality of
both injected cells had left the circulation and the majority had
migrated in the liver (34.5% 164T2 and 31.6% 267T2). In addition,
significant numbers of 164T2 and 267T2 cells were also found in the
kidneys (3.1% in both cases) and spleen (6% and 10.5%,
respectively), and only negligible numbers of both lymphoma cells were
retained in the lungs (0.21% 164T2 and 0.36% 267T2). These results
indicate that both lymphoma cells, independently of their metastatic
potential, had the same capacity to migrate to target organs with the
similar fate and at the same rate. It is noteworthy that no homing of
either lymphoma cells could be detected in the thymus.
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| Fig 2.
In vivo migration assays of 164T2 and 267T2 lymphoma
cells. Cells were labeled with 111In and 106
cells were injected intravenously. Radioactivity was counted in the
organs at different times and expressed as the percentage of total
radioactivity injected. Data represent the mean values ± standard
deviation of five determinations based on three independent experiments. ( ) 164T2 cells; ( ) 267T2 cells.
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The migratory pattern obtained with 164T2 and 267T2 was specific to the
target organs in which 164T2 cells eventually form tumors. Lymphoma
YAC-1 and carcinoma H59 cells, which have been shown to preferentially
migrate to the lungs and the liver, respectively, were found to home to
their target organs and show different pattern from those of 164T2 and
267T2 cells. We found, indeed, that most of YAC-1 and H59 cells
accumulated in the lungs of mice, whereas 164T2 and 267T2 lymphoma had
a preferential homing to liver (Fig 2 v
Fig 3).
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| Fig 3.
In vivo migration assays of YAC-1 and H59 cells were
performed as described. Radioactivity was counted in the organs at 3 hours. Data represent the mean values ± standard deviation of five
determinations based on two independent experiments.
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| |
DISCUSSION |
In the present work, we showed that the metastatic potential of two
thymic lymphoma cell lines is regulated at a stage subsequent to their
migration into target organs. In vivo migration assays showed that the
nonmetastatic 267T2 cells migrated at the same rate and showed similar
homing specificity to that of the metastatic 164T2 cells. In both
cases, homing occurred between 3 and 24 hours postinjection and almost
half of total injected cells had passed from the circulation to target
organs within this short time. The homing of both lymphoma cells had
the same target organ specificity, yet only the 164T2 cells gave rise
to secondary tumors, indicating that homing is not a determinant factor
of their metastatic potential.
This conclusion appears to be at variance with those of previous
studies that have shown that extravasation and subsequent homing of
cancer cells are major rate-limiting events in hematogenous metastasis.4-6,15,34 Of particular relevance to the present work are the reports that the interactions of Raw 117 large cell and
AKR lymphomas with endothelial cells correlated not only with their
extravasation and homing capacities but also with their metastatic
potential.16,17 However, this correlation was based on in
vitro adhesion between tumor cells and endothelial cells on the one
hand and on the development of secondary tumors after injection into
mice on the other hand; the migration of injected cells had not been
monitored. The different parameters measured in those studies and in
the present work probably explain the apparently conflicting
conclusions. It seems that, although interactions between tumor cells
and endothelial cells in vivo are a prerequisite for the former's
extravasation, in vitro interactions may not always be a reliable
indicator of the in vivo situation. Considerable variation in the
expression of cell adhesion molecules at the surface of tumor cells
and/or in the heterogeneous binding properties of tumor cells
to high endothelial venules35-37 can also explain differences in metastatic properties among lymphoma cells. For normal
lymphocytes, for instance, it has been shown that the in vitro binding
of lymphocytes to high endothelial venules did not reflect homing in
vivo.38 Furthermore, the correlation established between
the in vitro invasive capacity and the metastatic potential of mammary
carcinoma cell lines is not reflected in vivo,24,39 indicating that the mechanisms governing cell invasion in vivo depend
on additional factors than those governing cell invasion in vitro.
In addition, our results indicate that survival of lymphoma cells
within the microcirculation might not be the reliable regulator of
hematogenous metastasis that it was thought to be. In previous studies,
only a very limited number of cancer cells in the microcirculation reached target organs to form distant tumors. Most of the cells simply
died or were destroyed by the host's immune system or by lethal
deformation.4,5,40 However, in our case, almost half of the
lymphoma cells migrated to their target organs (44.5% of 164T2 and
46.7% 267T2 cells at 24 hours postinjection). We thus conclude that
the metastatic potential of the lymphoma cell lines used in this study
is not determined by survival and homing but by events occurring after
extravasation. In agreement with our work, Koop et al,24
using intravital videomicroscopy to monitor metastasis in vivo, showed
that more than 80% of the tumor cells entering circulation survived
and successfully extravasated and migrated into target organs. In a
similar vein, melanoma and mammary carcinoma cell lines of high and low
metastatic potential had similar capacities to extravasate and invade
target organs; however, they differed in subsequent migration through
perivascular tissue and in their tumor growth.25,26
Therefore, whenever it was tested, the metastatic potential of cancer
cells was shown to be determined by postextravasation events. Whether
the differential growth of 164T2 and 267T2 lymphoma cells is due to
differential responses to paracrine and/or autocrine growth
factors remains to be determined. What other mechanisms could
differentially affect metastasizing and nonmetastasizing tumors?
Smithson et al41 showed that susceptibility to NK cell
lysis affected the metastatic potential of lymphoma cells within target
organs. In the case of those investigators, only 5% of total cells
were recovered at 20 hours postinjection.33 This is not so
in our model, in which half of total 164T2 and 267T2 cells were
recovered at 24 hours postinjection, and in vitro cell lysis assay
showed that, in contrast to YAC-1 cells, neither lymphoma was sensitive
to NK cell lysis (data not shown). These findings suggest
that, although NK cell lysis may affect the survival of lymphoma in
vivo, it is not sufficient to explain the differential metastatic
potential of these lymphoma cells. However, the differential effects of other immune cells such as cytotoxic T lymphocytes (CTLs)
and macrophages cannot be ruled out.
Adhesion molecules have been implicated in the metastatic process of
several tumor cells, including lymphomas.7,42 Most relevant
to our work, LFA-1, CD44, and 53 are known to participate in
lymphoma metastasis.14,20-22 Based on the fact that
lymphoma cells use similar mechanisms of extravasation and migration as their normal counterparts,7 it has been suggested that it
is by blocking such mechanisms that MoAbs to these CAMs inhibit
metastasis. Because control of lymphoma metastasis appears to occur at
the postextravasation level, one must suppose that, in addition to extravasation, adhesion molecules may somehow also be implicated in the
control of tumor growth during postextravasation events, a model that
is supported by the recent observation that expression of 4
integrins inhibits metastasis formation of lymphoma without affecting
homing33 and that VLA-2 adhesion molecule is involved in
rhabdomyosarcoma cell metastasis during migration through the perivascular tissue.43 One possibility is that cell-cell
interactions between tumor cells and host stroma may regulate the
expression of matrix metalloproteinases,31 which are
abundantly expressed in cases of malignant lymphomas.44
Several indications indeed suggest that active tissue remodeling by
matrix metalloproteinases is determinant in the development of tumor
growth.45 Postextravasation events involving adhesion
molecules and matrix metalloproteinases in the metastatic process of
164T2 and 267T2 cells are now under investigation.
The indium labeling technique is a very well-established method to
assess the kinetic distribution of leukocytes and lymphoma cells in
patients with malignancy, because 111In-oxine is a
cytoplasmic marker with very low spontaneous release and is not
significantly incorporated into cell membranes.46-48 It was
important, nevertheless, to start our kinetic analysis very early after
entry of the cells into circulation while stopping after 24 hours for
the following reasons. (1) Tumor cells migrate to their target organ
very rapidly, most of them within 24 hours. (2) Although released
indium as a consequence of cell mortality is not reused by other
cells,46 engulfment of labeled-lymphoma cells by resident
macrophages could have interfered with recirculation of tumor cells in
long-term study. (3) Previous studies had reported that high
concentrations of radioactivity by 111In-oxine-labeling may
affect long-term cellular functions of labeled leukocytes.48,49 This latter issue was further addressed by comparing the migratory pattern of our lymphoma cells with that of
other tumorigenic cell lines. The specific migratory pattern observed
with all the different tumorigenic cell lines used in our study suggest
that 111In-oxine-labeled cells preferentially migrated to
organs in which they form tumors after intravenous inoculation of
unlabeled cells. Moreover, the kinetics obtained in terms of blood
clearance of labeled cells were similar to that previously obtained
using radiolabeled cells or fluorescently labeled cells visualized by
intravital videomicroscopy studies. The stable
accumulation of 164T2 and 267T2 lymphoma cells in liver, kidneys, and
spleen compared with their transient accumulation into the lungs is in
agreement with previous studies showing that liver, spleen, and kidneys
are preferred target sites for lymphoma metastasis.7,22,33
This pattern of migration has also been observed with circulating
lymphoblasts and activated mature lymphocytes that show significant
affinity for the liver and lungs, although the retention in the lungs
appears to be transient for the most circulating blasts.50
The higher retention in the lungs at 3 hours for YAC-1 and H-59 cells
compared with that of 164T2 and 267T2 cells could due to their larger
size. In fact, cell arrest by size restriction has been
documented.51 Alternatively, differential responses among
the cancer cells to organ-specific soluble factors and chemoattractants
may also explain the differences observed in the migration pattern.
In summary, in this study, we show that metastasis of lymphoma cells is
determined subsequently to their migration and invasion of target
organs. These results complement those obtained from IVVM studies of
carcinoma and melanoma cell metastasis. Together, these results point
to postextravasation events as the focus of future investigation on
metastasis control.
| |
FOOTNOTES |
Submitted February 3, 1997;
accepted September 12, 1997.
Supported by a grant from the Cancer Research Society of Canada (to
E.F.P.). F.A. is supported by a Biochem Pharma Fellowship Award
attributed by La Fondation Armand-Frappier.
Address reprint requests to Yves St-Pierre, PhD, Immunology Research
Center, Institut Armand-Frappier, PO Box 100, Laval, Québec,
Canada H7N 4Z3.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section 1734 solely
to indicate this fact.
| |
ACKNOWLEDGMENT |
The authors thank Doris Legault and Claire Beauchemin for excellent
technical assistance.
| |
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Abstract
Introduction
Abstract
