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Promotes Tumor Growth of Lewis Lung Carcinoma by Induction of Angiogenic Factors: In Vivo Analysis of Tumor-Stromal Interaction1
* Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan; and
Department of Molecular Preventive Medicine, School of Medicine, University of Tokyo, Tokyo, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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is a multifunctional and proinflammatory cytokine that affects
nearly all types of cells. To investigate the role of IL-1 in tumor
growth in vivo, we transduced the retroviral vector coding human
IL-1 gene into mouse Lewis lung carcinoma
(LLC) cells and subsequently inoculated the transformant (LLC/IL-1)
to syngeneic C57BL/6 mice. Tumors derived from LLC/IL-1 grew faster
(240%, day 18, vs null-vector control LLC/neo; p
< 0.01) and showed more abundant vasculature (250%, vs LLC/neo;
p < 0.05), whereas LLC/IL-1 cells, LLC/neo
cells, and wild-type LLC cells did not show any significant difference
in the growth rate in vitro. As compared with LLC/neo cells,
LLC/IL-1 cells secreted 2-fold the amount of vascular endothelial
growth factor and >10-fold the amount of macrophage-inflammatory
protein-2 (CXCL2), one of whose main functions is angiogenesis.
Although LLC/IL-1 itself did not secrete hepatocyte growth factor
(HGF), the tumor derived from LLC/IL-1 cells also contained a
>4-fold higher concentration of HGF, another angiogenic factor.
In situ hybridization of HGF mRNA in LLC/IL-1 tumor sections
demonstrated that stromal fibroblasts and infiltrating cells
overexpressed HGF mRNA. Moreover, when cultured in the presence of HGF
in vitro, LLC/IL-1 cells secreted even larger amounts of vascular
endothelial growth factor and macrophage-inflammatory protein-2. The
antiangiogenic agent TNP-470 and anti-CXCR2 Ab inhibited the tumor
growth of LLC/IL-1 cells in vivo. These results indicated that
secreting IL-1 into the tumor milieu induces several angiogenic
factors from tumor and stromal cells and thus promotes tumor growth
through hyperneovascularization. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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is a highly inflammatory and prototypical multifunctional cytokine that
affects nearly all cell types, often in concert with other cytokines or
small mediator molecules (1). It is produced mainly from
activated monocytes and macrophages involved in inflammatory and immune
responses. Nonmicrobial products as well as microbial products induce
IL-1 expression in monocytes and macrophages (2, 3).
IL-1 elicits important proinflammatory and immunological responses,
such as fever, hypotension, increasing circulating NO, recruiting
neutrophils, and costimulating T cell activation by increasing IL-2R
expression and inducing IL-2 production (4). The basis of
the various biologic properties of IL-1 depends on its regulatory
effects on the expression of various genes and/or receptors. IL-1
induces the gene expression of the IL-1 family, other inflammatory
cytokines, CSFs, and mesenchymal growth factors
(5, 6, 7).
The natural history of certain diseases as well as epidemiology studies
have revealed a strong association between particular chronic
inflammatory conditions and carcinogenesis in several human cancers
(8, 9). Sustained inflammation causes tissue damage, then
increases the cellular proliferation activity, and finally develops
tumors (10). It has been reported that inhibition of
chronic inflammation can inhibit carcinogenesis in a murine tumor model
(11). Mice deficient in TNF-
, a proinflammatory
cytokine, are resistant to skin carcinogenesis (12). The
effects of inflammation on tumor growth have been reported in human and
murine tumors. Inflammatory breast cancer, which is fast growing,
invasive, and angiogenic, overexpresses several genes involved in
angiogenesis (13, 14). The proinflammatory cytokine
TNF- has been shown to enhance tumor growth in vivo
(15).
IL-1 exhibited direct cytocidal effects and increasing nonspecific
host immune responses, resulting in tumor regression in vitro in
particular tumors (16, 17). In sharp contrast to the
growth-inhibitory effects, administration of IL-1 to mice with a
s.c. melanoma increases the tumor size and pulmonary metastasis
(18, 19).
To investigate the controversial role of IL-1 in tumor growth in
vivo, we constructed a retroviral vector expressing a hybrid gene of
the signal sequence of human growth hormone and human
IL-1 gene that enables the transduced cells to secrete
efficient, mature IL-1 proteins. Murine Lewis lung carcinoma
(LLC)3 cells, infected
with human IL-1-expressing vector, grew rapidly in mice, despite the
lack of a difference in the cell growth in vitro. This rapid growth was
associated with hyperneovascularization induced by several angiogenic
factors secreted from tumor cells and from stromal cells in the tumor
milieu.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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LLC cells were cultured in Eagle’s MEM supplemented with 10% FBS. Male C57BL/6 mice (5 wk old) and male BALB/c nu/nu mice (5 wk old) were purchased from Charles River Breeding Laboratories (Kanagawa, Japan). All animal experiments were conducted in accordance with the institutional guidelines of the Institute of Development, Aging, and Cancer (Tohoku University, Sendai, Japan). TNP-470 (6-O-(N-chloroacetyl-carbamoyl)-fumagillol), a semisynthetic analog of fumagillin derived from Aspergillus fumigatus, was kindly provided by Takeda Chemical Industries (Osaka, Japan).
Transduction of human IL-1 gene into LLC cells
A plasmid pSV1003 containing a hybrid gene coding for the signal
sequence of human growth hormone and the mature form of IL-1 was
kindly provided by Dr. J. Lupker (Sanofil Recherche, Centre de
Labege, Labege Cedex, France) (20). This hybrid gene was
subcloned into a retroviral vector PLXIN (Clontech Laboratories, Palo
Alto, CA) containing neoR cDNA. Retroviral
supernatants were generated using these proviral constructs and a
CRIP packaging cell line. LLC cells (5 x
105 per 6-cm diameter dish) were infected with
these viral supernatants of the producer cell lines in the presence of
polybrene (8 µg/ml). As a negative control, a retroviral vector PLXIN
carrying only the neoR gene was used.
Infected cells were subsequently selected by G418 (600 µg/ml), and
G418-resistant colonies were collected as a mass population and
designated as LLC/IL-1 and LLC/neo. Secretion of human IL-1 from
these infected LLC cells was measured with an ELISA kit (R&D Systems,
Minneapolis, MN).
Growth of LLC cells in vitro and in vivo
The in vitro growth of LLC/IL-1, LLC/neo, and LLC cells was
analyzed by seeding 5 x 105 cells in 6-cm
diameter dishes in 10% FBS medium and in 2% FBS medium. Viable cell
numbers were counted every day for 6 days in triplicate.
LLC/IL-1 cells (5 x 105 per mouse) were
inoculated s.c. into syngeneic C57BL/6 male mice and BALB/c
nu/nu male mice, and tumors were measured with calipers in
two perpendicular diameters every 2 or 3 days. Tumor volumes were
calculated from the length (a) and width (b) by
using the following formula: volume (mm3) =
ab2/2.
Histology of the tumors
For histological evaluation, the tumors were surgically removed when they reached almost 1 cm in diameter. For conventional histology, tumors were fixed with 10% buffered formaldehyde and embedded in paraffin. Tissue sections were stained with H&E. For immunohistochemistry, the tumor tissues were embedded in Tissue-Tek OCT embedding medium (Sakura Finetechnical, Tokyo, Japan) and stored at -80°C until use. The cryostat sections were fixed in acetone at room temperature for 10 min and then stained with rat anti-mouse CD31 (PECAM-1, a specific marker for vascular endothelial cells) mAb (1/200 dilution; BD PharMingen, San Diego, CA) and visualized with a streptavidin-peroxidase complex (HISTOFINE; Nichirei, Tokyo, Japan). The intratumoral microvessel density was determined as described previously (21). Briefly, in the area of most intense neovascularization (hot spots), individual microvessel counts were made on a x200 field. Any brown-staining endothelial cells clearly separate from adjacent microvessels, tumor cells, and other connective tissue elements were considered to constitute a single, countable vessel.
Secretion of VEGF, MIP-2, and HGF from LLC/IL-1 cells in
vitro
To determine the secretion of vascular endothelial growth factor
(VEGF), macrophage-inflammatory protein-2 (MIP-2; functional homolog to
human IL-8), and hepatocyte growth factor (HGF) from LLC/IL-1 cells
in vitro, LLC/IL-1 cells (1 x 106/2 ml)
were cultured for 24 h in 1 and 10% FBS medium. The production of
VEGF, MIP-2, and HGF was determined by ELISA kits (R&D Systems) and
expressed as nanograms per 1 x 106/24
h.
HGF concentration in the tumor tissues
When the tumors reached 
1 cm in diameter, they were removed
and washed three times with PBS to remove blood. A 4x volume of
solution containing 20 mM Tris-HCl (pH 7.5), 2 M NaCl, 0.1% Tween 80,
1 mM PMSF, and 1 mM EDTA was added to the tumors and homogenized
vigorously. This homogenized solution was then centrifuged at 15,000
rpm at 4°C for 30 min. The second layer of centrifuged solution was
applied for determination of the HGF contents by an ELISA kit
(Institute of Immunology, Tokyo, Japan).
ISH of HGF mRNA in tumor tissues
RNA-RNA in situ hybridization (ISH) was performed with a riboprobe (cRNA) of a 603-bp murine HGF cDNA fragment (575–1177 nt). After linearization of the template cDNA, single-stranded antisense RNA probes labeled with digoxigenin-UTP were generated using a non-radioactive labeling kit (Genius 4; Boehringer Mannheim, Indianapolis, IN). Frozen tissue sections of the tumors were fixed with 4% paraformaldehyde and incubated with RNA probe (200 ng/ml) overnight at 42°C. For signal amplification, a HRP rabbit anti-digoxigenin Ab (DAKO, Carpinteria, CA) was used to catalyze the deposition of biotin-tyramide in a GenPoint kit (DAKO). Further amplification was achieved by adding HRP rabbit anti-biotin (DAKO), biotin-tyramide, and then alkaline-phosphatase rabbit anti-biotin (DAKO). Signals were detected with an alkaline-phosphatase substrate Fast Red TR/Napthol AS-MX (Sigma-Aldrich, St. Louis, MO).
Growth inhibition of LLC tumors in vivo by TNP-470 and CXCR2 Ab
To determine the in vivo inhibitory effect of the angiogenesis inhibitor TNP-470, TNP-470 (30 mg/kg) was s.c. administered every other day from day 1 to 9 after tumor inoculation as described previously (22). TNP-470 was dissolved in 0.5% ethanol plus 5% Arabic gum in saline as recommended by the manufacturer (Takeda Chemical Industries, Osaka, Japan). Tumor volumes were determined on day 15.
Neutralizing polyclonal rabbit anti-CXCR2 Ab (CXCR2 Ab) was
prepared as described previously (23). Mice inoculated
with LLC/IL-1 cells (5 x 105/mouse) at
day 0 received i.p. injections of 200 µg of either anti-CXCR2 Ab
or control IgG from day 2 to 6 every other day. Tumor volumes were
determined on day 9.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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from LLC/IL-1 cells and its cell
growth in vitro
LLC cells transduced with a hybrid gene of human growth hormone
signal sequence and human IL-1 gene (LLC/IL-1)
secreted human IL-1 protein into the supernatant at 1.6 ± 0.23
µg (106 cells/24 h), whereas neither LLC cells
nor LLC/neo secreted any detectable human IL-1 protein (<10
pg/106 cells/24 h). No secretion of mouse IL-1
protein from LLC, LLC/neo, or LLC/IL-1 cells was detected by the
mouse IL-1 ELISA kit. The in vitro cell growth and morphology of
LLC/IL-1 cells were not substantially different from those of
LLC/neo and LLC cells in 10% FBS (Fig. 1
) and 2% FBS medium (data not
shown).
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promotes tumor growth in both syngeneic
and nude mice
In contrast to the absence of any significant change of the in
vitro cell growth, tumors of LLC/IL-1 cells transplanted to the
syngeneic C57BL/6 male mice grew strikingly faster than those of
LLC/neo and LLC cells as shown in Fig. 2A. The tumor weight of
LLC/IL-1 reached 3.63 ± 0.69 g, while those of LLC/neo
and LLC reached 1.53 ± 0.4 and 1.45 ± 0.51 g at day 18
after inoculation. The tumor weight of LLC/IL-1 was 2.4 times
greater than those of LLC/neo and LLC (p <
0.01). Consistently, this acceleration of tumor growth in LLC/IL-1
cells was also observed in BALB/c nu/nu male mice
(Fig. 2B). The tumor volume of LLC IL-1 cells was more
than three times greater than the control tumors
(p < 0.01). These results suggested that this
promotion of tumor growth was not associated with T cell-mediated
immune responses against tumor cells.
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tumor
To investigate the mechanisms of the enhanced tumor growth of
LLC/IL-1 cells in vivo, tumor sections were first stained with H&E.
As shown in Fig. 3A, abundant
blood vessels and RBCs were noted in the LLC/IL-1 tumor. In higher
magnification (Fig. 3A, insets), inflammatory cells such as
leukocytes and monocytes were massively infiltrated into the
LLC/IL-1 tumor compared with the LLC and LLC/neo tumors, suggesting
that the tumor growth enhancement was associated with
hyperneovascularization. As a next step, immunohistochemical staining
of CD31 vascular endothelial adhesion protein was performed to analyze
the neovascularization in the tumors. As shown in Fig. 3B,
the number of CD31-positive vessels was strikingly increased in the
LLC/IL-1 tumor, whereas the density of vessels in the LLC/neo tumor
was similar to that of the LLC tumor. In the quantification of the
vascular density in the tumor, the LLC/IL-1 tumor developed 2.5-fold
more microvessels than LLC and LLC/neo tumors
(p < 0.05) (Fig. 3C).
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cells
Because IL-1 is known to affect almost all types of cells and
induce multiple factors, including angiogenic factors, we analyzed
crucial angiogenic factors for tumor neovascularization, VEGF,
and CXC chemokine MIP-2 (CXCL2, mouse functional homolog to human IL-8)
secretion from LLC/IL-1 cells using ELISA kits. Although LLC cells
constitutively secreted VEGF (0.9 ± 0.1
ng/106 cells/24 h), LLC/IL-1 cells secreted
1.8-fold more VEGF (1.6 ± 0.09 ng/106
cells/24 h) in 1% FBS containing medium (Table I). Furthermore, over 10 times the amount
of MIP-2 was secreted from LLC/IL-1 cells (1.8 ± 0.21
ng/106 cells/24 h) than from LLC (0.08 ±
0.01 ng/106 cells/24 h) and LLC/neo cells
(0.1 ± 0.02 ng/106 cells/24 h). Similar
results were obtained in the 10% FBS medium (data not shown).
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tumor tissue
Regarding tumor angiogenesis, HGF is known as another major
angiogenic factor. In contrast to control LLC cells, LLC/IL-1 cells
did not secrete HGF protein in vitro that was detectable by ELISA. The
expression of HGF mRNA was also not detected in LLC/IL-1 cells even
by RT-PCR (data not shown). However, the LLC/IL-1 tumors in mice
contained a concentration of HGF protein over four times higher than
did the control LLC tumors (p < 0.05) (Fig. 4A). Based on the observation
that LLC/IL-1 cells themselves did not express HGF, we performed ISH
of HGF mRNA to investigate what type of cell secreted HGF in the
LLC/IL-1 tumor (Fig. 4B). A positive signal of HGF mRNA
was detected in the LLC/IL-1 tumor (Fig. 4Ba), whereas no
significant signal was detected in the LLC/neo tumor (Fig. 4Bb). In high magnification, with the data of H&E staining,
infiltrating cells other than LLC/IL-1 cells overexpressed HGF mRNA
in the LLC/IL-1 tumor (Fig. 4B, c and
d). In low magnification, although a positive signal of HGF
mRNA was detected inside of the LLC/IL-1 tumor, a stronger signal
was observed in interstitial cells surrounding the tumor tissue (Fig. 4Be). In contrast, only a fine signal of HGF mRNA was
detected in the cells surrounding the LLC/neo tumor (Fig. 4Bf). Taken together, analyses of in vitro and in vivo
revealed that stromal cells consisting of fibroblasts, monocytes, and
macrophages overexpressed HGF mRNA in the LLC/IL-1 tumor tissue.
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tumor, we added
recombinant HGF protein (R&D Systems) to the LLC/IL-1 cells in vitro
and examined whether HGF could alter the growth capacity of LLC/IL-1
cells and induce the secretion of angiogenic factors from LLC/IL-1
cells. Although LLC cells expressed HGF receptor c-Met, no significant
stimulation of growth capacity was observed in vitro at the different
HGF concentrations (20 and 40 ng/ml) in 2% FBS medium (data not
shown). In contrast, the secretion of VEGF and MIP-2 from LLC cells and
LLC/neo cells was induced by HGF (40 ng/ml) (Table I
). In addition, of
interest, the secretion of VEGF and MIP-2 from LLC/IL-1 cells was
further induced by HGF (Table I). These data suggested that LLC/IL-1
cells induced angiogenic factors by autocrine and paracrine loops in
the in vivo condition.
Growth inhibition of the LLC/IL-1 tumor by TNP-470 and by
neutralizing anti-CXCR2 receptor homolog Ab (CXCR2 Ab)
Because the LLC/IL-1 tumors showed hyperneovascularization, the
LLC/IL-1 tumors were treated with the antiangiogenic agent TNP-470
to investigate whether hyperneovascularization in LLC/IL-1 tumor was
directly associated with their accelerated growth in vivo. As shown in
Fig. 5A, the growth of the
LLC/IL-1 tumors was strongly inhibited by TNP-470 compared with that
of the control tumors (81% compared with 12% inhibition). Moreover,
neovascularization in the LLC/IL-1 tumors was decreased
significantly by 60% with the TNP-470 treatment.
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cells secreted over 10 times more MIP-2 than
did the control cells, the LLC/IL-1 tumors were treated with CXCR2
Ab. As shown in Fig. 5B, CXCR2 Ab partially inhibited the
tumor growth of the LLC/IL-1 cells (44% inhibition). However, after
termination of the CXCR2 Ab treatment, the inhibitory effect
disappeared and the LLC/IL-1 tumor began to grow faster (data not
shown). |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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from tumor cells accelerates the growth rate of LLC
transplanted in mice. A direct effect of IL-1 on the in vivo
proliferation of LLC cells seems unlikely because LLC/IL-1 cells
exhibited similar proliferation properties to control cells in vitro
even in the presence of HGF. This promoting of the tumor growth of
LLC/IL-1 cells in vivo can be attributed to the
hyperneovascularization. Secretion of IL-1 from tumor cells into the
tumor milieu induces several angiogenic factors, not only from tumor
cells but also from stromal cells, including fibroblasts and
macrophages, and thus promotes tumor neovascularization. Antiangiogenic
agent TNP-470 strongly inhibited the growth of the LLC/IL-1 tumor.
Although we used human IL-1 expression system in this murine model
that expresses mouse IL-1R, it is known that human IL-1 was able to
bind and stimulate mouse IL-1R as well as murine IL-1
(24). The progressive growth of a malignant solid tumor is dependent on the development of new blood vessels that provide oxygen and nutrients to the tumor cells (25). The extent of angiogenesis is determined by a balance between positive- and negative-regulating molecules, which are released by tumor cells and/or host cells in the tumor microenvironment. Although many factors are considered to be angiogenic, VEGF, IL-8, and HGF are all exceptionally important and powerful inducers of angiogenesis for solid tumors and are constitutively or inductively secreted from tumor cells and/or mesenchymal stromal cells (26, 27, 28, 29, 30, 31). The stromal fibroblasts are induced to secrete HGF and VEGF by the stimulation of IL-1, basic fibroblast growth factor, and platelet-derived growth factor derived from tumor cells and macrophages in the tumor tissue (32, 33, 34, 35, 36).
In our system, the transduction of IL-1 into LLC cells leads to
hyperneovascularization due to the overexpression of VEGF, MIP-2
(CXCL2, mouse functional homolog of human IL-8), and HGF by cross-talk
between tumor cells and stromal cells. LLC/IL-1 cells overexpress
VEGF and MIP-2 by themselves, but not HGF. However, high amounts of HGF
in the LLC/IL-1 tumor were found by ELISA, and HGF mRNA was
overexpressed in stromal fibroblasts and infiltrating macrophages as
demonstrated by ISH. IL-1 from tumor cells could stimulate the
secretion of HGF from stromal cells. Furthermore, HGF further induces
VEGF and MIP-2 production from LLC/IL-1 cells (37).
Direct evidence of a correlation between angiogenic factors and tumor promotion has been reported. Inhibition of IL-8 by neutralizing Abs abrogated the tumor size of human non-small cell lung cancer in SCID mice (38). VEGF overexpression in murine hepatocellular carcinoma cells by tetracycline-regulated retrovirus vector revealed the direct effect of tumor promotion by VEGF (39). Another report, using VEGFnull fibrosarcoma cells, concluded that, in addition to the VEGF derived from stromal cells, VEGF derived from tumor cells is a critical factor in tumor expansion and vascular function (26).
HGF, originally identified as a mitogen of mature hepatocytes, is a
multifunctional cytokine that stimulates mitogenesis, motogenesis, or
morphogenesis in a wide variety of epithelial and endothelial cells in
vitro (40, 41, 42). In vivo, HGF is a strong inducer of
angiogenesis as well as invasion and metastasis of tumor cells. A
recent report provides evidence that HGF promotes angiogenesis
indirectly through the induction of other angiogenic factors, VEGF and
CXC chemokine, as well as directly (39). A specific
receptor of HGF, c-MET protein, is frequently overexpressed in human
tumor cells and is recognized as an oncogene (43). HGF is
produced mainly from stromal fibroblasts and macrophages in solid
tumors. NK4, an antagonist of HGF, inhibits tumor growth by the
suppression of tumor angiogenesis (44, 45). We have
demonstrated that the growth of LLC/IL-1 tumors was inhibited by the
antiangiogenic agent TNP-470 and by neutralizing CXCR2 Ab.
In contrast to our results, two previous studies showed tumor growth
inhibition by human IL-1 gene transfer to murine tumor
cells. Peplinski and colleagues (46, 47) demonstrated that
intratumoral and i.v. injection of recombinant vaccinia virus-encoding
IL-1 gene into murine pancreas tumors reduced the tumor growth in
vivo. Another report revealed that constitutive expression of IL-1
gene in murine melanoma B16 resulted in reduced tumor growth in vivo
(48). Immunohistochemical analyses have noted the severe
infiltration of macrophages into B16 tumors transduced with IL-1
gene. A possible explanation for this discrepancy is the different
biological effects of IL-1 according to the tumor type. In early
reports using recombinant human IL-1 protein, IL-1 exhibited
direct cytocidal or cytostatic effects on tumor cells and tumor
regression in certain types of tumors by increasing the host immune
responses (16, 17, 49), whereas it promoted tumor growth
and metastases in other types of tumors (18, 19). These
results indicate that the biological effects of IL-1 on tumor cells
may depend on the type of tumor, doses of IL-1, and a condition of
IL-1 administration.
Numerous studies have shown the constitutive expression of IL-1 gene
in human leukemia in which IL-1 acts as an autocrine and/or
paracrine growth factor (50, 51). Although human solid
tumors secrete a variety of molecules (52, 53), IL-1 is
secreted from a limited number of tumors, i.e., melanoma, sarcoma, and
hepatoblastoma, but not other common types of cancer because a
proteolytic process from proIL-1 to mature IL-1 by
IL-1-converting enzyme is necessary for the secretion of active IL-1
(54). IL-1 expression was not detectable by either
RT-PCR or ELISA in human lung cancer cells, even the presence of
inflammatory stimuli in our experiments.
Various hematological cells infiltrate and perform a wide variety of
functions depending on the physiologic or pathophysiologic conditions
in solid tumor tissues. Macrophages infiltrating into tumor tissues,
referred to as tumor-associated macrophages (TAMs), are reported to
correlate with angiogenesis and thus poor prognosis in several human
cancers (55, 56). TAMs activated by TGF-1 secreted from
tumor cells produce both IL-1 and TNF-, which in turn stimulate
tumor cells to secrete IL-8 and VEGF, and stromal cells to secrete HGF
(32). In another experiment, macrophage
migration-inhibitory factor produced from tumor cells induced monocytes
to increase their expression of CXC chemokine (57). Taken
together, IL-1 might be secreted from TAMs activated by tumor cells
and promote tumor angiogenesis through the stimulation of secretion of
angiogenic factors from both tumor cells and stromal cells.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Yasuo Saijo, Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging, and Cancer, Tohoku University, 4-1 Seiryomachi, Aobaku, Sendai, 980-8575, Japan. E-mail address: yasosj{at}idac.tohoku.ac.jp
3 Abbreviations used in this paper: LLC, Lewis lung carcinoma; TAM, tumor-associated macrophage; VEGF, vascular endothelial growth factor; HGF, hepatocyte growth factor; ISH, in situ hybridization; MIP-2, macrophage-inflammatory protein-2.
Received for publication February 20, 2002. Accepted for publication April 30, 2002.
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, LLC cells
transduced by control retroviral vector PLXIN-neo (LLC/neo); 
, LLC
cells transduced with IL-1
); f, low-power field of ISH of HGF mRNA
of the LLC/neo tumor (*) and surrounding interstitial cells (