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Stimulation of Tumor Growth by Human Soluble Intercellular Adhesion Molecule-1

Craniofacial Developmental Biology and Regeneration Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland 20892 [Y. S. G., P. N. K., H-C. L., M. E., H. K. K.], and Graduate School of East-West Medical Science, Kyunghee University, Yong In, Korea [Y. S. G.]

	ABSTRACT

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Because serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) are elevated in cancer and sICAM-1 is angiogenic, we tested the ability of sICAM-1 to promote tumor growth. Our preliminary experiments showed that exogenous sICAM-1 significantly stimulated the growth of human tumors in vivo. Human fibrosarcoma transfectants, which express ICAM-1, produce ICAM-1 on the cell surface and release sICAM-1 into the medium without any apparent effect on cell growth in vitro. We found that conditioned medium from sense ICAM-1 transfectants compared with mock or antisense ICAM-1 transfectants stimulates endothelial cell migration in vitro and neovascularization in the chick chorioallantoic membrane assay. Tumor cells transfected with sense constructs form faster growing tumors than mock- and antisense-transfected cells in both chick embryos and nude mice models. Serum levels of human sICAM-1 from nude mice bearing sense ICAM-1 transfectants correlate positively with tumor weight. Sense ICAM-1 transfectants are more proliferative and induce more blood vessel formation than mock and antisense transfectants in nude mice. Because expression of ICAM-1 does not affect tumor cell growth in vitro, the angiogenic activity of sICAM-1 produced by sense ICAM-1 transfectants may be involved in the stimulation of tumor growth. Therefore, sICAM-1 may perform dual functions that are essential for tumor growth: angiogenesis and escape from immune surveillance.

	INTRODUCTION

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Angiogenesis, the formation of new blood vessels from preexisting blood vessels, occurs under normal and pathological conditions. Although neovascularization in physiological processes is finely tuned by a balance of stimulatory and inhibitory factors (1) , persistent and unregulated growth of new capillaries plays a prominent role in the development of pathological diseases such as tumor growth, rheumatoid arthritis, diabetic retinopathy, and various inflammatory disorders (2, 3, 4) . Recently, it was demonstrated that soluble forms of CAMs² , including ICAM-1, vascular cell adhesion molecule-1, E-selectin, and P-selectin, promoted angiogenesis (5, 6, 7) .

Endothelial CAMs mediate cell-cell interactions and play a critical role in regulating both leukocyte emigration into inflamed tissues and interactions between T cells and antigen-presenting cells. In angiogenesis-associated diseases, soluble angiogenic mediators, such as cytokines produced by tumor and inflammatory cells, stimulate the expression and shedding of endothelial CAMs. In turn, these soluble CAMs can stimulate neovascularization (5, 6, 7) . ICAM-1 is present on resting endothelial cells where it functions in the attachment and subsequent transendothelial migration of leukocytes to sites of inflammation. Endothelial cells and various other cell types activated by cytokines produce large amounts of membrane ICAM-1 and shed the soluble form (sICAM-1) during inflammation (5, 6, 7, 8, 9) .

Although its pathological role is not completely understood, serum sICAM-1 levels are elevated 3–5-fold in cancer, and there is a positive correlation with progression of malignancy (8 , 9) . Previously (5) , we found that sICAM-1 acts as an angiogenic factor. It stimulated chemokinetic endothelial cell migration, endothelial cell differentiation, and vessel sprouting from explanted aortic rings in vitro and angiogenesis in vivo (5) . The growth of tumors requires vigorous neovascularization induced by the angiogenic factors released by tumor and host cells (10) . We proposed that sICAM-1 produced by activated endothelial cells and/or tumor cells may support tumor growth. In this study, we report that (a) sICAM-1 produced by sense ICAM-1-transfected tumor cells has angiogenic activities both in vitro and in vivo in a variety of assays and that (b) sICAM-1 promotes tumor growth in vivo.

	MATERIALS AND METHODS

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Materials.
Recombinant human sICAM-1, anti-ICAM-1, anti-ICAM-1 polyclonal antibody, control isotype-matched mouse IgG1, and ELISA kit for sICAM-1 were purchased from R&D Systems (Minneapolis, MN). pCEP4 and hygromycin B were from Invitrogen (Carlsbad, CA). FuGENE 6 transfection reagent, chemiluminescence ELISA reagent, and complete protease inhibitor cocktail were from Boehringer Mannheim (Indianapolis, IN). Peroxidase-labeled goat antimouse IgG was from Kirkegaard & Perry Laboratories (Gaithersburg, MD). Tissue culture inserts (10 mm) with an 8-µm polycarbonate membrane and Thermonox discs were purchased from Nunc (Naperville, IL). Collagen IV was obtained from Trevigen (Gaithersburg, MD). Diff-Quik was from Baxter Healthcare Corporation (McGraw Park, IL). Collagen I (4.38 mg/ml) was from Collaborative Biomedical Products (Bedford, MA).

Cell Culture.
Human prostate adenocarcinoma (PC3), human fibrosarcoma (HT1080), and immortalized HMECs (11) were grown in RPMI 1640 containing 10% fetal bovine serum.

Cloning, Transfection, and Construction of Stable Transfectants.
The cDNA for full-length ICAM-1 was amplified by reverse transcription-PCR using the sense primer (5'-GATCGGATCCTCAGCCTCGCTATGGCTCCCAGCA-3') and antisense primer (5'-GCTAGGATCCCGGGATAGGTTCAGGGAGGCG-3') as described previously (12) . We used PC3 human prostate adenocarcinoma total RNA as a template. The 1.6-kb ICAM-1 cDNA fragment was purified from agarose gels, digested with BamHI, and ligated into the BamHI site of pCEP4. The nucleotide sequence of full-length cDNA was determined. Using FuGENE 6 transfection reagent, plasmids (pCEP4 and harboring sense and antisense ICAM-1 cDNA) were transfected into HT1080 cells, and pools of stably transfected cells were selected in the presence of 250 µg/ml hygromycin B.

Cell ELISA for ICAM-1.
HT1080 transfectants were cultured in 96-well plates (2 x 10⁴ cells/well) for 2 days. Cells were washed with PBS and fixed with 3.7% formaldehyde in PBS for 15 min. After blocking with 3% BSA/PBS, wells were incubated with 0.2 µg/ml of anti-ICAM-1 monoclonal antibody in 1% BSA/PBS for 1 h at room temperature and washed three times with PBS. After a 1-h incubation with a 1:5000 dilution of peroxidase-labeled goat antimouse IgG in PBS + 1% BSA, wells were washed three times with PBS + 0.05% Tween 20. The bound peroxidase was detected using the chemiluminescence ELISA reagent. This assay was performed three times.

Preparation of Conditioned Medium.
HT1080 transfectants were plated onto 150-mm dishes (4 x 10⁶ cells/dish) and cultured for 2 days. Cells were washed twice with serum-free RPMI 1640, and 15 ml of serum-free RPMI 1640 was added. After 2 days, cell culture supernatants were centrifuged to remove cell debris. The conditioned medium was stored at -80°C until use.

Level of Human ICAM-1 in Conditioned Medium and Serum.
The amount of ICAM-1 present in conditioned medium produced by HT1080-transfected cells or in the serum of tumor-bearing mice was determined with the ELISA kit for sICAM-1 according to the manufacturer’s instructions.

Immunoprecipitation and Western Blotting.
Anti-ICAM-1 monoclonal antibody (10 µg) was incubated for 3 h with RPMI 1640 or conditioned medium (1 ml), and then 75 µl of protein G-agarose beads were added to the mixture. After an overnight incubation, the beads were washed with Tris-buffered saline. Bound materials were eluted by boiling with 0.1 ml of SDS-loading buffer (nonreducing) and separated by SDS-PAGE (6% gels). After transferring to a nitrocellulose filter, ICAM-1 was detected using anti-ICAM-1 polyclonal antibody and antirabbit-horseradish peroxidase. Bound peroxidase was visualized by enhanced chemiluminescence. This experiment was performed three times.

Migration Assays: Coculture and Boyden Chamber.
For coculture experiments, overnight cultures of HT1080 transfectants in 24-well plates (1 x 10⁵ cells/well) were washed twice with serum-free RPMI 1640, and 0.8 ml of serum-free RPMI 1640 was added to each well. After a 24-h incubation, 5 x 10⁴ HMEC (cells were harvested using versene) in 0.25 ml of serum-free RPMI 1640 were added to the chamber dishes containing tissue culture inserts coated with 0.1 mg/ml of collagen IV. After a 4-h incubation, the cells on the upper side of the filters were removed with cotton swabs, and the filters were fixed and stained using Diff-Quik. The cells that migrated through the filter were quantitated by visual counting in a 36-box grid at 20x using an Olympic CK2 microscope. The Boyden chamber migration assay was performed as described previously (5) using a 1:1 mix of conditioned medium from transfectants and 0.2% BSA in RPMI 1640. Each condition was studied in triplicate wells, and each experiment was performed twice.

Chick Chorioallantoic Membrane Assay.
To investigate the in vivo angiogenic activity of conditioned medium produced by HT1080 transfectants, a modified chick chorioallantoic membrane assay was carried out (13) . Briefly, 10 µl of the mixture containing 0.1 ml of a collagen I solution (3x) with either 0.2 ml of RPMI 1640 or conditioned medium was loaded onto a quarter piece of a Thermonox disc and gelled by warming to room temperature for 15 min. Collagen I solution (3x) was prepared by mixing 1.8 ml of collagen I + 4.14 µl of 10 N NaOH + 0.2 ml of 10 x RPMI 1640/200 mM HEPES (pH 7.4). The disc was then applied to the chorioallantoic membrane of a 10-day-old embryo. After 70 ± 4-h incubation, the negative or positive response was assessed under a microscope. Positive response, i.e., the appearance of a typical spokewheel pattern of new blood vessels around the loaded samples, was determined by two observers in a double-blind manner. Assays for each test sample were carried out three times, and each experiment contained 10 to 12 eggs/data point.

Tumor Growth in Vivo.
Tumor cells (1 x 10⁶ cells/0.5 ml) in RPMI 1640 + Matrigel (1:1 mix) were injected into nude mice. Tumor growth was monitored by measuring tumor volume with a caliper. After sacrificing the animals, blood was collected by intracardiac puncture, and serum was obtained by centrifugation and stored at -80°C. Tumors were excised, weighed, and fixed with formalin.

We also investigated the growth of the transfected tumor cells using the chick chorioallantoic membrane. Tumor cells (1 x 10⁶ cells/0.1 ml) in RPMI 1640 + a 2 x collagen I solution (1:1 mix) were added directly onto the chorioallantoic membrane of the 7-day-old embryo. After a 7-day incubation, tumors were excised and weighed.

Statistical Analysis.
Ps were calculated from Student’s t test, based on comparisons with appropriate control samples tested at the same time.

	RESULTS AND DISCUSSION

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Exogenous sICAM-1 Increases Tumor Growth in Vivo.
Because the circulating levels of sICAM-1 are increased during the progression of cancer (8 , 9) and sICAM-1 has angiogenic activity (5) , we investigated the effect of sICAM-1 on human tumor growth using nude mice. When sICAM-1 is s.c. coinjected with human tumor cells, tumor growth is significantly stimulated (Fig. 1) . The presence of sICAM-1 (0.5 µg/0.5 ml Matrigel/mouse) caused more than a 2-fold increase in PC3 (P = 0.034) and a 3-fold increase in HT1080 (P = 0.007) growth. Higher doses (2.5 µg/0.5 ml Matrigel/mouse) also caused an increase in tumor weight but to a lesser extent. It is not clear at this time why the higher doses resulted in a slight decrease in tumor growth, but the findings were reproducible. Maximum stimulation of vessel sprouting from explanted aortic rings occurs at 750 ng/ml of sICAM-1 (5) . This concentration may correlate with serum levels of sICAM-1 in a number of pathological conditions (8 , 9) .

View larger version (16K): [in this window] [in a new window] [Download PPT slide]   Fig. 1. Stimulation of tumor growth by sICAM-1 in vivo. Tumor cells (1 x 106) in Matrigel containing exogenous sICAM-1 were s.c. injected. A and B, tumor volumes of PC3 and HT1080 were measured with a caliper, respectively. C, mice were sacrificed on day 30, and tumor weights were determined. Bars, the mean ± SE of tumor volume or weight (n = 5). * and **, P < 0.05 and P < 0.01, respectively. This experiment was repeated with similar findings.

Characteristics of HT1080 Transfectants in Vitro.
We constructed human fibrosarcoma (HT1080) transfectants, which can stably express ICAM-1, to determine the role of endogenous expression on tumor growth and angiogenesis.

Sense ICAM-1 transfectants produce ICAM-1 on the cell surface and release a significant amount of sICAM-1 (1.2 ± 0.03 µg/10⁶ cells/day) into the medium (Table 1) . Mock and antisense ICAM-1 transfectants have less cell surface ICAM-1 and do not produce detectable amounts of sICAM-1. Using Western blotting, sICAM-1 was detected in the conditioned medium of sense ICAM-1 transfectants (Fig. 2) . We could not detect sICAM-1 in the mock and antisense ICAM-1 transfectants. Expression of ICAM-1 does not affect tumor cell growth in vitro (Table 1) . Therefore, sense ICAM-1 transfectants express ICAM-1 on their cell surfaces and release significant amounts of sICAM-1 into the culture medium without any apparent effect on cell growth in vitro.

View larger version (83K): [in this window] [in a new window] [Download PPT slide]   Fig. 2. Identification of sICAM-1 from the conditioned medium of sense ICAM-1 HT1080 transfectants. Preparation of conditioned medium, immunoprecipitation, and Western blotting were carried out as described in "Materials and Methods." sICAM-1 was detected in the conditioned medium of sense ICAM-1 transfectants but not in the mock and antisense ICAM-1 transfectants. Lane 1 and Lane 2–4, RPMI 1640 and conditioned media, respectively. Lane 2, mock; Lane 3, sense; Lane 4, antisense ICAM-1 transfectants. Arrow, sICAM-1. These experiments were done three times with similar results.

View larger version (21K): [in this window] [in a new window] [Download PPT slide]   Fig. 3. Stimulation of endothelial cell migration by sICAM-1. A, sense ICAM-1 transfectants stimulate endothelial cell migration in coculture. Control, RPMI 1640 medium alone (no transfected cells). Ps versus mock transfectants were as follows: sense ICAM-1, 0.0006; antisense ICAM-1, 0.622. B, conditioned medium produced by sense ICAM-1 transfectants stimulates endothelial cell migration in the Boyden chamber assay. Control, RPMI 1640 medium alone. bFGF was used as a positive control. Ps versus mock transfectants: sense ICAM-1, 0.0012; antisense ICAM-1, 0.4429. C, conditioned medium (sense ICAM-1) immunodepleted with anti-ICAM-1 antibody did not induce the migration of HMECs. However, a control isotype-matched mouse IgG1-treated sample still induced migration. Bars, the mean ± SD of the number of cells that migrated in triplicate wells.

Sense ICAM-1-transfected HT1080 Cells Grow Faster in Vivo than Mock and Antisense Transfectants.
We investigated the growth of the ICAM-1-transfected tumor cells in vivo in two models: chick embryos and nude mice. When transfected tumor cells were placed on the chick chorioallantoic membrane, sense ICAM-1 transfectants grew faster than mock and antisense transfectants (Fig. 4A ; P = 0.043 and P = 0.031, respectively). In addition, s.c. injected sense ICAM-1 transfectants also grew faster in nude mice than mock and antisense transfectants (Fig. 4B ; P = 0.033 and P = 0.025, respectively). Both models yielded comparable findings and confirm the role of sICAM-1 in promoting tumor growth. Previously (14) , it was shown that serum levels of human sICAM-1 from nude mice bearing human melanoma tumors correlated positively with tumor weight. We also found a positive correlation between the serum level of human ICAM-1 and tumor weight with the sense ICAM-1 transfectants (Fig. 4C) . No human ICAM-1 was detected in the serum of mice bearing mock and antisense ICAM-1 transfectants, because these transfectants do not produce detectable ICAM-1 and the ELISA kit used does not detect murine ICAM-1.

View larger version (14K): [in this window] [in a new window] [Download PPT slide]   Fig. 4. Sense ICAM-1-transfected HT1080 cells grow faster in vivo than mock and antisense transfectants. Bars, the mean ± SE of tumor weight. A, tumor growth on chick embryos. Tumor cells (5 x 105) in a collagen I gel were loaded on 7-day-old chick chorioallantoic membrane, and tumor weights were determined after 7 days (n = 6). Ps versus mock transfectants were as follows: sense ICAM-1, 0.043; antisense ICAM-1, 0.737. B, tumor growth in nude mice. Tumor cells (1 x 106) in Matrigel were s.c. injected, and tumor weights were determined after 15 days (n = 8). Ps versus mock transfectants: sense ICAM-1, 0.033; antisense ICAM-1, 0.828. This experiment was repeated with similar findings. C, positive correlation between serum level of human ICAM-1 and tumor weight of sense ICAM-1 HT1080 cells in nude mice.

View larger version (94K): [in this window] [in a new window] [Download PPT slide]   Fig. 5. Sense ICAM-1-transfected human fibrosarcoma cells are more proliferative and induce more blood vessel formation in vivo than mock and antisense transfectants. Tumors were surgically removed 9 days after tumor cell inoculation (1 x 106). Formalin-fixed tumor tissues were paraffin embedded, sectioned at 10 µm, and stained with H&E for examination of tumor cell proliferation and vessel density. Top, representative areas were photographed at x200 (A, C, and E) and x630 (B, D, and E). A and B, mock; C and D, sense ICAM-1; E and F, antisense ICAM-1-transfected tumors. Bottom, quantification of blood vessel formation. The vascular density in the tumors was determined in the areas with the highest vascularization by a blinded observer. Two to three fields/tumor and five to seven tumors/group were analyzed. Columns, means of the number of blood vessels in tumors; bars, SE. Ps versus mock were as follows: sense ICAM-1, 0.0006; antisense ICAM-1-transfected tumors, 0.0054.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom requests for reprints should be addressed, at Craniofacial Developmental Biology and Regeneration Branch, National Institute of Dental and Craniofacial Research, NIH, Building 30, Room 433, 30 Convent Drive MSC-4370, Bethesda, MD 20892-4390. Phone: (301) 496-4069; Fax: (301) 402-0897; E-mail: hkleinman{at}dir.nidcr.nih.gov

² The abbreviations used are: CAM, cellular adhesion molecule; ICAM-1, intercellular adhesion molecule-1; sICAM-1, soluble ICAM-1; HMEC, human microvascular endothelial cell; bFGF, basic fibroblast growth factor.

Received 9/22/00. Accepted 3/16/01.

	REFERENCES

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