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Cell Growth & Differentiation Vol. 11, 635-639, December 2000
© 2000 American Association for Cancer Research


Articles

Retinoblastoma Protein Activation of Interleukin 8 Expression Inhibits Tumor Cell Survival in Nude Mice1

Hongquan Zhang, Sheng Wei, Jiazhi Sun, Domenico Coppola, Bin Zhong, Gary D. Wu, Bonnie Goodwin, Said Sebti, Julie Y. Djeu and George Blanck2

Departments of Pathology and Laboratory Medicine [H. Z., D. C., G. B.], and Biochemistry and Molecular Biology [S. W., J. S., B. Z., B. G., S. S., J. Y. D., G. B.], H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, Florida 33612 [S. W., J. S., D. C., B. Z., S. S., J. Y. D., G. B.]; and Department of Internal Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 [G. D. W.]

Abstract

Lossof retinoblastoma protein (Rb) has been implicated in the formation of a variety of human malignancies. Restoration of Rb expression in the cell lines representing these tumors eliminates or significantly reduces tumorigenicity in nude mice, but the mechanism for this Rb effect is unknown. Results from this study indicated that Rb expression reduced tumor cell survival in nude mice by dramatically enhancing interleukin 8 (IL-8) secretion. IL-8 secreted by the Rb-transformed cells attracted neutrophils in vitro and tumor-infiltrating neutrophils in vivo, which is consistent with the Rb-mediated tumor regression being dependent on IL-8. The apparent, contradictory roles of IL-8 as a protumorigenic and antitumorigenic cytokine are discussed.

Introduction

Rb3 is an important regulator of cell proliferation and differentiation (1, 2, 3) . Rb regulates the G1 phase of the cell cycle by binding to the E2F family of transcription factors and a variety of other cellular proteins (2, 3, 4) . Through complex formation with E2F, Rb represses transcriptional activation of genes containing E2F sites (5 , 6) . When Rb is phosphorylated by cyclin-dependent kinases (4, 5, 6, 7) , E2F is released, which leads to the activation of transcription of genes encoding proteins that promote cell cycle progression from the G1 to S phase (2, 3, 4, 5, 6, 7) . Recently, Rb has also been shown to repress transcription by recruitment of a histone deacetylase (8 , 9) . Rb has been shown to facilitate the activation of gene expression (10 , 11) , but the link between Rb-mediated gene activation and the tumorigenic phenotype is not as well established as the link between the role of Rb as a transcriptional repressor and the tumorigenic phenotype. Rb mutations or deletions have been found in a diverse group of human malignant tumors, including retinoblastoma, osteosarcoma, and carcinomas of the lung, breast, bladder, and prostate (1 , 12 , 13) . Reconstitution of Rb by introducing Rb expression vectors into these tumor cells results in either markedly reduced tumorigenicity or lack of tumor formation in nude mice; however, there has never been an explanation for this phenomenon. Two reports have revealed that Rb prevents nude mice tumor development even when Rb restoration does not alter the tumor cell growth rate or morphology in vitro (14 , 15) . Data presented here indicate that Rb-enhanced IL-8 secretion explains, at least in part, why Rb transformation prevents tumor cell growth in nude mice.

Results and Discussion

In a previous study, we found that Rb-transformed human bladder carcinoma cells secrete higher levels of IL-8 than do Rb-defective control cells and that enhanced IL-8 secretion mediated by Rb is attributed in part to reduced DNA-binding activity of Oct-1 in the Rb transformants (11) . Oct-1 is a repressor of the IL-8 promoter (16) . To determine whether Rb-mediated secretion of IL-8 leads to the enhancement of neutrophil migration, we added IL-8-neutralizing antibodies to the media conditioned by the Rb-transformed 12-27 cells (11 , 17) . Results indicated that the number of neutrophils trapped in the filter of a chemotaxis chamber, reflecting neutrophil migration toward the conditioned media, decreased as the amounts of IL-8-neutralizing antibody were increased (Fig. 1)Citation , establishing that the enhancement of neutrophil migration in response to the media conditioned by the Rb-transformed cells is due to IL-8.



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Fig. 1. Neutrophil migration in response to conditioned media from the Rb-transformed 12-27 cells. Increasing amounts of mouse antihuman IL-8 neutralization antibody or the isotype control (R&D Systems) were added to conditioned media from the Rb-transformed 12-27 cells, and neutrophil migration was quantified by counting the neutrophils migrating into the filter of a chemotaxis chamber (32) . RPMI 1640 with 10% FCS or recombinant human IL-8 (100 ng/ml; R&D Systems) was used as a negative and positive control, respectively, as indicated. The data are representative of three independent experiments.

 
As reported by several groups (12, 13, 14, 15) , Rb-transformed human tumor cells have reduced tumorigenicity in nude mice. We repeated earlier experiments by injecting the Rb-defective bladder carcinoma cell line, 5637, and the Rb-transformed subclone, 12-27, into nude mice. One month after injection, as expected, the mice with the 5637 cells grew tumors, but no visible tumor was detected in the mice that received the 12-27 cells (data not shown). Then, in a separate experiment, we divided the nude mice inoculated with the 12-27 Rb transformants into two groups. One group of mice received IL-8-neutralizing antibody, and the other group received an isotype control (before injection, all the cells were screened for mycoplasma and found to be completely free of mycoplasma). In both cases, there was initial tumor formation at the inoculation sites. However, the tumors in the mice that received the isotype control regressed rapidly, whereas the tumors in the mice with IL-8-neutralizing antibody persisted (Tables 1Citation and 2)Citation . The tumors in the IL-8 neutralization group were larger and were eliminated at a slower rate than those in the mice that received the isotype control (Figs. 2Citation and 3Citation ; compare tumor volumes between the two groups starting from day 12 to day 27 in experiment 2; P < 0.05, Student’s t test).


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Table 1 Survival of 12-27 cells with or without IL-8-neutralizing antibody (experiment 1)a

 

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Table 2 Survival of 12-27 cells with or without IL-8-neutralizing antibody (experiment 2)a

 


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Fig. 2. A comparison of tumor volume in the nude mice with or without the IL-8-neutralizing antibody at week 2 (P < 0.05, Student’s t test). The Rb-transformed 12-27 cells (3 x 106/cells mouse) were injected s.c. in the right flanks of the BALB/c nu/nu mice (Taconic) at day 0. Antihuman IL-8 neutralization antibody or control mouse IgG (R&D Systems) were administered i.p. as scheduled. A measurement of tumor size was performed at week 2 after the tumor cell injection.

 


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Fig. 3. A comparison of tumor regression rate in nude mice with or without the IL-8-neutralizing antibody. The Rb-transformed 12-27 cells (1 x 107 cells/mouse) were injected s.c. in the nude mice. Fifty µg of the IL-8-neutralizing antibody or isotype control were injected i.p. every third day, and measurement of the tumor size was performed before the injections. Data represent the mean ± SD of the tumor volume from four mice.

 
There is a report indicating that IL-8 can inhibit tumor cell proliferation in a lung carcinoma cell line (18) . To determine whether an IL-8-mediated change in the rate of cell proliferation could be a factor in the reduced tumorigenicity of the Rb transformants, IL-8-neutralizing antibody or the isotype control was added to the culture media of the 12-27 cells, and cells were counted at regular time intervals. There was no growth difference attributable to the IL-8-neutralizing antibody (Fig. 4)Citation . Thus, an IL-8-mediated antiproliferative effect on tumor cell growth is unlikely.



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Fig. 4. In vitro growth of the Rb-transformed cells in the presence of IL-8-neutralizing antibody. Two x 104 cells/well of 12-27 or the Rb-defective control clone 1A4 were seeded in 6-well tissue culture plates. Five µg/ml IL-8 antibody or isotype control (R&D Systems) was added at plating. Cell counting was performed using Coulter Counter at days 1, 2, 3, 5, 7, and 10 after plating. At day 5, cells received fresh media with the same concentration of IL-8 antibody or isotype control. Data represent the mean ± SD of triplicate wells.

 
As indicated earlier, IL-8 is a chemoattractant for neutrophils, which are cytotoxic to tumor cells, as reported in several studies (19, 20, 21, 22) . By immunochemical staining of the tumor section using an antineutrophil antibody (anti-Gr-1), we observed a large number of Gr-1-positive TINs in the mice receiving the isotype control and few TINs in the mice receiving the IL-8-neutralizing antibody (Fig. 5Citation and Table 3Citation ). These results are consistent with the discoveries made by Hirose et al. (23) and Lee et al. (24) , indicating that cells stably transfected with an IL-8 expression vector attract neutrophils and produce smaller tumors in nude mice compared with control transformants.



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Fig. 5. Immunohistochemical staining of the neutrophils at the 12-27 cell inoculation sites. 12-27 cells (107 cells/mouse) were injected s.c. in the right flanks of the BALB/c nu/nu mice (Taconic), with 50 µg of IL-8-neutralizing antibody or isotype control administered i.p. simultaneously. Seventy-two h after injection, mice were sacrificed, and tissue was obtained from the tumor cell inoculation sites. Immunohistochemical stain of the frozen sections to identify neutrophils was performed by using a biotin-conjugated rat antimouse neutrophil antibody (Gr-1; 1:300 dilution; PharMingen), as described previously (24) . Photomicrographs are representative fields of the immunostained tissues. Tissues represented in A and B are from mice injected with 12-27 cells and the isotype control, tissues in C and D are from the mice injected with 12-27 cells and the IL-8-neutralizing antibody. A and B (x250 and x400, respectively) show a diffuse collection of neutrophils (staining in red) as compared with C and D (x250 and x400, respectively), in which only rare neutrophils are identified (see arrow).

 

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Table 3 Quantification of TINsa

 
The human lung carcinoma cell line A549 has been reported to constitutively secrete high levels of IL-8 and to grow large tumors in nude mice. In this case, neutralization of IL-8 leads to tumor shrinkage, consistent with the angiogenic functions of IL-8 (25) . In an effort to resolve this apparent contradiction, we considered the possibility that inhibitory factors for neutrophil infiltration and/or cytotoxicity might be secreted by the A549 cells. TGF-ß inhibits neutrophil lytic activity against tumor cells by suppressing mitogen-activated protein kinase-mediated neutrophil activation and by down-regulating tumor cell IL-8 expression (22) , which reduces neutrophil infiltration in tissue (26 , 27) . IL-10 has also been shown to inhibit neutrophil functions (28 , 29) . We assayed the media conditioned by the 12-27 and A549 cells for both TGF-ß and IL-10. In comparison to the Rb-transformed 12-27 cells, A549 cells secreted more than twice the level of TGF-ß in vitro. Neither cell line secreted IL-10 (Table 4)Citation . Also, IL-8 secretion by the A549 was less than one half of that observed in 12-27 cell culture media (Table 5)Citation . In sum, the secretion profiles for cytokines affecting neutrophil functions for these two cell lines are different, and therefore the anti-IL-8 experiments for these two cell lines are not comparable. Interestingly, the cytokine secretion profiles of these two cell lines, as determined above, are consistent with the opposite effects of the IL-8-neutralizing antibody on the survival of the two cell lines in nude mice.


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Table 4 TGF-ß and IL-10 secretions by A549 cellsa

 

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Table 5 IL-8 secretion by a variety of human tumor cell linesa

 
In summary, reconstitution of Rb in the Rb-defective tumor cells enhanced secretion of IL-8, which was responsible for reducing the survival of the Rb-transformed tumor cells in nude mice and led to abundant TINs. This work provides direct evidence that Rb can modulate antitumor immune or inflammatory responses by activation of gene expression. However, because Rb transformant-bearing mice treated with anti-IL-8 do not establish a growing tumor, the question of whether Rb prevents tumor formation solely by up-regulating IL-8 expression has not been resolved. Thus, the anti-IL-8 treatments described above may be insufficient to completely and indefinitely block effector cell functions, or Rb functions unrelated to IL-8 may also contribute to the ability of Rb to prevent tumor formation.

Therapeutic administration of IL-8 has been shown to be cytotoxic to tumor cells in experimental studies (30 , 31) , but its usefulness as an antitumor agent needs to be further verified and better understood. The results presented above raise the question of whether IL-8 could be particularly effective in the treatment of a subset of tumors characterized by low IL-8 secretion and an overall profile of cytokine secretion that would not inhibit the function of effector cells, including neutrophils. Therapies based on cytokine secretion profiles may require neutralization of some cytokines and therapeutic applications of other cytokines. Further work will determine whether Rb-defective tumors exclusively fall into the subset of tumors that could be eradicated by IL-8 treatment.

Materials and Methods

Cell Culture.
The human bladder carcinoma cell line 5637 (American Type Culture Collection) and its subclones, 1A4 and 12-27, and the human melanoma cell lines 729, 1102, 1286, 1287, and 1379 (generously provided by J. Wunderlich; NIH, Bethesda, MD) were cultured in RPMI 1640 supplemented with 10% FCS (Hyclone), 100 units/ml penicillin-streptomycin, 3mM L-glutamine, and 1mM sodium pyruvate. WM9 (generously provided by M. Herlyn, Wistar Institute, Philadelphia, PA), another human melanoma cell line, was maintained in MCDB153/L-15 (Sigma) with 2% FCS. A549 (American Type Culture Collection), a human non-small cell lung carcinoma cell line, was cultured in F-12K (Life Technologies, Inc.) with 10% FCS.

ELISA and Neutrophil Migration Assay.
Forty-eight h after cell plating, culture media from different tumor cell lines were collected. ELISA determinations of human IL-8, TGF-ß, and IL-10 concentration were performed by the Cytokine Core Laboratory (University of Maryland, Baltimore, MD). Neutrophil migration assay was done as described previously (32) .

Nude Mice Tumorigenicity and Immunohistochemical Staining.
BALB/c nu/nu mice (female, 4–8 weeks-old; Taconic) were maintained under pathogen-free conditions in the experimental animal facilities at University of South Florida College of Medicine. For injection, 3 x 106 (experiment 1) or 1 x 107 (experiment 2) of 5637 or 12-27 cells were resuspended in sterile 200 µl of PBS. Cells were injected s.c. in the lower right flanks of the nude mice at day 0, and 50 µg of IL-8 neutralization antibody or the IgG isotype control (R&D Systems) were administered i.p. at day 0 and every third day thereafter. Tumor size was measured with a dial caliper, and tumor volume was calculated as described previously (22 , 23) . For examination of the neutrophil infiltration in tumor tissue, frozen sections from tumor cell inoculation sites were prepared 72 h after injection. Staining of neutrophil by a Gr-1 antibody (1:300 dilution; PharMingen) was performed as described previously (24) .

Acknowledgments

We gratefully acknowledge the expert technical assistance of Sandy Livingston and the Pathology Core Facility in preparation of the antineutrophil stains.

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 Supported by NIH Grant R01 CA81497 and American Cancer Society Grant RPG-98-184-01-CIM (to G. B.). Back

2 To whom requests for reprints should be addressed, at Department of Biochemistry and Molecular Biology, University of South Florida College of Medicine, 12901 Bruce B. Downs Boulevard, Tampa, FL 33612. Phone: (813) 974-9585; Fax: (813) 974-7280; E-mail: gblanck{at}com1.med.usf.edu Back

3 The abbreviations used are: Rb, retinoblastoma protein; IL, interleukin; TGF, transforming growth factor; TIN, tumor-infiltrating neutrophil. Back

Received for publication 8/ 4/00. Revision received 10/20/00. Accepted for publication 10/23/00.

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Cancer Research Clinical Cancer Research
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