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Clinical Cancer Research Vol. 7, 1287-1292, May 2001
© 2001 American Association for Cancer Research

Molecular Oncology

Significant Correlation between Interleukin 10 Expression and Vascularization through Angiopoietin/TIE2 Networks in Non-small Cell Lung Cancer1

Hiroyuki Hatanaka, Yoshiyuki Abe2, Masao Naruke3, Tetsuji Tokunaga, Yoshiro Oshika, Tsutomu Kawakami, Hideo Osada, Junko Nagata, Jun-ichiro Kamochi, Takashi Tsuchida, Hiroshi Kijima, Hitoshi Yamazaki, Hiroshi Inoue3, Yoshito Ueyama and Masato Nakamura4

Department of Pathology, Tokai University School of Medicine, Kanagawa 259-1193, Japan


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The expression of interleukin 10 (IL-10) is correlated with clinical prognosis in non-small cell lung cancer [NSCLC (H. Hatanaka et al., Ann. Oncol., 11: 815–819, 2000)]. However, the effects of IL-10 expression on vascularization in NSCLC are not apparent. We examined the gene expression of IL-10/IL-10 receptor and various angiogenic/angioinhibitory factors in 95 NSCLC samples to determine the correlation between IL-10 production and vascularization. Vascular endothelial growth factor, angiopoietin [Ang (Ang-1 and Ang-2)], thrombospondin, brain-specific angiogenesis inhibitor 1, vascular endothelial growth factor receptors (KDR and flt-1), and Ang receptor (TIE2) gene expression were evaluated by reverse transcription-PCR. The cellular localization of these factors and vascularity in the cancer stroma were examined immunohistochemically. Seventy-eight (82.1%) and 93 (97.9%) of these 95 NSCLCs were positive for IL-10 and IL-10 receptor, respectively. Ang-1, Ang-2, and TIE2 gene expression was seen in 76 (97.4%), 73 (93.6%), and 78 (100%) of 78 IL-10-positive NSCLCs, respectively, and was significantly correlated with IL-10 gene expression (P < 0.0088, <0.0008, and 0.0305, respectively; Fisher’s exact method). The localizations of Ang-1, Ang-2, and TIE2 were confirmed within tumor cells immunohistochemically. Vascular number and measurement area were significantly higher in the IL-10-positive NSCLCs (33.500 ± 9.299/µm2 and 4.742 ± 1.287%) as compared with IL-10-negative NSCLCs (10.611 ± 2.839/µm2 and 0.718 ± 0.331%; Mann-Whitney U test, P = 0.0039). The IL-10 expression did not show any significant correlation with the expression of other factors. These results suggested that tumor-produced IL-10 promotes stromal vascularization through expression of Ang-1, Ang-2, and TIE2.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Angiogenesis is controlled by complicated mechanisms involving various factors (1) . Several angiogenic factors, such as basic fibroblastic growth factor, transforming growth factor ß, tumor necrosis factor {alpha}, and VEGF5 , have been reported. Angioinhibitory factors, such as angiostatin, platelet factor 4, TSP, and IFN-{alpha}, rather than angiogenic factors are predominant in many normal tissues (2, 3, 4, 5, 6) . Ang-1 has been shown to be essential as an angiogenic factor for normal vascular development in the mouse (7 , 8) . Ang-1 is a ligand for the tyrosine kinase receptor TIE2, which is a member of the endothelial cell-specific receptor tyrosine kinase family (9, 10, 11) , and TIE2 has been suggested to play an important role in vascular remodeling and sprouting (12) . Ang-2 also binds to the TIE2 receptor, whereas Ang-2 does not induce receptor phosphorylation.

The cytokine network, which is divided into two patterns, type 1 and type 2, is involved in the local immune response to tumors (13 , 14) . Recent studies have indicated that a type 2 cytokine pattern is present at the tumor site and suggested that these cytokines may mediate immunosuppression (15 , 16) . It has been reported that some cytokines regulate angiogenesis in NSCLC (17) . IL-10, a type 2 cytokine, was reported to possess several properties that may be inhibitory to the generation of antitumor immunity (18 , 19) and to be produced by tumor cells in lung cancer (20) . We reported previously that IL-10 expression was correlated with clinical prognosis and that it is a prognostic factor for NSCLC (21) .

In this study, we examined IL-10 and IL-10R gene expression. Various vascular factors including VEGF, Ang-1, Ang-2, TSP1, TSP2, and BAI1 were evaluated in 95 NSCLC samples by RT-PCR. Receptors for these factors (KDR, flt-1, and TIE2) were also examined. The cellular localization of the factors was confirmed by IHC. Vascularity of the cancer stroma was estimated by morphometric analysis on immunohistochemically stained sections. We discuss here the relationship between IL-10 expression and stromal vascularization through Ang/TIE2 networks in NSCLC.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Tumor Samples.
Ninety-five specimens of NSCLC were obtained at surgical resection from previously untreated patients with their informed consent. Tissues were frozen and stored at -80°C. Total cellular RNA was prepared from the frozen specimens by standard procedures. Surgical specimens were also processed for routine histopathological analysis. Morphological classification was based on histological typing of lung tumors (22) . Two pathologists histologically classified the tumors. The specimens consisted of 56 adenocarcinomas, 32 squamous carcinomas, 5 large cell carcinomas, and 2 adenosquamous carcinomas. The pathological stages of the NSCLCs were also estimated (22 stage Ia, 24 stage Ib, 3 stage IIa, 10 stage IIb, 27 stage IIIa, 3 stage IIIb, and 2 stage IV NSCLCs; pathological stage was unknown for 4 NSCLCs).

Expression of IL-10 and Various Vascular Factors.
IL-10 gene expression was semiquantitatively examined by densitometric analysis of RT-PCR/Southern blots, according to our previous reports (30 rounds of denaturation at 94°C for 1 min, annealing at 45°C for 1 min, and extension at 72°C for 2 min; Gene Amp PCR System 9600; Perkin-Elmer, Norwalk, CT; Ref. 21 ). IL-10R, Ang-1, Ang-2, and TIE2 gene expression was examined by similar methods (annealing at 55°C for IL-10R and at 53°C for Ang-1, Ang-2, and TIE2; Refs. 23, 24, 25, 26 ). The following primers were used: (a) IL-10 sense primer, 5'-ATGCACAGCTCAGCACTGC-3'; (b) IL-10 antisense primer, 5'-TCAGTTTCGTATCTTCATTGTC-3'; (c) IL-10R sense primer, 5'-ATGCTGCCGTGCCTCGTAGTGC-3'; (d) IL-10R antisense primer, 5'-ACTCTGGCCCGGTAGCCATTGC-3'; (e) Ang-1 sense primer, 5'-GATGGACACAGTCCACAACC-3'; (f) Ang-1 antisense primer, 5'-ATTCCTTCCAGCCTCTTTGG-3'; (g) Ang-2 sense primer, 5'-TTTCCTCCTGCCAGAGATGG-3'; (h) Ang-2 antisense primer, 5'-GCGTTTGCTCAGCTGTTTGG-3'; (i) TIE2 sense primer, 5'-CTGCAGTGCAATGAAGCATGC-3'; and (j) TIE2 antisense primer, 5'-CTGCAGACCCAAACTCCTGAG-3'.

Probes were prepared by PCR amplification with appropriate cDNA as the template. The sequences of the probes were confirmed using a Genetic Analyzer 310 (Perkin-Elmer). Blots of RT-PCR products (Zeta-Probe; Bio-Rad, Hercules, CA) were hybridized with photochemically labeled probes (ECL; Amersham Pharmacia Biotech, Uppsala, Sweden) and exposed to Kodak AR film. RT-PCR was also performed with primers for other vascular factors (VEGF, VEGF isoform, TSP1, TSP2, BAI1, KDR, and flt-1), according to our previous reports (27, 28, 29, 30) , and the housekeeping gene ß2m was used as a control.

IHC.
Immunohistochemical analysis was performed using the Catalyzed Signal Amplification system (DAKO Co. Ltd., Glostrup, Denmark), according to the manufacturer’s recommendations. Specific goat polyclonal antihuman Ang-1 and Ang-2 and rabbit polyclonal antihuman TIE2 antibodies were purchased from Santa Cruz Biotechnology (Santa Cruz, CA). The tissue sections were deparaffinized and dehydrated through a xylene and alcohol series. After antigen retrieval (autoclaving at 121°C for 10 min in 0.01 M citrate buffer), blocking of endogenous peroxidase activity (3% H2O2 for 5 min), and blocking of nonspecific binding (serum-free protein in PBS for 5 min), sections were incubated with the primary antibody (anti-Ang-1, -Ang-2, and -TIE2; x100) overnight. Then, the immune complex on the sections was amplified with the biotinylated secondary antibody (rabbit antimouse immunoglobulin), streptavidin-biotin complex, and streptavidin peroxidase. The amplified products were visualized by a 3,3'-diaminobenzidine tetrahydrochloride reaction.

Tumor sections (formalin fixed and paraffin embedded) were also incubated with anti-CD34 antibody (NCL-end; Novocastra Laboratories Ltd.; Newcastle, United Kingdom; x20) and anti-CD31 antibody (DAKO Co. Ltd.; x10) and biotin-labeled antimouse IgG (Nichirei, Tokyo, Japan) and horseradish peroxidase-conjugated streptavidin (Nichirei), according to our previous report (23) . Reaction products were visualized by 3,3'-diaminobenzidine tetrahydrochloride. Then, a computer image analysis system (Video Analyzing System, VIDAS; Carl Zeiss, Oberkochen, Germany) was used for quantitative evaluation of vascularity in the tumor.

Statistical Analysis.
We examined the statistical significance of correlations between IL-10 and vascular factors/receptors in NSCLC by Fisher’s exact method. The statistical significance of differences in vascular density between IL-10-positive and -negative NSCLCs was examined by Mann-Whitney U test.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
IL-10 and IL-10R Expression.
Seventy-eight of the 95 (82.1%) NSCLCs showed IL-10 gene expression (Fig. 1)Citation . IL-10 gene expression was detected in 20 of 22 (90.9%) stage Ia NSCLCs, 20 of 24 (83.3%) stage Ib NSCLCs, 2 of 3 (66.7%) stage IIa NSCLCs, 10 of 10 (100%) stage IIb NSCLCs, 19 of 27 (70.4%) stage IIIa NSCLCs, 1 of 3 (33.3%) stage IIIb NSCLCs, 2 of 2 (100%) stage IV NSCLCs, and 4 of 4 (100%) NSCLCs of unknown stage. IL-10 gene expression was detected histopathologically 47of 56 (83.9%) adenocarcinomas, 24 of 32 (75%) squamous cell carcinomas, 5 of 5 (100%) large cell carcinomas, and 2 of 2 (100%) adenosquamous carcinomas. No significant correlations were observed between IL-10 gene expression and clinicopathological features, including tumor-node-metastasis (TNM) score and pathological stage (Table 1)Citation . IL-10 production was confirmed in the tumor cells of NSCLC by IHC (data not shown; Ref. 23 ). Most NSCLC tumor specimens (93 of 95 tumors, 97.9%) showed IL-10R gene expression (Fig. 1)Citation . Only two specimens (one adenocarcinoma and one squamous cell carcinoma) were negative for IL-10R gene expression.



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  		Fig. 1. IL-10, IL-10R, Ang-1, Ang-2, TIE2, and ß2m gene expression in NSCLC (Lanes 2–10). ß2m gene expression was examined as a control for the quality of RNA specimens used as templates. Lane 1, positive control gene expression from cell lines. The lengths of RT-PCR products of IL-10, IL-10R, Ang-1, Ang-2, TIE2, and ß2m were 537, 299, 269, 287, 389, and 114 bp, respectively.

 

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  		Table 1 IL-10/IL-10R expression and clinicopathological features in NSCLC

 
Expression of Vascular Factors (Ang-1, Ang-2, VEGF, TSP1, TSP2, and BAI1) and Their Receptors.
Ang-1 and Ang-2 gene expression were detected in 89 of 95 (93.7%) and 83 of 95 (87.4%) cases, respectively (Table 2)Citation . VEGF, TSP1, TSP2, and BAI1 gene expression was detected in 71 of 74 (95.9%), 44 of 67 (65.7%), 35 of 69 (50.7%), and 73 of 97 (75.3%) cases examined, respectively. The gene expression of VEGF isoform 189 was detected in 64 of 74 (86.5%) cases.


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  		Table 2 Gene expression of IL-10 and vascular factors in NSCLC

 
To identify the cellular localizations of Ang-1 and Ang-2, we performed immunohistochemical analysis of sections from 10 lung tumors (5 adenocarcinomas, 4 squamous cell carcinomas, and 1 large cell carcinoma) that were stained with anti-IL-10 antibody previously. These 10 specimens coexpressed Ang-1 and Ang-2 genes. The Ang-1 and Ang-2 proteins were confirmed in the cytoplasm of the neoplastic cells, whereas no definite staining was observed in the stroma (Fig. 2)Citation .



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  		Fig. 2. Immunohistochemical staining of NSCLC using specific antibodies (x300). The specimen of squamous cell carcinoma showed positive staining for Ang-1 (A) and Ang-2 (B) in the cytoplasm of tumor cells.

 
TIE2 gene expression was seen in 93 of 95 (97.9%) NSCLCs, whereas KDR and flt-1 gene expression were detected in 75 of 78 (96.2%) and 61 of 78 (78.2%) of these cases, respectively (Table 3)Citation .


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  		Table 3 Gene expression of IL-10 and vascular factor receptors in NSCLC

 
Correlations between IL-10 Production and Vascular Factors.
There were significant statistical correlations between IL-10 and Ang (Ang-1 and Ang-2) gene expression (P < 0.0088 and P < 0.0008, respectively, Fisher’s exact method). IL-10 expression was significantly correlated with TIE2 expression (P < 0.0305, Fisher’s exact method). No significant correlations were observed between IL-10 and VEGF (VEGF isoform 189), TSP1, TSP2, BAI1, KDR, and flt-1 expression.

Vascular Density.
Vascular density (vascular number and measurement area) was quantitatively evaluated by immunohistochemical staining for CD34 on the walls of blood vessels in the cancer stroma (Fig. 3)Citation . Labeling was evaluated in three distinct visual fields at x200 magnification. Vascular number was significantly higher in IL-10-positive NSCLCs (33.500 ± 9.299/µm2) than in IL-10-negative NSCLCs (10.611 ± 2.839/µm2). Vascular measurement area was also significantly higher in IL-10-positive NSCLCs (4.742 ± 1.287%) than in IL-10-negative NSCLCs (0.718 ± 0.331%). Vascular density in the tumor specimens was significantly correlated with IL-10 gene expression (vascular number, P = 0.0039; vascular measurement area, P = 0.0039, Mann-Whitney U test). The data obtained with anti-CD31 antibody were similar to those obtained with anti-CD34 antibody.



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  		Fig. 3. Vascularity was evaluated immunohistochemically using anti-CD34 antibody in squamous cell carcinoma (x120). IL-10-positive NSCLC (A) showed significantly abundant vessels as compared with IL-10-negative NSCLC (B) in the cancer stroma.

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this study, we evaluated the gene expression of IL-10/IL-10R and various vascular factors/receptors in NSCLC. Eighty-two percent of the NSCLCs were positive for IL-10, and IL-10 expression was significantly correlated with Ang-1, Ang-2, and TIE2 gene expression, whereas no such correlations were observed with expression of other vascular factors. Ang-1, Ang-2, and TIE2 production was immunohistochemically confirmed in the cancer cells. IL-10-positive NSCLCs showed increased vascular density as compared with those negative for IL-10. Recent studies suggested that IL-10, a type 2 cytokine, was produced by tumor cells in lung cancer (20) . Arenberg et al. (17) reported that chemokines played a role in regulation of angiogenesis in NSCLC. Previously, we reported that cytoplasmic IL-10 expression was significantly correlated with poor clinical prognosis in NSCLC (21) . The above results suggested that tumor-produced IL-10 promotes stromal vascularization through coexpression of Ang-1, Ang-2, and TIE2. The poor prognosis of NSCLC expressing IL-10 can be partly explained by the increased vascularization induced by the Ang-1/Ang-2-TIE2 network.

We reported previously that expression of the cell-associated isoform of VEGF189 is closely associated with progression in NSCLC (27) . The reduction of TSP2 expression is correlated with vascularity resulting in tumor progression (29) . No significant correlation was observed between expression of IL-10 and VEGF189/TSP2. BAI1 was first described as a novel brain-specific p53 target gene and contains TSP-type 1 repeats, which were reported to inhibit experimental angiogenesis induced by basic fibroblastic growth factor (31) . We also showed that BAI1 functions as an angioinhibitory factor and that reduction of its expression resulted in increased vascularization in 48 pulmonary adenocarcinomas (23) . In this study, however, no significant relationship was noted between IL-10 and BAI1 expression in NSCLC.

Infiltration of inflammatory cells is activated in malignant tumors, which contributes to angiogenesis. Tumor-associated macrophages have been suggested to contribute to angiogenesis (32) . IL-10 was reported to be expressed by tumor-associated lymphocytes and peripheral blood mononuclear cells of NSCLC patients but not by tumor cells (33) . We reported previously that IL-10 was detected in tumor cells of NSCLC (21) . Here, we showed that IL-10 produced by tumor cells was correlated with neovascularization in the cancer stroma through Ang/TIE2 networks in NSCLC. The expression of IL-10R was detected in almost all NSCLCs examined (97.9%). These results suggested that IL-10 regulates vascularization through autocrine and/or paracrine mechanisms via the Ang-1/Ang-2-TIE2 network in NSCLC.


   ACKNOWLEDGMENTS
 
We thank Yuichi Tada, Masashi Tomisawa, Akihiko Serizawa, Johbu Ito, Tamaki Sasou, and Kyoko Murata for technical assistance.


   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 in part by Grants-in-Aid for Scientific Research 11670227 (to M. N.) and 11680825 (to Y. U.) from the Ministry of Education, Science, and Culture and Tokai University School of Medicine Research Project (H. K. and T. Ts.). Back

2 Present address: Department of Respiratory Disease, National Sanatorium Kanagawa Hospital, Ochiai 666-1, Hadano, Kanagawa 257-8585, Japan. Back

3 Present address: Department of Surgery, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa 259-1193, Japan. Back

4 To whom requests for reprints should be addressed, at Department of Pathology, Tokai University School of Medicine, Bohseidai, Isehara-shi, Kanagawa 259-1193, Japan. Phone: 463-93-1121; Fax: 463-91-1370; E-mail: mnakamur{at}is.icc.u-tokai.ac.jp Back

5 The abbreviations used are: VEGF, vascular endothelial growth factor; TSP, thrombospondin; Ang, angiopoietin; BAI1, brain-specific angiogenesis inhibitor 1; IL-10, interleukin 10; IL-10R, IL-10 receptor; NSCLC, non-small cell lung cancer; RT-PCR, reverse transcription-PCR; IHC, immunohistochemistry; ß2m, ß2-microglobulin. Back

Received 9/18/00; revised 1/29/01; accepted 1/29/01.


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Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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