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INTRODUCTION
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DISCUSSION
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Tumor growth and metastasis are angiogenesis-dependent processes initiated and regulated by a number of cytokines. Vascular endothelial growth factor (VEGF) is a potent angiogenic protein with a selective mitogenic effect on vascular endothelial cells. Osteopontin (OPN) induces endothelial cell migration and upregulates endothelial cell migration induced by VEGF. To clarify the cooperative role of VEGF and OPN in tumor angiogenesis, we stained VEGF, OPN, and CD34 immunohistochemically in 87 cases of stage I non-small cell lung cancer (adenocarcinoma, 55, and squamous cell carcinoma, 32). Of the 87 patients studied, 27 patients had postoperative relapse and 60 patients did not. VEGF was found in 34 of 55 cases of adenocarcinomas and 14 of 32 squamous cell carcinomas, and OPN was found in 30 of 55 adenocarcinomas and 10 of 32 squamous cell carcinomas. In adenocarcinoma, microvessel counts of VEGF-positive and OPN-positive tumors were significantly higher than VEGF-negative and OPN-negative tumors, respectively, whereas in squamous cell carcinoma they were not. More importantly, patients with VEGF- and OPN-positive stage I lung adenocarcinoma had significantly worse prognosis as compared with other groups. Cooperation of OPN is important in VEGF-mediated tumor angiogenesis in stage I lung adenocarcinoma.
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INTRODUCTION
METHODS
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DISCUSSION
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Tumor angiogenesis is certainly one of the most important factors involved in the development and progression of some solid human tumors (1, 2). Recent studies (3) have demonstrated that angiogenesis assessed by microvessel counts (MVCs) is closely related to postoperative relapse, especially distant metastasis, indicating that MVC within tumors is a prognostic factor in non-small cell lung carcinoma (NSCLC), especially stage I NSCLC.
Vascular endothelial growth factor (VEGF) is a potent angiogenic protein with a selective mitogenic effect on vascular
endothelial cells, known to be involved in physiologic (embryogenesis) and pathophysiologic (rheumatoid arthritis, tumor) angiogenesis (11). Recent investigations (10, 14)
have demonstrated that VEGF is a significant cytokine in angiogenesis of lung cancer, and its expression correlates with
clinical outcome. Our recent study (10) has documented a
wide distribution of MVCs in VEGF-positive stage I lung
adenocarcinoma. VEGF is shown to stimulate endothelial cell migration through cooperative mechanisms involving interaction of integrin 
v
3 and osteopontin (OPN) (18). OPN
expression is observed in human cancers (19), and OPN
expression has been reported to be associated with tumor progression and metastasis in breast cancer (22) and gastric cancer (23). We hypothesized that VEGF-mediated tumor angiogenesis is upregulated in the presence of OPN in lung cancer.
The present study was designed to investigate immunohistochemistry of VEGF, OPN, and CD34 in 87 cases of stage I
NSCLC and analyze the clinical outcome in patients with stage I NSCLC.
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Patients
The subjects consisted of consecutive patients with stage I NSCLC who were treated only by surgery at Sapporo Medical University Hospital between January 1981 and December 1992. Lymph nodes were extensively sampled at thoracotomy, and they were pathologically confirmed to have no metastasis in mediastinal lymph nodes. We excluded patients with stage I NSCLC who died of unrelated diseases. The subjects consisted of 87 patients (57 men and 30 women); 59 patients had T1 tumors and 28 patients had T2 tumors. These tumors included 55 cases of adenocarcinoma, 32 cases of squamous cell carcinoma, and no cases of large cell carcinoma. Forty-nine patients had well-differentiated carcinoma (adenocarcinoma, 31, and squamous cell carcinoma, 18), 29 patients had moderately differentiated carcinoma (adenocarcinoma, 16, and squamous cell carcinoma, 13), and nine patients had poorly differentiated carcinoma (adenocarcinoma, eight, and squamous cell carcinoma, one). Of the 55 cases of adenocarcinoma, 18 cases were bronchioloalveolar carcinoma and the remaining were not. Postoperative follow-up comprised three or six monthly office visits, with yearly restaging or as indicated clinically. All reasonable attempts were made to confirm tumor recurrence/metastasis cytologically or histologically, using radiologic-guided or echo-guided fine needle aspiration or bronchoscopic biopsy. Twenty-seven patients had postoperative relapse, and 60 patients were disease-free and alive with a follow-up of 65 to 210 mo (median, 137 mo). When the survivals were calculated using the Kaplan-Meier method, there were no significant differences between patients with lung adenocarcinoma and squamous carcinoma, among different histologic differentiated subgroups of adenocarcinoma and between moderately and well differentiated subgroups of squamous cell carcinoma.
Immunohistochemistry
Immunohistochemical analyses were performed on at least two paraffin blocks of resected lung tissue per patient. Tumor tissue specimens were fixed with 10% buffered formalin and embedded in paraffin. Five-micrometer-thick sections were mounted on silanized slides (Dako Japan, Kyoto, Japan) and deparaffinized with xylene and ethanol. To retrieve the antigen, sections were pretreated in 10 mM citrate buffer, pH 6.0 with autoclave for 15 min at 120° C before the immunohistochemical staining of CD34 and OPN. The sections were then washed three times with phosphate-buffered solution (PBS) for 5 min. The sections were soaked in absolute methanol containing 0.3% hydrogen peroxide for 30 min at room temperature to remove endogenous peroxidase activity. To suppress nonspecific binding, the sections were incubated with 1.5% nonimmune goat serum for 20 min. The sections were then incubated with mouse monoclonal antibody QBEND10 to CD34 (5 µg/ml; Immunotech, Cedex, France), with rabbit polyclonal antibody to VEGF (5 µg/ml; Santa Cruz Biotechnology, Santa Cruz, CA), or with mouse monoclonal antibody 10A16 to human OPN (5 µg/ml; Immuno-Biological Laboratories, Fujioka, Japan) for 60 min at room temperature. 10A16 recognizes a, b, and c isoforms of human OPN. After being washed with PBS, the slides were subsequently incubated with biotin-conjugated goat antimouse or goat antirabbit IgG antibody for 30 min. Then, after being washed again with PBS, the sections were incubated with avidin-biotin-peroxidase complex (Vector Laboratories, Burlingame, CA) for 30 min, and washed once more with PBS. The sections were finally incubated with 0.03% hydrogen peroxide and 0.05% 3,3-diaminobenzidine.The slides were then washed in running tap water, counterstained with hematoxylin, and mounted in Canadian balsam. Nonimmunized mouse IgG was used as a negative control. No significant immunohistochemical reaction occurred in the control sections.
To assess intratumoral MVCs, immunohistochemical reactivities for CD34 were evaluated. We assessed delineated CD34-positive cells as a microvessel. In the areas that were considered to be most active for neovascularization, stained vessels were counted in a ×200 microscopic field (i.e., ×20 objective lens and ×10 ocular lens, 0.723 mm2/ field) and the average of MVCs counted in five fields was calculated, as described elsewhere (10). The MVCs were assessed without knowledge of patient outcome (the presence or absence of relapse or any other pertinent variable) by two investigators.
To evaluate immunohistochemical expression of VEGF and OPN,
we established a score corresponding to the sum of both staining intensity (0 = negative; 1 = weak; 2 = intermediate; 3 = strong) and percentage of positive cells (0 = 0% positive cells; 1 
25% positive cells;
2 = 26-50% positive cells; 3 
50% positive cells), as described elsewhere (10). The sum of a + b reached a maximum score of 6. A score
greater than 3 represented a positive immunohistochemical survey.
Statistical Analysis
Data are expressed as means ± standard deviation. The Mann-Whitney U test was used for analysis of two unpaired samples. Contingency tables were analyzed for trends with the chi-square test. Survivals were calculated from the day of operation using the Kaplan-Meier method and differences in the survivals were examined by the log-rank test. The level of critical significance was assigned at p < 0.05.
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MVCs and VEGF and OPN Expression
The MVCs were assessed in the most intensive areas of neovascularization within tumors by an immunohistochemical survey of CD34. Delineated CD34-positive cells (Figure 1A) were counted as a microvessel. The mean MVC in stage I lung adenocarcinoma (79.0 ± 38.9 per ×200 microscopic field) was significantly higher than that in stage I lung squamous cell carcinoma (33.8 ± 15.7; p < 0.0001). There were no significant differences in MVCs in sex, distinct tumor size, or distinct histologic differentiation degree subgroups in lung adenocarcinoma and in squamous cell carcinoma. There was no significant difference in MVCs between cases of bronchioloalveolar carcinoma (74.1 ± 28.2) and cases of nonbronchioloalveolar carcinoma (81.6 ± 26.1).
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The immunoreactivities of VEGF were found in the tumor cells (Figure 1B). A part of fibroblasts and smooth muscle cells within the intratumoral stroma were positive for VEGF as well. Immunohistochemical expression of VEGF was found in 34 of the 55 cases of stage I lung adenocarcinoma and in 14 of the 32 cases of stage I squamous cell carcinoma. There were no significant differences in VEGF expression in sex, distinct tumor size, distinct histologic differentiation degree groups, or in cases of bronchioloalveolar carcinoma and nonbronchioloalveolar carcinoma.
The immunoreactivities of OPN were found in the tumor cells (Figures 1C and 1D). A part of macrophages and endothelial cells are positive as well. Immunohistochemical expression of OPN was found in 30 of the 55 cases of stage I lung adenocarcinoma and in 10 of the 32 cases of stage I squamous cell carcinoma. There were no significant differences in OPN expression in sex, distinct tumor size, distinct histologic differentiation degree groups, or in cases of bronchioloalveolar carcinoma and nonbronchioloalveolar carcinoma.
The mean MVC in VEGF-positive adenocarcinomas (93.5 ± 40.5) was significantly higher than that in VEGF-negative adenocarcinomas (55.7 ± 28.4; p < 0.0005; Figure 2A), whereas there was no significant difference between VEGF-positive (36.7 ± 16.8) and VEGF-negative squamous cell carcinomas (31.6 ± 14.9). The mean MVC in OPN-positive and adenocarcinomas (91.3 ± 42.5) was significantly higher than that in OPN-negative adenocarcinomas (64.2 ± 28.4; p < 0.05; Figure 2A), whereas there was no significant difference between OPN-positive (31.7 ± 13.7) and OPN-negative squamous cell carcinomas (34.8 ± 16.8). The mean MVC in VEGF-positive and OPN-positive adenocarcinomas (100.6 ± 43.7) was prominently high, whereas that in VEGF-positive and OPN-positive squamous cell carcinomas (31.5 ± 19.1) was not.
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Relationship of Clinical Outcome to VEGF and OPN Expression
We analyzed the postoperative relapse rates in patients with stage I lung adenocarcinoma and squamous cell carcinoma (Table 1). In adenocarcinoma, the postoperative relapse rate in the VEGF-positive tumor group (41.2%) was 4.3-fold of that in VEGF-negative tumor group (9.5%, p < 0.05) and that in the OPN-positive tumor group was 5.8-fold of that in the OPN-negative tumor (8.0%, p < 0.005). However, in squamous cell carcinoma, there were no significant differences in the postoperative relapse rates in the VEGF-positive (42.9%) and VEGF-negative tumor groups (27.8%) or in the OPN-positive (50%) and OPN-negative tumor groups (27.3%). More importantly, we found that the postoperative relapse rate in patients with VEGF-positive and OPN-positive stage I lung adenocarcinoma (56.5%) was extremely significantly higher than that in patients with VEGF-negative or OPN-negative stage I lung adenocarcinoma (9.4%; p < 0.0001), unlike patients with stage I lung squamous cell carcinoma.
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Using the Kaplan-Meier survival estimates, we compared survivals among VEGF-positive and OPN-positive, VEGF-positive or OPN-positive, and VEGF-negative and OPN-negative tumor groups (Figures 3A and 3B). Patients with VEGF-positive and OPN-positive adenocarcinoma (n = 23) had significantly worse prognosis than those with VEGF-positive or OPN-positive adenocarcinoma (n = 18; p < 0.005) and VEGF-negative and OPN-negative adenocarcinoma (n = 14; p < 0.005). But there were no significant differences of survival curves among patients with VEGF-positive and OPN-positive (n = 5), VEGF-positive or OPN-positive (n = 19), and VEGF-negative and OPN-negative squamous cell carcinoma (n = 8).
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DISCUSSION |
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ABSTRACT
INTRODUCTION
METHODS
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DISCUSSION
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Neovascularization is crucial for sustained tumor growth because it allows oxygenation and nutrient perfusion of the tumor as well as removal of waste products. Increased angiogenesis coincides with increased tumor cell entry into circulation and thus facilitates metastasis (1, 2). Increased numbers of microvessels within tumors are closely related to postoperative relapse in patients with NSCLC, indicating that angiogenesis assessed by MVCs is a significant prognostic factor (3- 10). Recent studies (7) have demonstrated that angiogenesis is a significant prognostic factor in stage I NSCLC. However, Yuan and coworkers (4) have demonstrated that the mean MVC in cases of lung adenocarcinoma is significantly higher than in cases of lung squamous cell carcinoma. The result in the present study also demonstrates that the degree of angiogenesis is different between stage I lung adenocarcinoma and squamous cell carcinoma. We emphasize the need for considering separately the different histologic subgroups of lung carcinoma in further evaluation of prognostic markers with regard to angiogenesis.
To date, at least 20 angiogenic molecules have been identified. Among these factors with angiogenic activity, VEGF is thought to be one of the most important, because specific inhibition of VEGF decreases tumor neovascularization and substantially inhibits primary tumor growth in vivo (24, 25). We and other investigators detected VEGF expression in NSCLC (10, 14). In this study, VEGF expression was found in 34 of 55 cases of lung adenocarcinoma and in 14 of 32 cases of lung squamous cell carcinoma; however, VEGF expression correlated with intratumoral MVCs only in lung adenocarcinoma but not in lung squamous cell carcinoma. The evidence is in accordance with results in the previous reports (10, 15, 16). VEGF alone weakly influenced prognosis in patients with lung adenocarcinoma (10,15), and VEGF alone did not influence prognosis in patients with lung squamous cell carcinoma (16). Several lines of evidence collectively indicate the possibility that some other molecule(s), including angiogenesis inducer(s) and inhibitor(s) in addition to VEGF, is involved in tumor angiogenesis.
OPN is a secreted arginine-glycine-aspartate (RGD)-containing
acidic glycoprotein with cell-adhesive and migratory properties (26).
OPN expression has been found in human cancer, including breast
carcinoma (21, 22), gastric carcinoma (23), and lung carcinoma (20).
OPN stimulates vascular smooth muscle cell migration in a 3 integrin-dependent manner (27) and augments endothelial cell migration
induced by VEGF in an v3-dependent manner (18). Some investigators have demonstrated augmented expression of v3 integrin in
intratumoral microvessels of lung cancer tissues as compared with normal lung tissues (28). In this regard, it should be noted that the expression of v3 integrin in angiogenic vessels correlates with the survival
of growing vascular bud, and antibody to v3 integrin induces apoptosis of endothelial cells (29). More importantly, overexpression of OPN
correlates with progression of gastric (23) and breast carcinoma (22).
We documented OPN expression in significant numbers of both
stage I lung adenocarcinoma and lung squamous cell carcinoma. However, significantly increased MVCs were noted only in cases of VEGF-positive and OPN-positive stage I lung adenocarcinoma, but not in
cases of VEGF-positive and OPN-positive stage I lung squamous
cell carcinoma, suggesting cooperation of OPN in VEGF-mediated tumor angiogenesis in lung adenocarcinoma, but not in lung squamous cell carcinoma. A recent observation (30) has documented that exposure of endothelial cells to tumor necrosis factor- and interferon-
results in a reduced activation of integrin v3, leading to a decreased v3-dependent endothelial cell adhesion and survival. The
difference of MVCs in VEGF-positive and OPN-positive lung adenocarcinoma and squamous cell carcinoma may be elucidated by the different production of cytokine(s) that has properties to decrease endothelial cell activation and survival. We also document that patients
with VEGF-positive and OPN-positive stage I lung adenocarcinoma
have significantly worse prognosis after tumor resection than patients
with VEGF-negative and/or OPN-negative stage I lung adenocarcinoma, in contrast with patients with stage I lung squamous cell carcinoma. This is the first report to document the cooperative role of
VEGF and OPN in angiogenesis-dependent metastasis of stage I lung adenocarcinoma.
We conclude that co-expression of VEGF and OPN correlates with angiogenesis and clinical outcome in stage I lung adenocarcinoma. Cooperation of OPN is important in VEGF-mediated tumor angiogenesis in stage I lung adenocarcinoma.
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Footnotes |
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Supported in part by grant-in-aid no. 10557024 from the Ministry of Education, Culture, Sports, and Science of Japan.
Correspondence and requests for reprints should be addressed to Noriharu Shijubo, Third Department of Internal Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo ku, Sapporo, 060-8543 Japan. E-mail: shijubo @
(Received in original form July 16, 1998 and in revised form November 10, 1998).
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References |
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 M. Gattorno, A. Gregorio, F. Ferlito, V. Gerloni, A. Parafioriti, E. Felici, E. Sala, C. Gambini, P. Picco, and A. Martini Synovial expression of osteopontin correlates with angiogenesis in juvenile idiopathic arthritis Rheumatology, September 1, 2004; 43(9): 1091 - 1096. [Abstract] [Full Text] [PDF]
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S. Schneider, J. Yochim, J. Brabender, K. Uchida, K. D. Danenberg, R. Metzger, P. M. Schneider, D. Salonga, A. H. Holscher, and P. V. Danenberg Osteopontin But Not Osteonectin Messenger RNA Expression Is a Prognostic Marker in Curatively Resected Non-Small Cell Lung Cancer Clin. Cancer Res., March 1, 2004; 10(5): 1588 - 1596. [Abstract] [Full Text] [PDF]
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J.-H. Kim, D. Herlyn, K.-k. Wong, D.-C. Park, J. O. Schorge, K. H. Lu, S. J. Skates, D. W. Cramer, R. S. Berkowitz, and S. C. Mok Identification of Epithelial Cell Adhesion Molecule Autoantibody in Patients with Ovarian Cancer Clin. Cancer Res., October 15, 2003; 9(13): 4782 - 4791. [Abstract] [Full Text] [PDF]
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P. N. Lara Jr., P. Frankel, P. C. Mack, P. H. Gumerlock, I. Galvin, C. L. Martel, J. Longmate, J. H. Doroshow, H. J. Lenz, D. H. M. Lau, et al. Tirapazamine Plus Carboplatin and Paclitaxel in Advanced Malignant Solid Tumors: A California Cancer Consortium Phase I and Molecular Correlative Study Clin. Cancer Res., October 1, 2003; 9(12): 4356 - 4362. [Abstract] [Full Text] [PDF]
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 D. Leali, P. Dell'Era, H. Stabile, B. Sennino, A. F. Chambers, A. Naldini, S. Sozzani, B. Nico, D. Ribatti, and M. Presta Osteopontin (Eta-1) and Fibroblast Growth Factor-2 Cross-Talk in Angiogenesis J. Immunol., July 15, 2003; 171(2): 1085 - 1093. [Abstract] [Full Text] [PDF]
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M. Sugita, M. Geraci, B. Gao, R. L. Powell, F. R. Hirsch, G. Johnson, R. Lapadat, E. Gabrielson, R. Bremnes, P. A. Bunn, et al. Combined Use of Oligonucleotide and Tissue Microarrays Identifies Cancer/Testis Antigens as Biomarkers in Lung Carcinoma Cancer Res., July 15, 2002; 62(14): 3971 - 3979. [Abstract] [Full Text] [PDF]
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 J.-H. Kim, S. J. Skates, T. Uede, K.-k. Wong, J. O. Schorge, C. M. Feltmate, R. S. Berkowitz, D. W. Cramer, and S. C. Mok Osteopontin as a Potential Diagnostic Biomarker for Ovarian Cancer JAMA, April 3, 2002; 287(13): 1671 - 1679. [Abstract] [Full Text] [PDF]
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G. Dong, E. Loukinova, Z. Chen, L. Gangi, T. I. Chanturita, E. T. Liu, and C. Van Waes Molecular Profiling of Transformed and Metastatic Murine Squamous Carcinoma Cells by Differential Display and cDNA Microarray Reveals Altered Expression of Multiple Genes Related to Growth, Apoptosis, Angiogenesis, and the NF-{{kappa}}B Signal Pathway Cancer Res., June 1, 2001; 61(12): 4797 - 4808. [Abstract] [Full Text] [PDF]
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 F. Takahashi, K. Takahashi, T. Okazaki, K. Maeda, H. Ienaga, M. Maeda, S. Kon, T. Uede, and Y. Fukuchi Role of Osteopontin in the Pathogenesis of Bleomycin-Induced Pulmonary Fibrosis Am. J. Respir. Cell Mol. Biol., March 1, 2001; 24(3): 264 - 271. [Abstract] [Full Text] [PDF]
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A. J. Marrogi, W. D. Travis, J. A. Welsh, M. A. Khan, H. Rahim, H. Tazelaar, P. Pairolero, V. Trastek, J. Jett, N. E. Caporaso, et al. Nitric Oxide Synthase, Cyclooxygenase 2, and Vascular Endothelial Growth Factor in the Angiogenesis of Non-Small Cell Lung Carcinoma Clin. Cancer Res., December 1, 2000; 6(12): 4739 - 4744. [Abstract] [Full Text]
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