Vascular Endothelial Growth Factor and Osteopontin in Stage I Lung Adenocarcinoma

Abstract

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.

Thymidine phosphorylase and vascular endothelial growth factor in patients with Stage I lung adenocarcinoma

“…1,2 The process of tumor angiogenesis is the outcome of an imbalance between positive and negative regulators of neovasculazation. 1,3,4 TP, an enzyme catalyst in the reversible phosphorylation of thymidine to thymine and deoxyribe-1-phosphate, is identical to PD-ECGF 7 and has several biologic actions, including chemotactic activity of endothelial cells and angiogenic activity in vivo. [5][6][7][8] In addition, the metabolite, deoxyriose-1-phosphate, showed angiogenic activity.…”

“…The association of tumor cell-VEGF expression with increased MVCs and poor clinical outcome in patients with NSCLC has been reported, supporting the clinical significance of VEGF as an important angiogenic factor and prognostic factor in NSCLC. 3,4,27,30 There has been no report on the broad expression of VEGF in tumor-associated stromal cells of NSCLC, although broad expression of TP and bFGF has been found in tumor-associated stromal cells of NSCLC. 24,31 The clinical significance of TP and bFGF as angiogenic factors and/or prognostic factors for NSCLC is still debated.…”

“…After washing the sections with phosphate-buffered saline (PBS), they were incubated with 2% normal goat serum to block nonspecific binding of antibodies for 30 minutes and then reacted with primary antibodies for 1 hour at room temperature. The antibodies used in this study were anti-TP monoclonal antibody (5 g/ mL; clone 654-1; Nippon Roche Research Center, Kanagawa, Japan), anti-VEGF polyclonal antibody (0.5 g/mL; A-20; Santa Cruz, Biotechnology, Santa Cruz, CA), anti-bFGF polyclonal antibody (1 g/mL; A-16; Santa Cruz Biotechnology), and anti-CD34 monoclonal antibody (5 g/mL; QBend10; Dako, Glostrup, Denmark), anti-CD68 monoclonal antibody (1 g/mL; KP-1; Dako), or antitryptase monoclonal antibody (1 g/mL; AA1; Dako 30 The sum of the staining intensity scores and the percentages of positive cells reached a maximum score of 6. A score Ͼ 3 represented a positive immunohistochemical survey.…”

“…The evaluation of MVCs, mast cell counts, and macrophage counts was determined by the use of an Axioscope microscope (Zeiss, Oberkochen, Germany) using the technique described in our prior publication 30 with minor modification. The entire tumor section was scanned systematically at ϫ100 magnification to search for hypervascular areas and for highdensity areas of mast cells and tumor-associated macrophages (excluding alveolar macrophages).…”

“…Vascular endothelial growth factor (VEGF) expression in tumor cells is associated with increased MVCs and a poor prognosis in patients with NSCLC, supporting the role VEGF as a mitogenic growth factor that is selective for vascular endothelial cells and as an important prognostic factor. 3,4,26,30 However, the clinicopathologic roles of TP and basic fibroblast growth factor (bFGF) on tumor angiogenesis and the prognosis of patients with NSCLC are still debated. 3,20 -24,31,32 The current study assessed the expression of TP, VEGF, bFGF, CD34 (microvessels), tryptase (mast cells), and CD68 (macrophages) immunohistochemically in patients with Stage I NSCLC.…”