Arora Shilpi, Kaur Jatinder, Sharma Chavvi, Mathur Meera, Bahadur Sudhir, Shukla Nootan K, Deo Suryanaryana V S, Ralhan Ranju
Department of Biochemistry, Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110-029, India.
Clin Cancer Res. 2005 Mar 15;11(6):2272-84. doi: 10.1158/1078-0432.CCR-04-0572.
Identification of molecular changes characteristic of development and progression of oral cancer are of paramount importance for effective intervention. Stromelysin 3 (MMP11) is a unique matrix metalloproteinase shown to have dual function during cancer progression. The transcription factor Ets-1 and vascular endothelial growth factor (VEGF) are important proangiogenic factors in cancer. This study was designed to test the hypothesis that concomitant expression of stromelysin 3, Ets-1, and/or VEGF affects the development, progression, and prognosis of oral cancer.
Immunohistochemical analysis of stromelysin 3, Ets-1, VEGF, and platelet/endothelial cell adhesion molecule 1 (a marker for intratumoral microvessel density) was carried out in serial paraffin embedded tissue sections of 220 oral squamous cell carcinomas (OSCC), 90 precancerous lesions (59 hyperplasias and 31 dysplasias), and 81 matched histologically normal oral tissues.
Ets-1, VEGF, and stromelysin 3 expression independently correlated with increased intratumoral microvessel density in precancerous lesions (P = 0.05, 0.001, and 0.026, respectively) as well as in SCCs (P = 0.005, 0.01, and 0.031, respectively). Logistic regression analysis revealed that concomitant expression of stromelysin 3 and Ets-1 (stromelysin 3(+)/ Ets-1(+) phenotype; odds ratio, 3.7; P = 0.001) was the most significant predictor for transition to precancerous stage, whereas dual expression of stromelysin 3 and VEGF (stromelysin 3(+)/ VEGF(+) phenotype; odds ratio, 2.07; P = 0.004) was the most important predictor for progression from precancerous stage to frank malignancy. Intriguingly, Ets-1 expression was significantly associated with VEGF expression and stromelysin 3 expression in precancerous tissues as well as OSCCs. Follow-up data for 144 patients for a maximum period of 115 months showed that VEGF [hazards ratio (HR), 4.532; P = 0.004] and Ets-1 (HR = 2.182; P = 0.049) expression significantly correlated with reduced disease-free survival in univariate analysis. In bivariate analysis, patients harboring Ets-1(+)/VEGF(+) phenotype had the worst survival (median disease-free survival, 50 months; HR, 2.943; P = 0.003). Multivariate analysis using Cox's proportional hazards model showed that increased VEGF expression was the most significant adverse prognosticator in OSCC patients (HR, 4.470; P = 0.004).
In conclusion, this study provides the first evidence of concomitant expression of stromelysin 3, VEGF, and Ets-1 in clinical specimens in different stages of development of oral cancer. In early stages, concomitant expression of stromelysin 3 and Ets-1 favors the development of a precancerous state, whereas dual expression of stromelysin 3 and VEGF is associated with progression from precancerous to cancerous state. VEGF expression is an adverse prognosticator for disease-free survival.
识别口腔癌发生发展过程中的分子变化特征对于有效干预至关重要。基质溶解素3（MMP11）是一种独特的基质金属蛋白酶，在癌症进展过程中具有双重功能。转录因子Ets-1和血管内皮生长因子（VEGF）是癌症中重要的促血管生成因子。本研究旨在验证基质溶解素3、Ets-1和/或VEGF的共同表达会影响口腔癌的发生、发展和预后这一假设。
对220例口腔鳞状细胞癌（OSCC）、90例癌前病变（59例增生和31例发育异常）以及81例组织学正常的口腔组织的连续石蜡包埋组织切片进行基质溶解素3、Ets-1、VEGF和血小板/内皮细胞黏附分子1（肿瘤内微血管密度标志物）的免疫组织化学分析。
Ets-1、VEGF和基质溶解素3的表达分别与癌前病变（分别为P = 0.05、0.001和0.026）以及鳞状细胞癌（分别为P = 0.005、0.01和0.031）中肿瘤内微血管密度增加独立相关。逻辑回归分析显示，基质溶解素3和Ets-1的共同表达（基质溶解素3(+)/Ets-1(+)表型；比值比，3.7；P = 0.001）是向癌前阶段转变的最显著预测因子，而基质溶解素3和VEGF的双重表达（基质溶解素3(+)/VEGF(+)表型；比值比，2.07；P = 0.004）是从癌前阶段进展为明显恶性肿瘤的最重要预测因子。有趣的是，在癌前组织以及OSCC中，Ets-1表达与VEGF表达和基质溶解素3表达显著相关。144例患者最长115个月的随访数据显示，在单因素分析中，VEGF [风险比（HR），4.532；P = 0.004]和Ets-1（HR = 2.182；P = 0.0
