胎盤生長因子和內皮生長因子在正常黏膜組織、上皮變 異及口腔癌的表現且與口腔癌病人預後關聯性之探討

Abstract

背景:血管內皮生長因子-A(Vascular endothelial growth factor-A，VEGF-A，簡稱VEGF)及胎盤生長因子(Placental growth factor，PLGF)都是屬於血管內皮生長因子家族(VEGF family)。VEGF 與VEGFR-2 結合可以引發腫瘤血管新生情形，在許多不同的人類癌症中，包括口腔癌，VEGF 有過度表現的情形。過度表現PLGF與病態的血管新生有關。迄今，PLGF在口腔癌中的表現還是未知；本研究以蛋白質層級觀察PLGF 在口腔癌及上皮變異的表現。 材料與方法:本研究利用免疫組織化學染色方法，探討VEGF和PLGF於100例口腔鱗狀細胞癌(OSCC)、66例口腔上皮變異(OED)及36例正常口腔黏膜(NOM)中的表現。利用 ANOVA、卡方檢定(Chi-square test)、Kaplan-Meier存活率方法及Cox proportional hazard regression model來分析VEGF及PLGF的表現與口腔鱗狀細胞癌患者臨床病理參數及存活率之相關性，並試圖尋找影響存活時間的獨立預後因子。 結果: VEGF在正常口腔黏膜的平均陽性標記指數為13% (最低)，口腔上皮變異組的平均陽性標記指數為22%(輕度上皮變異)、24%(中度上皮變異)、32%(重度上皮變異)，口腔癌組的平均陽性標記指數為 50% (最高)，可以看出從正常口腔黏膜、上皮變異至口腔癌，這個癌化的過程，VEGF 的表現增加的情形，且有達統計意義(P <0.001)；PLGF 平均陽性標記指數(LI)從正常黏膜組織(12%±4)、輕度上皮變異(20%±9)、中度上皮變異(26%±11)、重度上皮變異(30%±13)到口腔癌(51%±19)，有統計上顯著的增加(p<0.001)。在上皮變異中，隨著變異程度嚴重度，PLGF 表現也有顯著的增加(p<0.001)。VEGF 及PLGF 的表現和患者的性別、淋巴結轉移與否、癌症臨床分期有統計上相關。單變數分析當中，淋巴結轉移情形(N)、腫瘤分期(S)、VEGF 陽性標記指數(LI)、PLGF陽性標記指數(LI)、VEGF-PLGF 陽性標記指數(LI)都跟存活時間有關 ( p <0.05)；經過 Cox regression model 進行多變數分析以後, 僅有淋巴結轉移情形(N)、VEGF LI、PLGF LI、VEGF-PLGF LI 為影響存活時間的獨立因子 ( p <0.05 )。值得注意的是，當VEGF-PLGF同時表現多(> 40%)時，比起單獨VGEF 或PLGF 表現多時其影響存活率的危險率高達5.596 倍。 結論:在本研究中，VEGF及PLGF 在腫瘤中表現較高且具統計上意義；此外，VEGF及PLGF 的表現與口腔鱗狀細胞癌患者相關的臨床參數及存活率有相關。VEGF與PLGF 的協同作用可能可用來解釋較高hazard ratio 及較短存活時間。所以VEGF及PLGF 可以成為口腔癌預後的指標。

Background: Vascular endothelial growth factor-A (VEGF-A, abbrev. VEGF) and placenta growth factor (PLGF) belong to VEGF family. VEGF could induce tumor angiogenesis through binding to VEGFR-2, which was highly expressed in a variety of human cancers, including oral cancer. Over-expression of PLGF was known to be associated with pathological angiogenesis. The study examined PLGF expression at the protein level in oral cancer and oral epithelial dysplasia, in which no reports on the significance of PLGF expression is available to date. Material and Method: In this study, we examined the expression of VEGF and PLGF in 100 specimens of oral squamous cell carcinoma (OSCC)、66 specimens of oral epithelial dysplasia (OED) and 36 specimens of normal oral mucosa (NOM) by immunohistochemistry. The correlation between the expression of VEGF and PLGF in OSCCs and clinicopathological parameters or survival of OSCC patients was analyzed by ANOVA, Chi-square and Kaplan-Meier survival analysis. Univariate and multivariate analyses (Cox proportional hazard regression model) were used to find the correlation between expression of VEGF and PLGF, clinicopathological parameters and survival, and try to seek independent predictors for survival time. Results: The labeling indices of VEGF from NOM (13%±6), mild dysplasia (22%±8), moderate dysplasia (24%±13), severe dysplasia (32%±14) to OSCC (50%±18: the most abundant) were noted (p<0.001). PLGF expression increased as samples ranged from NOM (12%±4), mild dysplasia (20%±9), moderate dysplasia (26%±11), severe dysplasia (30%±13) to OSCC (51%±19: the most abundant) was noted (p<0.001). The VEGF and PLGF expression correlated with gender, lymph node status and clinical stage (p<0.05).Multivariate analysis demonstrated that lymph node metastasis, VEGF LI>40%, PLGF LI>40% and VEGF-PLGF LI>40% were independent predictors for the survival time.It was noteworthy that when VEGF-PLGF was expression above 40% concomitantly, which raised the hazard ratio to 5.596. Conclusion: In this study, PLGF and VEGF expression were significantly higher in OSCC than that in NOM and OED. In addition, VEGF and PLGF were correlated with some clinical parameters and survival. Synergism between VEGF and PLGF contributed to higher hazard ratio, and shorter survival time. VEGF and PLGF may be prognostic factors for OSCC patients.