犬貓腫瘤之甲型烯醇蛋白表現與其預後和組織病理學之相關性

Abstract

甲型烯醇酶 (alpha-enolase, ENO1)為一個物種演化高度保留之蛋白，且是一種醣解酵素。在細胞表面的ENO1作為胞漿素原(plasminogen)受體，幫助腫瘤細胞消化周圍的纖維結締組織，而達到入侵基質的目的，此功能被認為與腫瘤的入侵基質及轉移的能力有關。目前在醫學界對ENO1的研究，發現在高度惡性或有轉移性的肺癌及頭頸部的腫瘤，其ENO1基因的表現性有增強的現象；而在胰臟癌、肺小細胞癌、C型肝炎病毒所引發的肝癌及乳癌等，發現ENO1過度表現與癌症惡化程度有關。在獸醫學的研究，指出ENO1過度表現的犬惡性乳房腫瘤預後較差、存活期較短，在統計學上有顯著相關性。故希望以研究犬惡性乳房腫瘤的方式，探討ENO1在犬貓其他腫瘤的表現， ENO1表現是否與惡性程度及預後有關。 本研究藉由免疫組織化學染色配合Quick score評估，以卡方檢定探討ENO1過度表現與病理學上的相關性，並以Kaplan-Meier分析生存曲線，評估ENO1是否能成為犬貓腫瘤的可能預後因子。選定下列四種在犬貓較常見的腫瘤：鱗狀上皮細胞癌、肥大細胞瘤、淋巴瘤及黑色素瘤，以回溯性研究的方式，收集四種腫瘤之臨床及病理資訊。在收集的病例中，鱗狀上皮細胞癌：犬31例、貓7例；肥大細胞瘤：犬54例、貓5例；淋巴瘤：犬25例、貓7例；以及黑色素瘤：犬57例。結果顯示在犬鱗狀上皮細胞癌，當ENO1過度表現時，與腫瘤等級較惡性及較差的細胞分化有顯著相關，且有顯著較短的存活時間。在犬肥大細胞瘤，ENO1過度表現與年齡較小有顯著相關。在犬淋巴瘤，當ENO1過度表現時也有顯著較短的存活時間。在犬黑色素瘤，當ENO1過度表現時，與腫瘤細胞分化較差及有絲分裂相較旺盛有顯著相關，且有顯著較短的存活時間。因此，本研究顯示，ENO1過度表現應可做為犬鱗狀上皮細胞癌、犬淋巴瘤及犬黑色素瘤的預後評估因子。

Alpha-enolase (ENO1) is an evolutionally-conserved protein and a key glycolytic enzyme. ENO1 is found on the tumor cell surfaces and functions as one of the plasminogen receptors. Then it further degrades fibrin and several extracellular matrix components. It is implicating that it may be involved in tissue invasion during tumor metastasis. In recent years, upregulation of ENO1 gene has been observed in several highly tumorigenic or metastatic cell lines, including small cell lung cancer, head and neck cancer. In addition, its overexpression has been also suggested to be a prognostic biomarker in several types of human cancers such as non-small cell lung cancer, pancreatic carcinoma, hepatitis C virus -related hepatocellular carcinoma and breast cancer. In veterinary medicine, recently published research revealed that overexpression of ENO1 is detected in tumor cells of canine mammary carcinoma and significantly correlated with shorter survival. Based on previous study, we follow the canine mammary carcinoma study to investigate the ENO1 expression in other tumors and to verify whether ENO1 expression statuses are related to their malignancy or poor outcome. In this study, we investigated the ENO1 expression by immunohistochemistry and quantified by Quick score. Correlations of ENO1 overexpression and clinicopathologic parameters of tumors were examined by Pearson's chi-square test. Cause-specific survival was calculated by Kaplan-Meier analysis to verify whether ENO1 expression statuses can be a prognostic factor of other tumors. Four common tumors in dogs and cats including squamous cell carcinoma (SCC), mast cell tumor (MCT), lymphoma, and melanoma were retrospectively retrieved with their clinical and pathological information. A total of 38 cases of SCCs (31 dogs and 7 cats), 59 cases of MCTs (54 dogs and 5 cats), 32 cases of lymphomas (25 dogs and 7 cats) and 57 cases of canine melanomas were included. The results revealed that in canine SCCs, ENO1 overexpression was significantly correlation with higher grade, poorer tumor cell differentiation and shorter cause-specific survival. In canine lymphomas, ENO1 overexpression was significantly correlation with shorter cause-specific survival. In canine MCTs, ENO1 overexpression was significantly correlation with younger age. In canine melanomas, ENO1 overexpression was significantly correlation with poorer cell differentiation, higher mitotic activity and shorter cause-specific. Thus, ENO1 overexpression may be used as a biomarker for poorer prognosis in canine SCCs, lymphomas and melanomas.