白血球生成因子受體及防禦素與膀胱癌之關聯性研究

The Study of the Associations among granulocyte-colony stimulating factor receptor, defensin and bladder cancer

林漢青(Han-Ching Lin)

指導教授 ： 黃俊雄

高雄醫學大學/醫學院/醫學研究所/碩士(2007年)

摘要

背景: 膀胱癌是台灣地區常見的癌症。有關膀胱癌的研究相當多，但是白血球生長因子及防禦素和膀胱癌的相關研究並沒有。許多研究指出組織的白血球生長因子表現和腫瘤形成及癌症轉移等都有相關。但至今仍無臨床的數據可供參考。我們之前的研究已證實白血球生長因子在膀胱癌病人接受根除性膀胱切除手術和其術後存活率有關。防禦素和白血球生長因子皆為人體當中免疫系統對抗外來病菌所產生的蛋白質，而在膀胱癌的發生過程其功能尚未定論。在本實驗要進一步檢測白血球生長因子受體及防禦素在表淺性尿路上皮癌的表現情況及是否可以成為預測其復發的生物指標。
方法: 從2002至2007我們回顧性研究在本院初診斷為膀胱腫瘤並接受經尿道膀胱腫瘤刮除手術且經病理組織切片證實為尿路上皮癌的病人，共有138位病患進入本研究，進行回顧病歷、紀錄疾病分期並追蹤病患存活的資料外，也調出當時術後檢體，用特定的白血球生長因子受體及甲型防禦素抗體進行免疫組織染色以確認該組織白血球生長因子受體及甲型防禦素的表現。並比較其臨床表現及預後。

結果:
138位膀胱癌的病人其病理切片的白血球生長因子受體染色結果分為兩組: Strong expression及Weak expression。在腫瘤呈現Strong expression的病人其癌症復發比Weak expression有意義的增加(75% versus 39%, p<0.001)，復發所須要的時間也較短(16.1±15.7 months versus 28.1±20.9 months, p=0.002)。利用Kaplan-Meier log rank survival curve來檢驗白血球生長因子受體染色在癌症復發的角色，發現在Strong expression的病人較易有癌症復發的機會，並且集中於前20個月(log-rank test, p<0.0001)。
甲型防禦素免疫染色出現在腫瘤旁的基質細胞，結果分為兩組Strong expression及Weak expression。有68位病人呈現Strong expression， 佔了全部病人的49.3% 並發現和癌症惡性度有明顯相關，主要分布在低惡性度(Low grade)為主(72% versus 28%, p=0.009)。其分布和癌症病理分級無相關，但與發炎及癌症復發有邊緣性顯著相關(marginal significance; both p=0.087)。利用Kaplan-Meier log rank survival curve來檢驗甲型防禦素免疫染色在癌症復發的角色，發現在Strong expression的病人較不易有癌症復發的機會(log-rank test, p=0.0328)，有53%的病人在五年的追蹤下仍無復發的狀態。當我們將兩種不同染色結果進一步合併來看可發現腫瘤白血球生長因子受體染色中Strong expression合併基質甲型防禦素Weak expression在Kaplan-Meier log rank survival curve檢驗下預後最差，而相反的腫瘤白血球生長因子受體染色中Weak expression若同時呈現基質甲型防禦素Strong expression其預後最佳(log-rank test, p<0.0001)。更進一步驗證基質甲型防禦素Strong expression對膀胱癌復發有保護作用，而腫瘤白血球生長因子受體染色中Strong expression有增加癌症復發的風險。
在多變數比例風險分析下白血球生長因子受體染色中Strong expression和癌症分級(stage)仍是有顯著意義不被干擾的獨立因子，而白血球生長因子受體染色中Strong expression的風險比甚至大於癌症分級(stage) (Hazard ratio, 2.136; p= 0.007 versus Hazard ratio, 1.932; p=0.001)。

結論:
我們的研究顯示免疫系統中白血球生長因子受體及甲型防禦素的表現對表淺性膀胱癌的病人其接受尿道膀胱癌刮除手術後，有預測其復發的角色，利用調控這些因子未來可發展出預防膀胱癌復發的治療方式。

關鍵字

膀胱癌 ； 白血球生長因子受體 ； 甲型防禦素 ； 預後

並列摘要

OBJECTIVES:
Bladder cancer is common in Taiwan. Much research has discussed the pathophysiology of bladder cancer. But the relation of granulocyte colony-stimulating factor (G-CSF) and defensin with bladder cancer are not known. In our previous study, we provide reliable data and proved that the G-CSF expressions in bladder cancer were negatively associated with survival after radical cystectomy. Alpha-defensin and G-CSF receptor were parts of our immune system to resist bacteria and virus. In this study, we want to know if G-CSF receptor and defensin expression can be a useful biomarker for bladder cancer recurrence.
MATERIALS AND METHODS:
From 2002 to 2007, we consecutively collected 138 newly diagnosed bladder cancer cases who received transurethral resection in Kaohsiung Medical University Hospital. Clinical data including TMN stage, grade, and laboratory data were reviewed. Expressions of G-CSF receptor and alpha-defensin were detected by immunohistochemical staining. We examine the association between the expressions of G-CSF receptor, alpha-defensin and the clinical data by Chi-square or Fisher’s exact test.
RESULTS:
The expressions of G-CSF receptor in 138 bladder cancer are divided into 2 groups (strong expression and weak expression). In the group of strong expressions, we found the recurrence rate is higher than weak expressions (75% versus 39%, p<0.001)，The recurrence free survival in strong expressions was shorter than weak expressions (16.1±15.7 months versus 28.1±20.9 months, p=0.002)。Using the Kaplan-Meier log rank survival curves, we found a higher recurrent rate in strong expressions of G-CSF receptor, especially in the first 20 months (log-rank test, p<0.0001)。The stains of alpha-defensin are located on the stromal cell of bladder cancer. The results are divided into 2 groups, strong expression and weak expression.。Strong expression in the stromal cells are significant related with low grade of bladder cancer (72% versus 28%, p=0.009), and showed marginal significance with cancer recurrence and inflammation (both p=0.087). In the Kaplan-Meier log rank survival curves, we found less recurrence in strong expression of alpha-defensin (log-rank test, p=0.0328). After 5 years follow up, there is still no bladder recurrence in 53% of strong expressions of alpha-defensin.
When we combine the result in the expressions of G-CSF receptor and alpha-defensin, we found the best result in strong expression of G-CSF receptor and weak expression of alpha-defensin in Kaplan-Meier log rank survival curve. Weak expression of G-CSF receptor combined with strong expression of alpha-defensin demonstrates the poorest outcome in Kaplan-Meier log rank survival curve(log-rank test, p<0.0001)。It is further proved that the protective effect of alpha-defensin and strong expression of G-CSF receptor may increase the risk of bladder cancer recurrence.
In the multivariate Cox proportional hazard model, the strong expressions of G-CSF receptor and tumor stage were significant predictors after adjusting for other covariates. The hazard ratio of G-CSF receptor is higher than tumor stage (hazard ratio, 2.136; p= 0.007 versus hazard ratio, 1.932; p=0.001).
CONCLUSIONS:
Our results showed G-CSF receptor and alpha-defensin expression in own immune system also regulate the prognosis in superficial bladder cancer after transurethral bladder tumor resection (TURBT). Maybe some alternative treatment can be developed to improve the prognosis of bladder cancer by manipulating the expressions of these cytokines.

並列關鍵字

Bladder cancer ； granulocyte colony-stimulating factor ； defensin ； survival

參考文獻

參考文獻

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