老年結(jié)腸癌病人循環(huán)與腫瘤組織中Galectin-3水平及臨床意義

任麗麗 耿建

老年結(jié)腸癌病人循環(huán)與腫瘤組織中Galectin-3水平及臨床意義

任麗麗 耿建

目的 分析老年結(jié)腸癌病人循環(huán)和腫瘤組織中半乳糖凝集素-3(Galectin-3)表達(dá)情況，以及與病人一般情況、腫瘤分期及預(yù)后的關(guān)系。 方法 收集自1999年3月至2010年12月在我科住院明確診斷的老年結(jié)腸癌病人68例,另收集50例健康體檢者為對照組,測定其循環(huán)中Galectin-3水平。收集病人臨床信息與實(shí)驗(yàn)室檢查結(jié)果,采用雙抗體夾心法測定循環(huán)Galectin-3水平,切除的腫瘤組織行抗Galectin-3免疫組化染色。將循環(huán)Galectin-3水平和腫瘤組織Galectin-3表達(dá)情況與病人相關(guān)資料行相關(guān)分析。 結(jié)果 68例老年結(jié)腸癌病人循環(huán)Galectin-3水平顯著高于對照組(P<0.001);循環(huán)Galectin-3水平與腫瘤長徑、腫瘤轉(zhuǎn)移、TNM分期及預(yù)后無相關(guān)性(P>0.05);腫瘤組織Galectin-3表達(dá)陽性病例與陰性病例在血清CEA水平、腫瘤長徑、Duke 分期、TNM分期、淋巴結(jié)轉(zhuǎn)移、遠(yuǎn)處轉(zhuǎn)移、生存時(shí)間方面差異均有統(tǒng)計(jì)學(xué)意義(P均<0.01)。 結(jié)論 老年結(jié)腸癌病人循環(huán)Galectin-3水平顯著升高,腫瘤組織Galectin-3表達(dá)情況可預(yù)示病情和預(yù)后。

老年人; 結(jié)腸癌; 半乳糖凝集素-3; 預(yù)后

結(jié)腸癌是臨床常見的惡性腫瘤,居全球惡性腫瘤發(fā)病率第3位,每年新增惡性腫瘤病人中,結(jié)腸癌約占10%[1-2]。腫瘤細(xì)胞播散和轉(zhuǎn)移直接影響著結(jié)腸癌的預(yù)后,而腫瘤細(xì)胞與血管內(nèi)皮細(xì)胞之間的黏附又是腫瘤浸潤的關(guān)鍵環(huán)節(jié)。近年來,一類與細(xì)胞黏附過程有關(guān)的凝集素(Lectin)家族成員半乳糖凝集素-3(Galectin-3)引起臨床關(guān)注。Galectin-3是一種對含β-半乳糖苷殘基的糖化合物具有很高親和力的凝集素,在激活的巨噬細(xì)胞中高表達(dá),通過一種類似細(xì)胞胞吐的機(jī)制轉(zhuǎn)移至細(xì)胞外并進(jìn)入全身循環(huán)[3]。研究發(fā)現(xiàn),多種惡性腫瘤組織中可檢測出Galectin-3高表達(dá),其中包括結(jié)腸癌[4-5]。Galectin-3在細(xì)胞增殖和分化、細(xì)胞與間質(zhì)間黏附、炎癥反應(yīng)、血管生成、細(xì)胞凋亡、免疫調(diào)節(jié)及腫瘤浸潤等方面具有廣泛的生理和病理意義[6-7]。目前,以老年結(jié)腸癌病人為研究對象,同步分析循環(huán)中Galectin-3水平和腫瘤組織Galectin-3表達(dá)情況的臨床研究仍有限。本研究旨在研究循環(huán)與腫瘤組織中Galectin-3表達(dá)水平在老年結(jié)腸癌病人中的臨床意義。

1 對象與方法

1.1 研究對象 病例選自1999年3月至2010年12月在我科住院明確診斷的結(jié)腸癌病人68例,年齡≥60歲。排除標(biāo)準(zhǔn):腎功能不全、嚴(yán)重心功能不全(NYHA分級Ⅲ～Ⅳ級)、合并惡性腫瘤、嚴(yán)重肥胖或消瘦(體質(zhì)量指數(shù)>30或<18)。68例病人中,男43例(63%),女25例(37%),年齡60～73歲,平均(62.4±3.2)歲,Duke分期:A期18例(26.4%)、B期22例(32.3%)、C期19例(27.9%)和D期9例(13.4%);TNM分期1期23例(34.0%)、2期25例(36.7%)、3期14例(20.5%)、4期6例(8.8%)。另收集50例健康體檢者作為對照組,測定其循環(huán)中Galectin-3水平。所有研究對象均簽署書面知情同意書,本研究通過所在機(jī)構(gòu)醫(yī)學(xué)倫理審查。

1.2 研究方法 所有病人均接受手術(shù)切除病灶或探查。收集病人臨床資料，包括年齡、性別、Duke分期、TNM 分期、腫瘤體積、腫瘤分化程度、轉(zhuǎn)移情況,檢測血清癌胚抗原(CEA)水平。病人術(shù)前當(dāng)日抽取空腹肘靜脈血3 ml,分離血清后-80 ℃保存。循環(huán)中Galectin-3水平采用雙抗體夾心法進(jìn)行測定[8]。腫瘤組織Galectin-3表達(dá)采用免疫組織化學(xué)鼠抗人Galectin-3抗體染色。根據(jù)腫瘤組織表達(dá)Galectin-3染色情況將病人分為Galectin-3表達(dá)陽性組與陰性組。

1.3 統(tǒng)計(jì)學(xué)方法 采用SPSS 13.0軟件進(jìn)行統(tǒng)計(jì)學(xué)分析。正態(tài)分布計(jì)量資料以均數(shù)±標(biāo)準(zhǔn)差表示,偏態(tài)分布資料以中位數(shù)(四分位數(shù)) (Median,IQR) 表示,計(jì)數(shù)資料或等級資料采用含有頻數(shù)和頻率的列聯(lián)表表示。計(jì)量資料組間比較采用t檢驗(yàn)或方差分析,計(jì)數(shù)資料組間比較采用χ2檢驗(yàn)或Fisher精確概率法,相關(guān)關(guān)系分析采用Spearman方法,預(yù)后采用Kaplan-Meier 生存分析,P<0.05為差異有統(tǒng)計(jì)學(xué)意義。

2 結(jié)果

2.1 2組循環(huán)中Galectin-3水平比較 結(jié)腸癌病人循環(huán)中Galectin-3水平顯著高于對照組[(51.48±8.76) ng/ml比(10.29±4.91) ng/ml,P<0.001]。結(jié)腸癌病人血清CEA濃度為(153.10±124.56) ng/ml,腫瘤長徑為(47.3±8.9) mm,隨訪5年中位生存時(shí)間為4.6年。循環(huán)Galectin-3水平與血清CEA濃度、腫瘤長徑、Duke分期、TNM分期、分化程度、淋巴結(jié)轉(zhuǎn)移、遠(yuǎn)處轉(zhuǎn)移和生存時(shí)間均無相關(guān)性(P均>0.05)。

2.2 腫瘤組織表達(dá)Galectin-3情況 結(jié)腸癌病人腫瘤組織Galectin-3表達(dá)陽性52例(76.4%),Galectin-3表達(dá)陰性16例(23.6%),2組間循環(huán)Galectin-3水平差異無統(tǒng)計(jì)學(xué)意義。Galectin-3表達(dá)陽性病例較Galectin-3表達(dá)陰性病例在血清CEA濃度、腫瘤長徑、分化程度、Duke分期、TNM分期、淋巴結(jié)轉(zhuǎn)移和遠(yuǎn)處轉(zhuǎn)移差異均具有統(tǒng)計(jì)學(xué)意義(P均<0.01),見表1,且2組生存時(shí)間比較差異亦有統(tǒng)計(jì)學(xué)意義(P=0.02),見圖1。

3 討論

結(jié)腸癌嚴(yán)重威脅人類健康,據(jù)估計(jì)每年新增結(jié)腸癌病人120萬例,大約70%的結(jié)腸癌是散發(fā)的,無明確家族史和遺傳史[9-10]。尋找結(jié)腸癌診斷與判斷預(yù)后的血清學(xué)標(biāo)記物是近年來臨床重要研究方向之一。

表1 結(jié)腸癌病人Galectin-3表達(dá)陽性組與陰性組臨床與病理資料比較

項(xiàng)目Galectin-3表達(dá)陽性組(n=52)Galectin-3表達(dá)陰性組(n=16)P男性(n,%)33(63.4)9(56.3)0.66年齡( x±s,歲)61.3±2.064.3±3.90.01CEA( x±s,ng/ml)221.8±118.237.2±18.5<0.01腫瘤長徑( x±s,mm)49.6±9.043.3±7.30.03分化程度(n,%) 高分化22(42.3)12(75.0)0.01 中分化19(36.5)3(18.7) 低分化11(21.2)1(6.3)淋巴結(jié)轉(zhuǎn)移(n,%)22(42.3)4(25.0)<0.01遠(yuǎn)處轉(zhuǎn)移(n,%)13(25.0)2(12.5)<0.01Duke分期(n,%) A期15(28.8)4(25.0)<0.01 B期20(38.5)10(62.5) C期11(21.1)1(6.2) D期6(11.7)1(6.4)TNM分期(n,%) 1期12(23.0)5(31.2)0.01 2期22(42.3)9(56.2) 3期12(23.0)2(12.6) 4期6(11.7)0

圖1 腫瘤組織Galectin-3表達(dá)陽性病人與陰性病人生存時(shí)間比較

本研究對不同臨床與病理分期的結(jié)腸癌病人循環(huán)Galectin-3水平與腫瘤組織表達(dá)Galectin-3情況進(jìn)行分析。結(jié)果發(fā)現(xiàn),結(jié)腸癌病人循環(huán)Galectin-3水平遠(yuǎn)高于正常對照組,但循環(huán)Galectin-3水平與血清CEA濃度,腫瘤長徑、Duke分期、TNM分期、分化程度、淋巴結(jié)轉(zhuǎn)移、遠(yuǎn)處轉(zhuǎn)移均無顯著相關(guān)性,也與腫瘤組織表達(dá)Galectin-3的情況無相關(guān)性。該現(xiàn)象提示循環(huán)Galectin-3水平可能作為一種標(biāo)記物,具有指示病理狀態(tài)的意義,其升高機(jī)制不能僅以腫瘤細(xì)胞浸潤解釋。已知Galectin-3在激活的巨噬細(xì)胞、嗜堿性粒細(xì)胞和肥大細(xì)胞等細(xì)胞中高表達(dá),可溶性的Galectin-3以胞吐機(jī)制進(jìn)入全身循環(huán)。循環(huán)Galectin-3水平可在一定程度上反映腫瘤病人體內(nèi)炎癥負(fù)荷程度。類似研究在動(dòng)物模型與臨床觀察中都發(fā)現(xiàn)循環(huán)Galectin-3水平與血清粒細(xì)胞集落刺激因子(G-CSF)、白介素(IL)-6和可溶性細(xì)胞間黏附分子(sICAM)-1等炎癥因子濃度均相關(guān)[11-12]。由于Galectin-3表達(dá)與巨噬細(xì)胞的替代途徑活化(M2型)密切相關(guān),我們推測腫瘤組織浸潤的單個(gè)核細(xì)胞可能是循環(huán)Galectin-3的重要來源,至少在腫瘤組織表達(dá)Galectin-3陰性病例應(yīng)是如此。但在組織病理水平,我們未對M2型巨噬細(xì)胞進(jìn)行鑒定，因而上述推測有待進(jìn)一步研究驗(yàn)證。

本研究在結(jié)腸癌切除組織中對Galectin-3表達(dá)情況與病人臨床病理分期及預(yù)后的關(guān)系進(jìn)行分析,發(fā)現(xiàn)腫瘤組織表達(dá)Galectin-3陽性病例與Galectin-3陰性病例在血清CEA濃度、腫瘤長徑、Duke分期、TNM分期、分化程度、淋巴結(jié)轉(zhuǎn)移、遠(yuǎn)處轉(zhuǎn)移和生存時(shí)間上的差異均有統(tǒng)計(jì)學(xué)意義。既往研究認(rèn)為,Galectin-3在細(xì)胞黏附、腫瘤細(xì)胞浸潤與轉(zhuǎn)移中具有一定作用,也有促有絲分裂作用[6-7]。本研究進(jìn)一步肯定了分析組織水平Galectin-3表達(dá)情況對于臨床的重要價(jià)值。有關(guān)腫瘤組織Galectin-3表達(dá)與預(yù)后關(guān)系,可能與黏蛋白(mucin)基因MUC2表達(dá)[13]或凋亡[14]有關(guān),但本研究對相關(guān)機(jī)制未進(jìn)行探討。

總之,老年結(jié)腸癌病人循環(huán)Galectin-3水平顯著升高,腫瘤組織Galectin-3表達(dá)情況可預(yù)示病情和預(yù)后。

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Clinical and prognostic effects of Galectin-3 in elderly patients with colorectal cancer

RENLi-Li,GENGJian.

DepartmentofMedicalOncology,JinlingHospital,SchoolofMedicine,NanjingUniversity,Nanjing210002,China

Objective To evaluate the clinical relevance and prognostic effects of Galectin-3 in elderly patients with colorectal cancer. Methods Sixty-eight old patients with colorectal cancer who received surgical resection were enrolled in this study. The expression of Galectin-3 in tissue sections was evaluated using immunohistochemical staining. Serum level of Galectin-3 was measured using an enzyme-linked immunosorbent assay. In addition, fifty healthy volunteers were chosen as controls. The relationship of Galectin-3 expression in tissue sections and serum level of Galectin-3 with clinicopathological factors and prognosis was analyzed. Results Serum level of Galectin-3 was higher in the patients with colorectal cancer compared to the control group (P<0.001). Serum level of Galectin-3 was not significantly associated with tumor size, distant metastasis, TNM stage and prognosis in the patients with colorectal cancer. Patients with positive expression of Galectin-3 showed higher carcinoembryonic antigen level, tumor size, higher Dukes’ stage and TNM Stage, higher incidence of lymph node and distant metastasis than those with negative expression of Galectin-3 (P<0.01, respectively). However, the survival period in patients with positive expression of Galectin-3 was significantly poorer than those with negative expression of Galectin-3(P<0.01). Conclusions Serum level of Galectin-3 increases in the patients with colorectal cancer. Galectin-3 expression in tissue sections is an independent factor for the severity degree of the disease and prognosis of colorectal cancer.

aged; colorectal cancer; Galectin-3; prognosis

210002江蘇省南京市，南京大學(xué)醫(yī)學(xué)院附屬金陵醫(yī)院腫瘤內(nèi)科

耿建，Email: 1046772254@qq.com

R 735.35

A

10.3969/j.issn.1003-9198.2017.02.015

2016-03-07)