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目的:探讨小白菊内酯(parthenolide,PTL)对小鼠乳腺癌肿瘤干细胞(cancer stem cell,CSC)的杀伤作用,为临床应用PTL治疗乳腺癌提供实验依据。方法:采用5-氟尿嘧啶(5-fluorouracil,5-FU)化疗法制备富含CSC的小鼠4T1细胞乳腺癌模型,随机分为对照组、5-FU组、PTL组。4周后脱颈处死小鼠,检测各组小鼠肿瘤的体积和重量,流式细胞术检测小鼠肿瘤组织中CD44+CD24-/low细胞比例,Hoechst33342染色法检测侧群(side population,SP)细胞的比例,免疫组化法检测CD55和乙醛脱氢酶1(aldehyde dehydrogenase1,ALDH1)蛋白的表达,倒置显微镜观察乳腺癌细胞微球体的形成。结果:成功制备富含CSC的小鼠乳腺癌细胞移植瘤模型,PTL可下调小鼠肿瘤组织中CD44+CD24-/low细胞的比例[(42.5±3.7)%vs(68.7±3.2)%,P<0.05],有效降低荷瘤小鼠肿瘤组织中SP细胞的比例[(39.2±1.8)%vs(61.3±2.6)%,P<0.05],下调小鼠移植瘤组织中CD55和ALDH1蛋白的表达[(18.9±1.5)%vs(30.1±1.3)%,(8.1±2.3)%vs(18.0±1.4)%;均P<0.05],抑制小鼠肿瘤细胞在无血清培养条件下形成微球体,并可抑制小鼠移植瘤的体积和重量[(0.625±0.159)cm3vs(1.715±0.184)cm3,(1.467±0.373)g vs(3.367±0.398)g;均P<0.05]。结论:PTL在荷瘤小鼠体内可以明显降低肿瘤组织CSC含量,提示PTL可用来靶向杀伤乳腺癌CSC。
Objective: To investigate the killing effect of parthenolide (PTL) on mouse breast cancer stem cells (CSCs), and to provide experimental evidence for the clinical application of PTL in the treatment of breast cancer. Methods: CST-rich mouse model of 4T1 breast cancer was established by 5-fluorouracil (5-FU) chemotherapy and randomly divided into control group, 5-FU group and PTL group. After 4 weeks, the mice were sacrificed and their tumor size and weight were measured. The proportion of CD44 + CD24- / low cells in the tumor tissue was detected by flow cytometry. The side population (SP) was detected by Hoechst33342 staining ) Cells. The expression of CD55 and aldehyde dehydrogenase 1 (ALDH1) protein were detected by immunohistochemistry. The formation of microspheres in breast cancer cells was observed by inverted microscope. RESULTS: CSC-rich mouse breast cancer xenografts model was successfully established. PTL could down-regulate the proportion of CD44 + CD24- / low cells in tumor tissues [(42.5 ± 3.7)% vs (68.7 ± 3.2)%, P <0.05], and decreased the percentage of SP cells in tumor-bearing mice ([(39.2 ± 1.8)% vs (61.3 ± 2.6)%, P <0.05] [(18.9 ± 1.5)% vs (30.1 ± 1.3)%, (8.1 ± 2.3)% vs (18.0 ± 1.4)%, all P <0.05] inhibited the formation of microspheres in mouse serum- (0.625 ± 0.159) cm3vs (1.715 ± 0.184) cm3, (1.467 ± 0.373) g vs (3.367 ± 0.398) g; all P <0.05]. Conclusion: PTL in tumor-bearing mice can significantly reduce the CSC content in tumor tissue, suggesting that PTL can be used to target breast cancer CSC.