前列腺癌干细胞放化疗富集鉴定及其化疗耐药机制的研究
发布时间：2018-08-20 10:53
【摘要】：第一部分无血清培养、化疗及放疗富集前列腺癌干细胞的研究 目的：肿瘤干细胞(Cancer stem cells, CSCs)的发现为肿瘤研究及治疗带来了新的希望,但由于其在肿瘤细胞中所占比例极低,较难获得数量充足的CSCs以对其进行深入的研究。因此,我们采用三系前列腺癌细胞通过无血清悬球培养法、化疗药物法及放射治疗法三种方法分别富集前列腺癌干细胞,为前列腺癌干细胞领域的研究奠定基础。 方法：分别用含血清的培养基及添加了人表皮生长因子(EGF)、人碱性成纤维细胞生长因子(bFGF)和人白血病抑制因子(LIF)的无血清培养基培养DU145、PC-3、LNCap前列腺癌细胞,流式细胞仪检测两种不同培养条件下三系细胞中CD133+/CD44+前列腺癌干细胞的含量。采用无血清悬球培养法、化疗药物法(多西紫杉醇0.1μM)及放射治疗法(4Gy/次,2次／周,连续照射两周)三种方法分别富集DU145细胞中CD133+/CD44+前列腺癌干细胞,并使用流式细胞仪检测三种方法富集后DU145细胞中CD133+/CD44+前列腺癌干细胞的含量。 结果：在含血清的常规贴壁培养条件下,三系细胞中仅有DU145细胞能检测到CD133+/CD44+细胞,且含量极低(0.1%±0.01%)。少量DU145细胞和PC-3细胞能够在无血清培养基中存活并形成悬浮细胞球,且无血清悬球培养后两种细胞中CD133+/CD44+前列腺癌干细胞比例显著增高(DU145:10.3%; PC-3:3.0%)。使用化疗药物多西紫杉醇富集后DU145细胞中CD133+/CD44+前列腺癌干细胞比例增高至9.8%,放疗富集后DU145细胞中CD133+/CD44+前列腺癌干细胞比例增高至3.5%。 结论：常规培养条件下,前列腺癌三系细胞仅DU145细胞系中可检测到极微量的CD133+/CD44+前列腺癌干细胞。经无血清悬球培养富集后,在DU145及PC-3细胞系中可检测到CD133+/CD44+前列腺癌干细胞,而LNCap细胞中未能检测到。通过化疗及放疗富集后,DU145细胞中CD133+/CD44+前列腺癌干细胞比例明显上升。无血清培养、化疗及放疗三种方法均能有效富集CD133+/CD44+前列腺癌干细胞,为后期前列腺癌干细胞特性研究奠定基础。 第二部分CD133+/CD44+前列腺癌干细胞特性研究 目的：肿瘤干细胞(Cancer stem cells, CSCs)具有无限增殖、自我更新及多向分化潜能,是“肿瘤的种子”,是驱动肿瘤形成和生长、保持肿瘤异质性并促进肿瘤无限增殖、复发和转移的根源,也是化疗和放疗抵抗的重要原因之一。我们将富集、分选出的CD133+/CD44+前列腺癌干细胞通过体内、体外实验进一步证实其CSCs特性。 方法：DU145细胞经无血清培养富集后,利用流式细胞仪分选出CD133+/CD44+前列腺癌干细胞。平板克隆形成实验及Transwell细胞侵袭实验比较CD133+/CD44+DU145细胞和未分选亲代DU145细胞的增殖能力及侵袭性的差异。20只雄性BALB/c裸鼠,随机分为实验组(10只)及对照组(10只),分别皮下注射CD133+/CD44+DU145细胞(1×104)及未分选亲代DU145细胞(1×106),比较二者体内致瘤能力的差异。 结果：研究结果显示,在平板克隆形成实验中CD133+/CD44+DU145细胞的克隆形成率(colony-formation efficiency, CFE)为68.5±4.7%,而未分选亲代DU145细胞的CFE为19.7±3.4%,差异有统计学意义(P0.001)。在Transwell细胞侵袭实验中,显微镜下计数穿透小室膜的CD133+/CD44+DU145细胞数与未分选亲代DU145细胞数分别为416±47与109±24,差异有统计学意义(P0.001)。在裸鼠移植瘤实验中,实验组中10只裸鼠全部荷瘤成功,而对照组中仅有5只裸鼠荷瘤成功,同时实验组的出瘤时间早于对照组,且出瘤后生长速度显著快于对照组(P0.001)。 结论：体外和体内实验证实CD133+/CD44+DU145细胞与未分选亲代DU145细胞相比具有更高的增殖、侵袭能力及更强的致瘤能力,证实其具有干细胞特性,为前列腺癌干细胞。 第三部分Notch-1在前列腺癌干细胞化疗耐药中的作用研究 目的：目前针对肿瘤干细胞(Cancer stem cells.CSCs)耐药机制的研究,成为干细胞研究领域的热点也是难点。肿瘤干细胞产生耐药的机制相当复杂,目前尚不完全清楚。Notch信号通路在进化上高度保守,调控着细胞的增殖、分化、生存和凋亡,在细胞命运决定中起关键作用。最近的研究显示Notch信号通路与肿瘤耐药有关,NOtch通路能调控CSCs的形成以及上皮间质化(Epithelial-mesenchymal transition, EMT),这都与肿瘤的化疗耐药密切相关.以Notch信号通路为靶标的基因疗法及新药开发将为肿瘤耐药,特别是CSCs耐药研究开辟新的领域。我们将进一步探讨Notch-1在CD133+/CD44+前列腺癌干细胞化疗耐药中的作用,以期为前列腺癌的治疗提供新的靶点。 方法：MTT实验分别检测CD133+/CD44+DU145细胞及未分选亲代DU145细胞对化疗药物多西紫杉醇的敏感性。Real-time PCR分别检测两者中干细胞特有基因(Oct-4、Nanog)和Notch-1mRNA表达量的差异。6-8周的雄性BALB/c裸鼠16只,DU145细胞裸鼠移植瘤造模成功后,随机分为两组,实验组(8只),给予多西紫杉醇化疗,剂量为10mg/kg,每周一次,连续3周；对照组(8只)：未行化疗。3周后,裸鼠被处以安乐死,分别剥取对照组裸鼠皮下移植瘤及实验组裸鼠皮下残存肿瘤行Notch-1、Jagged-1的检测及流式细胞检测CD133+/CD44+前列腺癌干细胞的含量。 结果：研究结果显示,在MTT实验中给予不同浓度化疗药物多西紫杉醇48h后,CD133+/CD44+DU145细胞存活显著多于未经分选的亲代DU145细胞(P0.05),与第一部分实验中化疗富集CD133+/CD44+DU145前列腺癌干细胞结果一致。在相同多西紫杉醇浓度下,其对CD133+/CD44+DU145细胞的抑制率显著低于亲代DU145细胞,多西紫杉醇对CD133+/CD44+DU145细胞及亲代DU145细胞的IC50分别为0.075μM和0.665μM,耐药指数为8.87。Real-time PCR实验结果显示CD133+/CD44+DU145细胞与未分选亲代DU145细胞相比,高表达干细胞特定基因：Nanog、Oct-4,并且Notch-1表达水平显著增高(P0.01)。裸鼠移植瘤实验中,实验组与对照组相比,Notch-1、Jagged-1表达明显增高；流式细胞检测实验组残存肿瘤中CD133+/CD44+前列腺癌干细胞比例显著高于对照组(实验组：2.6%；对照组：0.1%)。 结论：CD133+/CD44+DU145前列腺癌干细胞对多西紫杉醇具有化疗耐药性,且高表达Notch-1。化疗后残存肿瘤高表达Notch-1、Jagged-1,且CD133+/CD44+前列腺癌干细胞比例显著升高,提示CD133+/CD44+前列腺癌干细胞对化疗耐药,Notch-1可能在前列腺癌干细胞化疗耐药中起一定作用。
[Abstract]:The first part is a study on the enrichment of prostate cancer stem cells by serum-free culture, chemotherapy and radiotherapy.
Objective: The discovery of cancer stem cells (CSCs) has brought new hope for tumor research and treatment, but because of its very low proportion in tumor cells, it is difficult to obtain enough CSCs for further study. Prostate cancer stem cells can be enriched by three methods: biological method and radiotherapy, which lay a foundation for the research of prostate cancer stem cells.
Methods: Du145, PC-3, LNCap prostate cancer cells were cultured in serum-containing medium and serum-free medium supplemented with human epidermal growth factor (EGF), human basic fibroblast growth factor (bFGF) and human leukemia inhibitory factor (LIF). CD133 +/CD44 + prostate cancer cells were detected by flow cytometry under two different culture conditions. The concentration of CD133 + / CD44 + prostate cancer stem cells in DU145 cells was enriched by serum-free suspension culture, chemotherapy (docetaxel 0.1 mu M) and radiotherapy (4 G Y / time, 2 times / week, continuous irradiation for 2 weeks), respectively. CD133 + / CD44 + prostate cancer stem cells in DU145 cells were detected by flow cytometry. The content of prostate cancer stem cells.
Results: Only DU145 cells could detect CD133 + / CD44 + cells in the three cell lines under the normal adherent culture condition with serum, and the content was very low (0.1% + 0.01%). The proportion of CD133 + / CD44 + prostate cancer stem cells in DU145 cells was increased to 9.8% after enrichment with chemotherapy drug docetaxel, and the proportion of CD133 + / CD44 + prostate cancer stem cells in DU145 cells was increased to 3.5% after enrichment with radiotherapy.
Conclusion: CD133 + / CD44 + prostate cancer stem cells can be detected only in DU145 cell lines under conventional culture conditions. CD133 + / CD44 + prostate cancer stem cells can be detected in DU145 and PC-3 cell lines after enrichment by serum-free suspension culture, but not in LNCap cell lines. The proportion of CD133 +/CD44 + prostate cancer stem cells in DU145 cells increased significantly after collection. Serum-free culture, chemotherapy and radiotherapy could effectively enrich CD133 +/CD44 + prostate cancer stem cells, which laid a foundation for the study of the characteristics of prostate cancer stem cells in the later stage.
The second part of CD133+/CD44+ prostate cancer stem cell characteristics
Objective: Cancer stem cells (CSCs) have the potential of infinite proliferation, self-renewal and multidirectional differentiation. They are the seeds of tumor, which drive tumor formation and growth, maintain tumor heterogeneity and promote tumor infinite proliferation, recurrence and metastasis. They are also one of the important reasons for chemotherapy and radiotherapy resistance. The CD133+/CD44+ prostate cancer stem cells were further confirmed by CSCs in vivo and in vitro.
Methods: CD133 + / CD44 + prostate cancer stem cells were separated by flow cytometry after enrichment of DU145 cells in serum-free medium. The proliferation and invasiveness of CD133 + / CD44 + DU145 cells and their unselected parental DU145 cells were compared by plate cloning assay and Transwell cell invasion assay. Twenty male BALB / C nude mice were randomly divided into two groups. The experimental group (10 rats) and the control group (10 rats) were subcutaneously injected with CD133+/CD44+DU145 cells (1 X 104) and the unselected parental DU145 cells (1 X 106), respectively. The differences of tumorigenicity between the two groups were compared.
Results: The results showed that the colony-formation efficiency (CFE) of CD133+/CD44+DU145 cells was 68.5 (+ 4.7%) and that of unselected parent DU145 cells was 19.7 (+ 3.4%). There was a significant difference in the number of CD133+/CD44+DU145 cells penetrating the ventricular membranes in the Transwell cell invasion test (P 0.001). The number of CD133+/CD44+DU145 cells and the number of unselected parental DU145 cells were 416+47 and 109+24, respectively. The difference was statistically significant (P 0.001). In the nude mice transplantation experiment, all the 10 nude mice in the experimental group were successful in tumor-bearing, while only 5 nude mice in the control group were successful in tumor-bearing. The degree was significantly faster than that of the control group (P0.001).
CONCLUSION: CD133+/CD44+DU145 cells have higher proliferation, invasion and tumorigenicity than the unselected parental DU145 cells in vitro and in vivo. It is proved that CD133+/CD44+DU145 cells have the characteristics of stem cells and are prostate cancer stem cells.
The third part is the role of Notch-1 in chemoresistance of prostate cancer stem cells.
OBJECTIVE: At present, the mechanism of drug resistance of cancer stem cells (CSCs) has become a hot and difficult point in the field of stem cell research. Recent studies have shown that Notch signaling pathway is associated with tumor resistance, and NOtch signaling pathway can regulate the formation of CSCs and epithelial-mesenchymal transition (EMT), which are closely related to chemotherapeutic drug resistance. We will explore the role of Notch-1 in the chemoresistance of CD133+/CD44+ prostate cancer stem cells in order to provide a new target for the treatment of prostate cancer.
METHODS: MTT assay was used to detect the sensitivity of CD133 +/CD44 + DU145 cells to docetaxel. Real-time PCR was used to detect the differences of stem cell-specific gene (Oct-4, Nanog) and Notch-1 mRNA expression between CD133 +/CD44 + DU145 cells and non-selected parental DU145 cells. After 3 weeks of chemotherapy, the nude mice were euthanized. The nude mice in the control group and the nude mice in the experimental group underwent Notch-1, Jagged-1 detection and flow cytometry respectively. The content of CD133+/CD44+ prostate cancer stem cells was measured.
Results: The results showed that CD133 + / CD44 + DU145 cells survived significantly more than their unselected parental DU145 cells (P 0.05) 48 hours after treatment with different concentrations of docetaxel in MTT assay, consistent with the results of CD133 + / CD44 + DU145 prostate cancer stem cells enriched by chemotherapy in the first experiment. The inhibitory rate of docetaxel on CD133+/CD44+DU145 cells was significantly lower than that of parental DU145 cells. The IC50 of docetaxel on CD133+/CD44+DU145 cells and parental DU145 cells were 0.075 and 0.665 mu M, respectively. The resistance index was 8.87. Real-time PCR results showed that CD133+/CD44+DU145 cells expressed stem cell-specific characteristics higher than that of parental DU145 cells. The expression of Notch-1 and Jagged-1 was significantly higher in nude mice than in the control group. The proportion of CD133+/CD44+ prostate cancer stem cells in the experimental group was significantly higher than that in the control group (experimental group: 2.6%; control group: 0.1%).
Conclusion: CD133+/CD44+DU145 prostate cancer stem cells are resistant to docetaxel and highly express Notch-1. After chemotherapy, the remaining tumors overexpress Notch-1 and Jagged-1, and the proportion of CD133+/CD44+ prostate cancer stem cells is significantly increased, suggesting that CD133+/CD44+ prostate cancer stem cells are resistant to chemotherapy. Notch-1 may be dry and thin in prostate cancer. Cellular chemotherapy plays a role in drug resistance.
【学位授予单位】：武汉大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R737.25
本文编号：2193331
[Abstract]:The first part is a study on the enrichment of prostate cancer stem cells by serum-free culture, chemotherapy and radiotherapy.
Objective: The discovery of cancer stem cells (CSCs) has brought new hope for tumor research and treatment, but because of its very low proportion in tumor cells, it is difficult to obtain enough CSCs for further study. Prostate cancer stem cells can be enriched by three methods: biological method and radiotherapy, which lay a foundation for the research of prostate cancer stem cells.
Methods: Du145, PC-3, LNCap prostate cancer cells were cultured in serum-containing medium and serum-free medium supplemented with human epidermal growth factor (EGF), human basic fibroblast growth factor (bFGF) and human leukemia inhibitory factor (LIF). CD133 +/CD44 + prostate cancer cells were detected by flow cytometry under two different culture conditions. The concentration of CD133 + / CD44 + prostate cancer stem cells in DU145 cells was enriched by serum-free suspension culture, chemotherapy (docetaxel 0.1 mu M) and radiotherapy (4 G Y / time, 2 times / week, continuous irradiation for 2 weeks), respectively. CD133 + / CD44 + prostate cancer stem cells in DU145 cells were detected by flow cytometry. The content of prostate cancer stem cells.
Results: Only DU145 cells could detect CD133 + / CD44 + cells in the three cell lines under the normal adherent culture condition with serum, and the content was very low (0.1% + 0.01%). The proportion of CD133 + / CD44 + prostate cancer stem cells in DU145 cells was increased to 9.8% after enrichment with chemotherapy drug docetaxel, and the proportion of CD133 + / CD44 + prostate cancer stem cells in DU145 cells was increased to 3.5% after enrichment with radiotherapy.
Conclusion: CD133 + / CD44 + prostate cancer stem cells can be detected only in DU145 cell lines under conventional culture conditions. CD133 + / CD44 + prostate cancer stem cells can be detected in DU145 and PC-3 cell lines after enrichment by serum-free suspension culture, but not in LNCap cell lines. The proportion of CD133 +/CD44 + prostate cancer stem cells in DU145 cells increased significantly after collection. Serum-free culture, chemotherapy and radiotherapy could effectively enrich CD133 +/CD44 + prostate cancer stem cells, which laid a foundation for the study of the characteristics of prostate cancer stem cells in the later stage.
The second part of CD133+/CD44+ prostate cancer stem cell characteristics
Objective: Cancer stem cells (CSCs) have the potential of infinite proliferation, self-renewal and multidirectional differentiation. They are the seeds of tumor, which drive tumor formation and growth, maintain tumor heterogeneity and promote tumor infinite proliferation, recurrence and metastasis. They are also one of the important reasons for chemotherapy and radiotherapy resistance. The CD133+/CD44+ prostate cancer stem cells were further confirmed by CSCs in vivo and in vitro.
Methods: CD133 + / CD44 + prostate cancer stem cells were separated by flow cytometry after enrichment of DU145 cells in serum-free medium. The proliferation and invasiveness of CD133 + / CD44 + DU145 cells and their unselected parental DU145 cells were compared by plate cloning assay and Transwell cell invasion assay. Twenty male BALB / C nude mice were randomly divided into two groups. The experimental group (10 rats) and the control group (10 rats) were subcutaneously injected with CD133+/CD44+DU145 cells (1 X 104) and the unselected parental DU145 cells (1 X 106), respectively. The differences of tumorigenicity between the two groups were compared.
Results: The results showed that the colony-formation efficiency (CFE) of CD133+/CD44+DU145 cells was 68.5 (+ 4.7%) and that of unselected parent DU145 cells was 19.7 (+ 3.4%). There was a significant difference in the number of CD133+/CD44+DU145 cells penetrating the ventricular membranes in the Transwell cell invasion test (P 0.001). The number of CD133+/CD44+DU145 cells and the number of unselected parental DU145 cells were 416+47 and 109+24, respectively. The difference was statistically significant (P 0.001). In the nude mice transplantation experiment, all the 10 nude mice in the experimental group were successful in tumor-bearing, while only 5 nude mice in the control group were successful in tumor-bearing. The degree was significantly faster than that of the control group (P0.001).
CONCLUSION: CD133+/CD44+DU145 cells have higher proliferation, invasion and tumorigenicity than the unselected parental DU145 cells in vitro and in vivo. It is proved that CD133+/CD44+DU145 cells have the characteristics of stem cells and are prostate cancer stem cells.
The third part is the role of Notch-1 in chemoresistance of prostate cancer stem cells.
OBJECTIVE: At present, the mechanism of drug resistance of cancer stem cells (CSCs) has become a hot and difficult point in the field of stem cell research. Recent studies have shown that Notch signaling pathway is associated with tumor resistance, and NOtch signaling pathway can regulate the formation of CSCs and epithelial-mesenchymal transition (EMT), which are closely related to chemotherapeutic drug resistance. We will explore the role of Notch-1 in the chemoresistance of CD133+/CD44+ prostate cancer stem cells in order to provide a new target for the treatment of prostate cancer.
METHODS: MTT assay was used to detect the sensitivity of CD133 +/CD44 + DU145 cells to docetaxel. Real-time PCR was used to detect the differences of stem cell-specific gene (Oct-4, Nanog) and Notch-1 mRNA expression between CD133 +/CD44 + DU145 cells and non-selected parental DU145 cells. After 3 weeks of chemotherapy, the nude mice were euthanized. The nude mice in the control group and the nude mice in the experimental group underwent Notch-1, Jagged-1 detection and flow cytometry respectively. The content of CD133+/CD44+ prostate cancer stem cells was measured.
Results: The results showed that CD133 + / CD44 + DU145 cells survived significantly more than their unselected parental DU145 cells (P 0.05) 48 hours after treatment with different concentrations of docetaxel in MTT assay, consistent with the results of CD133 + / CD44 + DU145 prostate cancer stem cells enriched by chemotherapy in the first experiment. The inhibitory rate of docetaxel on CD133+/CD44+DU145 cells was significantly lower than that of parental DU145 cells. The IC50 of docetaxel on CD133+/CD44+DU145 cells and parental DU145 cells were 0.075 and 0.665 mu M, respectively. The resistance index was 8.87. Real-time PCR results showed that CD133+/CD44+DU145 cells expressed stem cell-specific characteristics higher than that of parental DU145 cells. The expression of Notch-1 and Jagged-1 was significantly higher in nude mice than in the control group. The proportion of CD133+/CD44+ prostate cancer stem cells in the experimental group was significantly higher than that in the control group (experimental group: 2.6%; control group: 0.1%).
Conclusion: CD133+/CD44+DU145 prostate cancer stem cells are resistant to docetaxel and highly express Notch-1. After chemotherapy, the remaining tumors overexpress Notch-1 and Jagged-1, and the proportion of CD133+/CD44+ prostate cancer stem cells is significantly increased, suggesting that CD133+/CD44+ prostate cancer stem cells are resistant to chemotherapy. Notch-1 may be dry and thin in prostate cancer. Cellular chemotherapy plays a role in drug resistance.
【学位授予单位】：武汉大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R737.25
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