本文選題：膠質(zhì)瘤干細(xì)胞　切入點(diǎn)：喹硫平　出處：《第三軍醫(yī)大學(xué)》2015年博士論文　論文類(lèi)型：學(xué)位論文

【摘要】：惡性膠質(zhì)瘤細(xì)胞對(duì)放療、化療不敏感,導(dǎo)致其臨床治愈率低,術(shù)后復(fù)發(fā)率居高不下,患者5年存活率不到5%。因此,探尋該疾病行之有效的治療途徑,發(fā)現(xiàn)相應(yīng)的生物學(xué)治療途徑至關(guān)重要。膠質(zhì)瘤干細(xì)胞(glioma stem-like cells,GSLCs)是膠質(zhì)瘤組織中存在的極少數(shù)具有高度抵抗放療和化療的細(xì)胞,具有無(wú)限增殖和多向分化能力,可以分化為神經(jīng)元表型細(xì)胞,星形膠質(zhì)細(xì)胞表型細(xì)胞以及少突膠質(zhì)細(xì)胞表型細(xì)胞。GSLCs概念的提出為膠質(zhì)瘤治療提供了重要靶點(diǎn),因此尋找能夠促進(jìn)GSLCs定向分化藥物可能為臨床治療膠質(zhì)瘤提供新的途徑。流行病學(xué)調(diào)查發(fā)現(xiàn)一個(gè)有趣的現(xiàn)象:精神分裂癥患者的腫瘤發(fā)病率比正常人群明顯減少。研究人員發(fā)現(xiàn)多種抗精神病藥如氯丙嗪、奧氮平、利培酮等,均能明顯抑制膠質(zhì)母細(xì)胞瘤細(xì)胞系IMR32細(xì)胞增生,且對(duì)正常細(xì)胞影響甚微。喹硫平(Quetiapine,QUE)是繼氯氮平、利培酮和奧氮平之后的第4個(gè)非典型抗精神病藥物。本課題組前期研究首次發(fā)現(xiàn)喹硫平能顯著增加神經(jīng)干細(xì)胞(neuronal stem cells,NSCs)分化為少突膠質(zhì)細(xì)胞的比例,并能進(jìn)一步促進(jìn)少突膠質(zhì)細(xì)胞的成熟及髓鞘形成。我們?cè)趯?shí)驗(yàn)中還發(fā)現(xiàn)QUE能促進(jìn)少突膠質(zhì)前體細(xì)胞(oligodendrocyte progenitor cells,OPCs)分化成熟,考慮GSLCs與NSCs,OPCs關(guān)系密切,我們提出QUE可能具有抑制GSLCs增殖及促進(jìn)GSLCs定向分化為少突膠質(zhì)細(xì)胞表型的潛能。本研究利用GSLCs培養(yǎng)和移植成瘤模型,研究了QUE對(duì)膠質(zhì)瘤發(fā)生發(fā)展的作用,及其與膠質(zhì)瘤一線治療藥物替莫唑胺(Temozolomide,TMZ)的聯(lián)合藥效,探討了QUE對(duì)GSLCs增殖分化的調(diào)節(jié)作用及可能的分子機(jī)制研究總共分為三個(gè)部分:第一部分:喹硫平抑制膠質(zhì)瘤生長(zhǎng)的作用利用無(wú)血清條件培養(yǎng)系統(tǒng)從膠質(zhì)母細(xì)胞瘤細(xì)胞系GL261中篩選獲得膠質(zhì)瘤干細(xì)胞,建立膠質(zhì)瘤原位及皮下成瘤模型,分別采用QUE、TMZ以及二者聯(lián)合治療等方式,運(yùn)用熒光素酶活體成像技術(shù)、動(dòng)物行為學(xué)、HE染色、免疫組織化學(xué)和Western blot等方法檢測(cè)各種治療方式對(duì)膠質(zhì)瘤發(fā)生和生長(zhǎng)特性的作用。最后為了進(jìn)一步檢驗(yàn)QUE可能作用于GSLCs而抑制膠質(zhì)瘤的產(chǎn)生或生長(zhǎng)。我們分別對(duì)GSLCs移植裸鼠皮下成瘤以及腦室成瘤后使用TMZ 21天來(lái)殺死腫瘤細(xì)胞,停藥后再分別給予生理鹽水和QUE治療,利用熒光素酶活體成像技術(shù)觀察膠質(zhì)瘤的生長(zhǎng)情況。主要結(jié)果如下:1.免疫熒光染色顯示無(wú)血清培養(yǎng)條件下篩選GL261獲得的細(xì)胞表達(dá)腫瘤干細(xì)胞(cancer stem cells,CSCs)標(biāo)記物CD133、Sox2、NG2和Nestin,加入10%胎牛血清分化10天后大部分細(xì)胞表達(dá)神經(jīng)膠質(zhì)酸性蛋白(glial fibrillary acidic protein,GFAP),少部分表達(dá)髓鞘堿性蛋白(myelin basic protein,MBP)。以上結(jié)果表明所獲得細(xì)胞具有膠質(zhì)瘤干細(xì)胞特性,為膠質(zhì)瘤干細(xì)胞GSLCs。2.GSLCs皮下移植裸后7天后可見(jiàn)小的瘤體形成,21天后瘤體平均直徑達(dá)到1.5cm,而QUE處理組、TMZ處理組及QUE聯(lián)合TMZ組,成瘤時(shí)間均有所推遲,瘤體平均體積也小于對(duì)照組,其中尤以QUE聯(lián)合TMZ療效最明顯。組織學(xué)病理檢測(cè)發(fā)現(xiàn),治療組明顯減少了膠質(zhì)瘤細(xì)胞的分裂潛能,即核分裂像減少,增殖細(xì)胞核抗原(proliferating cell nuclear antigen,PCNA)陽(yáng)性細(xì)胞明顯減少。而同對(duì)照組相比,治療組,尤其是QUE和TMZ聯(lián)合治療組,Olig2陽(yáng)性細(xì)胞明顯減少,而MBP陽(yáng)性細(xì)胞則明顯增多(P0.01)。Western blot結(jié)果顯示QUE和QUE聯(lián)合TMZ治療組MBP表達(dá)明顯增多,而Vimentin,GFAP表達(dá)下降(P0.05)。3.GSLCs腦室移植后,活體熒光成像顯示小鼠于1周后出現(xiàn)腫瘤,而QUE,TMZ治療后腫瘤大小有所減少,而二者聯(lián)合用藥后腫瘤最小,動(dòng)物成活率增加。行為學(xué)曠場(chǎng)實(shí)驗(yàn)顯示,藥物治療組小鼠較原位腦膠質(zhì)瘤模型小鼠活動(dòng)總路程明顯提高(P0.05),提示其活動(dòng)能力保留較好。QUE對(duì)膠質(zhì)瘤生長(zhǎng)有抑制作用,而且QUE聯(lián)合替莫唑胺能更好抑制膠質(zhì)瘤生長(zhǎng),降低其惡性程度。4.TMZ治療21天后腫瘤生長(zhǎng)明顯抑制,但停藥后1周后,殘留的膠質(zhì)瘤干細(xì)胞開(kāi)始生長(zhǎng)至瘤。而QUE處理組,腫瘤生長(zhǎng)明顯減慢,大小明顯減小(P0.05)。說(shuō)明QUE可能抑制GSLCs增殖或促進(jìn)其分化。本部分實(shí)驗(yàn)說(shuō)明QUE對(duì)膠質(zhì)瘤的生長(zhǎng)有一定的抑制作用,而且QUE聯(lián)合替莫唑胺能更好抑制膠質(zhì)瘤生長(zhǎng),降低其惡性程度。這些結(jié)果提示QUE可能對(duì)GSLCs生長(zhǎng)分化有一定的影響。第二部分:喹硫平對(duì)腫瘤干細(xì)胞增殖及分化的作用為了證明QUE可能作用于GSLCs而抑制膠質(zhì)瘤干細(xì)胞的產(chǎn)生或生長(zhǎng)。我們利用無(wú)血清條件培養(yǎng)系統(tǒng)從膠質(zhì)母細(xì)胞瘤細(xì)胞系GL261中篩選獲得膠質(zhì)瘤干細(xì)胞,用MTT,RT-PCR,流式細(xì)胞檢測(cè)等技術(shù)觀察不同濃度QUE對(duì)膠質(zhì)瘤干細(xì)胞增殖作用。用免疫熒光及Western blot來(lái)檢測(cè)不同濃度QUE對(duì)膠質(zhì)瘤干細(xì)胞分化作用。主要結(jié)果如下:1.體外實(shí)驗(yàn)顯示QUE濃度50、100μmol/L能明顯抑制GSLCs的生長(zhǎng),懸浮的球團(tuán)明顯小于對(duì)照組(P0.01)。MTT實(shí)驗(yàn)也證實(shí)了QUE的抑制效應(yīng)(P0.01)。流式細(xì)胞檢測(cè)中QUE明顯減少S期細(xì)胞(P0.05),而且能顯著減少膠質(zhì)瘤干細(xì)胞中Sox2及Ki67的基因表達(dá)(P0.01)。2.以1%胎牛血清誘導(dǎo)GSLCs分化過(guò)程中,QUE處理可顯著提高少突膠質(zhì)細(xì)胞成熟蛋白MBP及CC1陽(yáng)性細(xì)胞數(shù);而且濃度依賴性降低干細(xì)胞因子Sox2,Olig2蛋白表達(dá)(P0.05),而升高少突膠質(zhì)細(xì)胞相關(guān)因子MBP,Olig1蛋白表達(dá)(P0.05)。本部分實(shí)驗(yàn)結(jié)果表明QUE能抑制膠質(zhì)瘤干細(xì)胞增殖并且能促進(jìn)其向類(lèi)似少突膠質(zhì)細(xì)胞分化。第三部分:喹硫平促進(jìn)膠質(zhì)瘤干細(xì)胞分化的分子機(jī)制初探由于Wnt/β-catenin通路在GSLCs增殖分化中發(fā)揮了至關(guān)重要的作用,而且QUE的抗精神病的藥物機(jī)制也涉及該途徑,所以我們利用免疫組化及Western blot等技術(shù)檢測(cè)了離體在體中QUE對(duì)膠質(zhì)瘤干細(xì)胞分化中Wnt/β-catenin信號(hào)通路的影響。主要結(jié)果如下:1.在體實(shí)驗(yàn)中,免疫組化顯示對(duì)照組β-catenin在細(xì)胞質(zhì)表達(dá)較多并且有入核現(xiàn)象,而QUE組中β-catenin在細(xì)胞質(zhì)表達(dá)較少。Western blot顯示QUE組中p-GSK-3β(ser9)減少(p0.01),促進(jìn)β-catenin降解,導(dǎo)致β-catenin表達(dá)減少(p0.01)。2.在膠質(zhì)瘤干細(xì)胞分化過(guò)程中,QUE可以減少p-GSK-3β(ser9)的表達(dá),提高磷酸化β-catenin(P-β-catenin)而降低β-catenin水平(P0.05)。這種作用呈時(shí)間濃度依賴性。而且這種作用可以被Wnt/β-catenin通路激活劑QS11和Li Cl拮抗。本部分實(shí)驗(yàn)說(shuō)明QUE可能通過(guò)激活GSK-3β,使β-catenin降解,進(jìn)而抑制Wnt/β-catenin通路而促進(jìn)GSLCs向少突膠質(zhì)樣細(xì)胞分化。以上所有結(jié)果提示QUE有可能成為與TMZ聯(lián)合用藥的候選,為惡性膠質(zhì)瘤的治愈提供新的策略。
[Abstract]:Radiotherapy for malignant glioma cells, not sensitive to chemotherapy, the clinical cure rate and low recurrence rate is high, with 5 year survival rate of less than 5%. so the search for the effective way of disease, found crucial biological treatment corresponding approaches. Glioma stem cells (glioma stem-like cells, GSLCs) is one of the few it is highly resistant to radiotherapy and chemotherapy of glioma cells exist in the organization, with unlimited proliferation and multi differentiation capacity and can differentiate into neuron cell phenotype, propose astrocytic phenotype cells and phenotype of oligodendrocytes.GSLCs concept provides an important target for glioma therapy, therefore can promote the differentiation of GSLCs for drugs may provide a new way for the clinical treatment of glioma. Epidemiological survey found an interesting phenomenon: the schizophrenia patients tumor incidence rate ratio The normal population decreased significantly. The researchers found that many antipsychotic drugs such as chlorpromazine, olanzapine, risperidone, can significantly inhibit glioblastoma cell line IMR32 cell proliferation, and has little effect on normal cells. Quetiapine (Quetiapine, QUE) is the second after clozapine, risperidone and olanzapine, fourth atypical antipsychotics. Our previous study found for the first time quetiapine can significantly increase the neural stem cells (neuronal stem cells, NSCs) to differentiate into oligodendrocytes and proportion, to further promote the formation of mature and myelin oligodendrocyte. We also found that in the experiment of QUE can promote oligodendrocyte precursor cells (oligodendrocyte progenitor cells, OPCs) differentiation and maturation, consider GSLCs and NSCs, OPCs are closely related, we proposed that QUE may inhibit GSLCs proliferation and promote the differentiation of GSLCs into oligodendrocytes form Type potential. This study culture and transplantation tumor model by using GSLCs, QUE to study the occurrence and development of glioma cells and glioma, and first-line therapy of temozolomide (Temozolomide, TMZ) of the combined effect, discuss the molecular mechanism of regulation of QUE on the proliferation and differentiation of GSLCs and the total is divided into three parts: the first part: quetiapine inhibited culture system from glioblastoma cell line GL261 in vitro glioma stem cells in serum-free conditions using glioma growth, establish glioma orthotopic and subcutaneous tumor model, respectively QUE, TMZ and the combination of the two treatment methods, the use of in vivo imaging of luciferase, animal behavior, HE staining, immunohistochemistry and Western blot methods to detect various treatments of glioma and growth characteristics. Finally, in order to further test QUE Effect on GSLCs and inhibit the production or growth of glioma. We were on GSLCs transplanted subcutaneous tumor formation and tumor ventricle using TMZ 21 days to kill tumor cells, after discontinuation were given normal saline and QUE treatment, and observed the growth of glioma by in vivo imaging of luciferase. The main results are as follows: 1. immunofluorescence staining showed that the serum-free medium GL261 cells obtained by screening the expression of tumor stem cells (cancer stem cells, CSCs) markers CD133, Sox2, NG2 and Nestin, with 10% fetal bovine serum for 10 days most of the cell differentiation and expression of glial fibrillary acidic protein (glial fibrillary acidic protein, GFAP), the expression of myelin basic protein a small part (myelin basic protein, MBP). The results show that the obtained cells have the characteristics of glioma stem cells, glioma stem cells of GSLCs.2.GSLCs skin grafting after 7 days naked down See the small tumor formation, 21 days after the tumor diameter reached 1.5cm, and the QUE treatment group, TMZ treatment group and QUE combined with TMZ group, the time of tumor formation was delayed, the average volume of the tumor is less than that of the control group, especially in the curative effect of QUE combined with TMZ. The most obvious histopathological detection, treatment group significantly reduced glioma cell division potential, namely the mitotic reduce proliferating cell nuclear antigen (proliferating cell nuclear antigen, PCNA). The positive cells were significantly decreased compared with the control group, treatment group, especially QUE and TMZ combined treatment group, Olig2 positive cells decreased significantly, while MBP positive cells was significantly increased (P0.01).Western blot showed that QUE and QUE combined with TMZ treatment group MBP was significantly increased, while Vimentin decreased expression of GFAP (P0.05).3.GSLCs ventricle after transplantation, in vivo fluorescence imaging showed that mice in 1 weeks after the tumor, and QUE, TMZ after the treatment of goiter The tumor size decreased, and the two combination tumor minimum, animal survival rate increased. The behavior of open field test showed that the drug treatment group compared with the mouse glioma model of mice significantly increased the total distance (P0.05), suggesting that the activity of well preserved.QUE has inhibitory effect on glioma growth, and QUE combined with temozolomide can better inhibit glioma growth, reduce the malignant degree of.4.TMZ could inhibit the growth of tumor after 21 days of treatment, but after 1 weeks after stopping the growth of glioma tumor cells began to dry. The residues in QUE treated group, the tumor length was significantly decreased, size decreased significantly (P0.05) QUE. May inhibit GSLCs proliferation or promote their differentiation. The results suggested that QUE had a certain inhibitory effect on the growth of glioma, and QUE combined with temozolomide can better inhibit glioma growth, reduce the degree of malignancy. These results suggest that QUE May have a certain impact on the growth and differentiation of GSLCs. The second part: the effect of quetiapine on the proliferation and differentiation of tumor stem cells in order to prove the possible role of QUE on GSLCs and inhibit the cell production or growth of glioma stem. We use the training system from the glioblastoma cell line GL261 was obtained from human glioma stem cells. With MTT, RT-PCR in serum-free conditions, flow cytometry were used to evaluate the different concentrations of QUE on glioma stem cell proliferation. By immunofluorescence and Western blot to detect different concentrations of QUE on glioma stem cell differentiation. The main results are as follows: 1. in vitro experiments showed that QUE concentration of 50100 mol/L could significantly inhibit the growth of GSLCs the suspension, the pellet was significantly less than the control group (P0.01).MTT experiments also confirmed the inhibitory effect of QUE (P0.01). Flow cytometry QUE significantly reduced S phase cells (P0.05), and can significantly reduce glioma The expression of Sox2 and Ki67 in stem cell gene (P0.01).2. with 1% fetal bovine serum to induce GSLCs differentiation, QUE treatment can significantly improve the oligodendrocyte maturation protein MBP and the number of CC1 positive cells; and concentration dependent decrease of stem cell factor Sox2, the expression of Olig2 protein (P0.05), and the increase of oligodendrocyte cell related cytokines MBP, Olig1 protein expression (P0.05). The experimental results show that QUE can inhibit the proliferation of glioma stem cells and can promote its similar to oligodendrocyte differentiation. The third part: the differentiation of glioma stem cells into the mechanism due to Wnt/ beta -catenin pathway play a crucial role in the proliferation and differentiation of GSLCs in the promotion of quetiapine, and antipsychotic drug mechanism of QUE is also involved in the way, so we use immunohistochemistry and Western blot were detected in vitro in QUE on glioma stem cell differentiation in W Effect of nt/ beta -catenin signal pathway. The main results are as follows: 1. in vivo experiment, control group P -catenin in the cytoplasm and more nuclear phenomena, and beta -catenin in the QUE group in the cytoplasm less.Western blot display QUE group p-GSK-3 beta (ser9) decreased (P0.01), promote beta the degradation of -catenin, resulting in decreased expression of beta -catenin (P0.01).2. in glioma stem cell differentiation process, QUE can reduce the p-GSK-3 beta (ser9) expression, increase the phosphorylation of beta -catenin (P- beta -catenin) decreased beta -catenin level (P0.05). This effect is dose dependent and time dependent. And this effect can. Wnt/ beta -catenin pathway activation agent QS11 and Li. The results suggested that Cl antagonist QUE may activate GSK-3 beta, the beta -catenin degradation, and inhibition of Wnt/ beta -catenin pathway and promote GSLCs to differentiate into oligodendrocytes. All of the above results. QUE may be a candidate for combination with TMZ, providing a new strategy for the cure of malignant gliomas.

【學(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類(lèi)號(hào)】：R739.41

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