本文選題：腫瘤干細(xì)胞 + 腫瘤耐藥��； 參考：《浙江大學(xué)》2016年博士論文

【摘要】：近年來的研究發(fā)現(xiàn),腫瘤干細(xì)胞的存在可能是腫瘤無法治愈的主要原因。腫瘤干細(xì)胞長期處于G0期,對作用于細(xì)胞分裂期的多數(shù)化療藥物不敏感。腫瘤干細(xì)胞具備普通干細(xì)胞的性質(zhì),受外界環(huán)境刺激后可分化形成新的腫瘤細(xì)胞,促進(jìn)腫瘤生長和腫瘤復(fù)發(fā)。此外腫瘤干細(xì)胞較強(qiáng)的成瘤特性,被認(rèn)為是腫瘤體內(nèi)轉(zhuǎn)移的主要原因。因此,靶向并清除腫瘤干細(xì)胞,成為腫瘤治療的難點(diǎn)與熱點(diǎn)。本研究旨在通過納米制劑技術(shù),靶向腫瘤干細(xì)胞、克服其耐藥性,達(dá)到殺傷腫瘤干細(xì)胞,提高化學(xué)藥物的抗腫瘤藥效的目的。本文的主要內(nèi)容如下:采用無血清懸浮球培養(yǎng)法,從乳腺癌細(xì)胞系MCF-7中富集乳腺癌腫瘤干細(xì)胞(Breast cancer stem cells,breast CSCs)。獲得的細(xì)胞球結(jié)構(gòu)致密、邊界清晰,直徑約200μm。經(jīng)檢測具備breast CSCs表面分子標(biāo)記物CD44+/CD24-的細(xì)胞比例為36.51%,干性基因Nanog、OCT4及SOX2的轉(zhuǎn)錄與蛋白表達(dá)均出現(xiàn)上調(diào),耐藥蛋白ABCG2表達(dá)增強(qiáng),證實(shí)該方法實(shí)現(xiàn)了腫瘤干細(xì)胞的富集。低分子量殼聚糖硬脂酸嫁接物(Stearic acid-g-chitosan oligosaccharide,CSOSA)形成的糖脂納米粒在細(xì)胞球上具有較強(qiáng)的攝取和滲透能力,可將藥物阿霉素(Doxorubicin,DOX)遞送到細(xì)胞球的內(nèi)部。酸性磷酸酶試驗(yàn)法(Acid phosphatase assay,APH assay)檢測細(xì)胞球的存活率,結(jié)果表明糖脂載藥納米粒(CSOSA/DOX)比市售鹽酸阿霉素制劑(DOX·HCl)有更強(qiáng)的細(xì)胞球生長抑制作用,其IC50值分別為1.07和2.64μg/mL。本文分別構(gòu)建了 MCF-7原位腫瘤動物模型及細(xì)胞球原位腫瘤動物模型,研究發(fā)現(xiàn)兩類腫瘤模型有較大的區(qū)別。細(xì)胞球腫瘤組織中,細(xì)胞成分組成復(fù)雜、呈細(xì)胞多樣性,可致原位乳腺結(jié)構(gòu)重塑,具備一定的耐藥性且微環(huán)境間質(zhì)豐富,結(jié)構(gòu)上更接近于原發(fā)腫瘤。為使相關(guān)研究更接近于臨床,本課題采用細(xì)胞球腫瘤模型,并選擇多周期給藥方案。結(jié)果顯示,第一治療周期,市售制劑抑瘤效果強(qiáng)于糖脂載藥納米粒。從第二周期開始,市售制劑組腫瘤體積繼續(xù)增大,糖脂載藥納米粒組腫瘤體積基本不變,兩組腫瘤的體積差逐漸縮小。第三周期結(jié)束時(shí),糖脂載藥納米組的抗腫瘤效果顯著優(yōu)于市售制劑組(**p0.01)。CSOSA/DOX在殺滅非breast CSCs的同時(shí),可同時(shí)殺滅breast CSCs,不會導(dǎo)致腫瘤干細(xì)胞的富集;市售制劑對照只能殺滅非breast CSCs,腫瘤干細(xì)胞比例由10.95%升高至69.36%。CSOSA/DOX還可通過影響腫瘤相關(guān)成纖維細(xì)胞活性,減少膠原蛋白的分泌,破壞腫瘤微環(huán)境的完整性,導(dǎo)致腫瘤血管數(shù)量增多變粗,進(jìn)一步提高抗腫瘤藥效。采用MCF-7腫瘤動物模型,考察多周期給藥對腫瘤耐藥的影響。研究發(fā)現(xiàn),經(jīng)過三周期的連續(xù)給藥治療,CSOSA/DOX組呈現(xiàn)更強(qiáng)的腫瘤生長抑制作用,其效果優(yōu)于DOX·HC1。DOX·HC1組腫瘤組織P-gp蛋白表達(dá)明顯上調(diào),CSOSA/DOX組腫瘤觀察不到明顯P-gp。采用高劑量脈沖法及低劑量連續(xù)刺激法,制備細(xì)胞耐藥模型,模擬體內(nèi)產(chǎn)生耐藥的過程。DOX·HC1刺激組,細(xì)胞對藥物的敏感性下降,高劑量與低劑量刺激法獲得的細(xì)胞其IC50值由0.27±0.04μg/mL升高為0.80±0.03及0.88±0.07μg/mL,耐藥能力增強(qiáng)。CSOSA/DOX刺激的細(xì)胞,對藥物的敏感度變化不大。與體內(nèi)結(jié)果相似,CSOSA/DOX不會誘導(dǎo)細(xì)胞P-gp蛋白表達(dá)上調(diào)。研究發(fā)現(xiàn),CSOSA/DOX不影響mdr1基因的轉(zhuǎn)錄水平,而市售制劑可刺激mdr1基因轉(zhuǎn)錄P-gp mRNA。低劑量刺激及高劑量刺激上調(diào)后的轉(zhuǎn)錄水平,分別為敏感MCF-7細(xì)胞的6154倍及1191倍,顯示CSOSA/DOX通過不增加P-gp蛋白表達(dá)水平,減少耐藥的發(fā)生。脂質(zhì)納米載體,以其良好的生物相容性及對難溶性藥物較強(qiáng)的包載能力,廣泛應(yīng)用于抗腫瘤治療。本文選用抗腫瘤藥物奧沙利鉑(Oxaliplatin,OXA)及腫瘤干細(xì)胞特異性藥物鹽霉素(Salinomycin,SAL)聯(lián)合治療肝癌。A54多肽通過PEG鏈段與脂肪鏈段十八胺(Octadecylamine,ODA)相連,合成A54-PEG-ODA嫁接物。A54-PEG-ODA嫁接物通過其疏水端插入固體脂質(zhì)納米粒(Solid lipid nanoparticle,SLN),構(gòu)建A54多肽修飾的脂質(zhì)納米粒(A54-PEG-SLN)。通過形成奧沙利鉑磷脂復(fù)合物,實(shí)現(xiàn)A54-PEG-SLN對OXA的有效包封。投藥量為5%時(shí),載藥量和包封率分別為3.46±0.12%和65.3±1.9%。研究表明,,A54多肽修飾的納米粒,可加快BEL-7402細(xì)胞的攝取速度,并具有攝取該細(xì)胞的特異選擇性。A15適配體可特異性識別腫瘤干細(xì)胞標(biāo)志物CD133分子且親和力強(qiáng),本文通過A15的端氨基與NH2-PEG-SLN/SAL脂質(zhì)納米粒表面的端氨基反應(yīng),制備A15修飾的納米粒A15-PEG-SLN/SAL。該納米粒對難溶性藥物鹽霉素可有效包封,投藥量為10%時(shí),載藥量及包封率分比為7.77±0.28%和84.42±0.55%。體外細(xì)胞藥效表明,游離奧沙利鉑及A54-PEG-SLN/OXA納米粒對BEL-7402細(xì)胞的IC50值分別為8.11±1.5及16.0±1.2μg/mL;包封后藥效下降,可能與藥物的釋放有關(guān)。游離鹽霉素對腫瘤干細(xì)胞殺傷作用不明顯,主要由溶劑二甲亞砜導(dǎo)致;而A15-PEG-SLN/SAL納米粒腫瘤干細(xì)胞藥效顯著IC50值為0.69±0.015μ/mL。A15-PEG-SLN/SAL納米粒對BEL-7402細(xì)胞殺傷能力較弱,10μg/mL時(shí)存活率為80%�？紤]到BEL-7402細(xì)胞對鹽霉素不敏感,在進(jìn)行體內(nèi)抗腫瘤藥效序貫給藥研究時(shí),采用先給予奧沙利鉑制劑,殺傷腫瘤敏感細(xì)胞,使腫瘤干細(xì)胞暴露出治療位點(diǎn)。當(dāng)連續(xù)給藥兩個(gè)周期后,腫瘤干細(xì)胞比例由0.1%升高至3.0%,此時(shí)再給予鹽霉素制劑。模型動物藥效學(xué)研究結(jié)果顯示,A54多肽修飾A54-PEG-SLN/OXA納米粒的抗腫瘤作用增強(qiáng),與游離奧沙利鉑相當(dāng)。聯(lián)合鹽霉素給藥后,制劑組抗腫瘤藥效顯著優(yōu)于游離藥物組。本論文研究結(jié)果表明,CSOSA/DOX在腫瘤的多周期治療中,發(fā)揮良好的抗腫瘤作用,殺傷腫瘤干細(xì)胞,抑制腫瘤復(fù)發(fā)。A54-PEG-SLN/OXA與A15-PEG-SLN/SAL聯(lián)合療法,增強(qiáng)化療藥物OXA的抗腫瘤藥效,發(fā)揮協(xié)同作用,有效治療肝癌。
[Abstract]:Recent studies have found that the existence of tumor stem cells may be the main reason for the inability of the tumor to be cured. The tumor stem cells are in the G0 phase for a long time and are insensitive to most of the chemotherapeutic drugs that act on the cell division stage. Growth and tumor recurrence. In addition, the strong tumorigenicity of tumor stem cells is considered to be the main cause of metastasis in the tumor. Therefore, targeting and removing tumor stem cells is the difficult and hot spot in the treatment of cancer. The main contents of the antitumor effect of high chemical drugs. The main contents of this article are as follows: using the serum-free suspension ball culture, the mammary cancer cancer stem cells (Breast cancer stem cells, breast CSCs) are enriched from the breast cancer cell line MCF-7. The obtained cell spheres are dense, the boundary is clear, and the diameter of the 200 u M. is detected with the breast CSCs surface points. The cell ratio of the submarker CD44+/CD24- was 36.51%, the transcriptional and protein expression of the dry gene Nanog, OCT4 and SOX2 increased, and the expression of the drug resistant protein ABCG2 was enhanced. It proved that the method realized the enrichment of the cancer stem cells. The glycolipid formed by the low molecular weight chitosan stearic acid receptor (Stearic acid-g-chitosan oligosaccharide, CSOSA) was formed. The nanoparticles have strong uptake and osmotic ability on the cell spheres, which can be delivered to the inside of the cell ball. The acid phosphatase test (Acid phosphatase assay, APH assay) is used to detect the survival rate of the cell ball. The results show that the glycolipid drug loaded nanoparticles (CSOSA/DOX) are compared to the commercial adriamycin hydrochloride (DOX HCl) (DOX. HCl). With a stronger inhibition of cell growth, the IC50 values were 1.07 and 2.64 g/mL. respectively. The MCF-7 in situ tumor animal model and the cell ball in situ tumor animal model were constructed respectively. The study found that the two types of tumor models were different. In the cell spheroid tumor tissue, the cell composition is complex and the cell diversity can cause in situ milk. In order to make the related research more close to the clinic, we adopt the cell ball tumor model and choose the multi cycle drug delivery scheme. The results show that the first treatment period is better than the drug loaded nanoparticles in the first treatment period, from second. At the beginning of the period, the volume of tumor in the market preparation group continued to increase, the tumor volume of the glycolipid drug loaded nanoparticles group was basically unchanged. The volume difference of the two groups was gradually reduced. The anti-tumor effect of the glycolipid drug loaded nanometers was significantly better than the market agent group (**p0.01).CSOSA/ DOX in killing non breast CSCs at the end of the period, and at the same time killing breas at the same time. T CSCs does not lead to the enrichment of tumor stem cells; the market preparation control can only kill non breast CSCs, the proportion of cancer stem cells increased from 10.95% to 69.36%.CSOSA/DOX, which can also affect the activity of tumor related fibroblasts, reduce the secretion of collagen, destroy the integrity of the tumor microenvironment, and lead to the increase of tumor blood vessels. MCF-7 tumor animal model was used to investigate the effect of multi cycle drug delivery on tumor resistance. The study found that after three cycles of continuous administration, the CSOSA/DOX group showed a stronger tumor growth inhibition effect, and the effect was better than that of the DOX HC1.DOX. HC1 group, the expression of P-gp protein was obviously up-regulated, and the CSOSA/DOX group was swollen. The tumor was not observed by P-gp. using high dose pulse method and low dose continuous stimulation method to prepare the cell resistance model, to simulate the drug resistance process in the.DOX. HC1 stimulation group, and to decrease the cell sensitivity to the drug. The IC50 value of the cells obtained by the high dose and low dose stimulation method increased from 0.27 + 0.04 Mu to 0.80 + 0.03 and 0.88 + 0.07 g/. ML, the resistance to.CSOSA/DOX stimulated cells, the sensitivity of the drug changed little. Similar to the results in the body, CSOSA/DOX did not induce the up regulation of P-gp protein expression. The study found that CSOSA/DOX did not affect the transcriptional level of the MDR1 gene, and the market preparation could stimulate the low dose stimulation of the MDR1 gene transcriptional P-gp mRNA. and the up-regulation of high dose stimulation. The post transcriptional level, 6154 times and 1191 times that of sensitive MCF-7 cells, shows that CSOSA/DOX can reduce the occurrence of drug resistance by not increasing the expression of P-gp protein. The lipid nanoscale is widely used in antitumor therapy with its good biocompatibility and its strong encapsulation ability to insoluble drugs. Oxaliplatin (OXA) and tumor stem cell specific drug Salinomycin (SAL) are combined to treat the.A54 polypeptide of liver cancer by connecting to the eighteen amine (Octadecylamine, ODA) of the fat chain segment through the PEG segment, and the A54-PEG-ODA marrying agent is inserted into the solid lipid nanoparticles (Solid lipid) through its water terminal. The A54 polypeptide modified lipid nanoparticles (A54-PEG-SLN) was constructed. By forming the oxaliplatin phospholipid complex, the effective encapsulation of OXA was achieved by A54-PEG-SLN. When the dosage was 5%, the drug loading and encapsulation efficiency were 3.46 + 0.12% and 65.3 + 1.9%. respectively. The A54 polypeptide modified nanoparticles could speed up the uptake of BEL-7402 cells and have the uptake. The specific selective.A15 aptamers of this cell can specifically identify CD133 molecules of tumor stem cell markers and have strong affinity. In this paper, the A15 modified nanoparticles A15-PEG-SLN/SAL., a nano particle of A15 modified nanoparticles, is prepared by the reaction of the amino terminal amino group of the A15 and the NH2-PEG-SLN/SAL lipid nanoparticles on the surface of the lipid nanoparticles. The drug loading and encapsulation ratio Ratio of 7.77 + 0.28% and 84.42 + 0.55%. in vitro showed that the IC50 value of free oxaliplatin and A54-PEG-SLN/OXA nanoparticles to BEL-7402 cells was 8.11 + 1.5 and 16 + 1.2 mu g/mL, respectively, and the drug effect decreased after encapsulation, which may be related to the release of drugs. The effect was not obvious, mainly caused by the solvent two a sulfoxide, and the significant IC50 value of the A15-PEG-SLN/SAL nanoparticle tumor stem cells was 0.69 + 0.015 mu /mL.A15-PEG-SLN/SAL nanoparticles with weak killing ability to BEL-7402 cells. The survival rate of 10 mu g/mL was 80%., considering that the BEL-7402 cells were insensitive to the salt mycophenycin, and the anti-tumor efficacy of the vivo was carried out in the body. In the study of drug administration, oxaliplatin was first given to kill tumor sensitive cells and to expose the tumor stem cells to the treatment site. After two cycles of continuous administration, the proportion of the tumor stem cells increased from 0.1% to 3%, and then the salt mycin preparation was given. The results of the model animal pharmacodynamics study showed that the A54 polypeptide modified the A54-PEG-SLN/OXA nanoparticles. The antitumor effect of the combined oxaliplatin was equal to that of free oxaliplatin. After the combination of salt mycin, the antitumor effect of the preparation group was significantly better than that of the free drug group. The results of this study showed that CSOSA/DOX played a good anti-tumor effect, killed tumor stem cells and inhibited the recurrence of tumor.A54-PEG-SLN/OXA and A15-PEG-SLN in the multi cycle treatment of the tumor. /SAL combined therapy can enhance the antitumor efficacy of OXA and play a synergistic role in the treatment of HCC.
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R943

【相似文獻(xiàn)】

相關(guān)期刊論文 前2條

1 喬明曦;張曉君;巴爽;胡海洋;趙秀麗;陳大為;;腫瘤干細(xì)胞靶向給藥系統(tǒng)的研究進(jìn)展[J];藥學(xué)學(xué)報(bào);2013年04期

2 ;[J];;年期

相關(guān)會議論文 前10條

1 胡以平;;關(guān)于腫瘤干細(xì)胞問題的一些思考[A];中國環(huán)境誘變劑學(xué)會第14屆學(xué)術(shù)交流會議論文集[C];2009年

2 甄紅英;王淑玲;;力達(dá)霉素抑制腫瘤干細(xì)胞的作用機(jī)制研究[A];2009醫(yī)學(xué)前沿論壇暨第十一屆全國腫瘤藥理與化療學(xué)術(shù)會議論文集[C];2009年

3 金潤銘;;腫瘤干細(xì)胞及其生物學(xué)特點(diǎn)[A];基因開啟未來：新時(shí)代的遺傳學(xué)與科技進(jìn)步——湖北省遺傳學(xué)會第八次代表大會暨學(xué)術(shù)討論會論文摘要匯編[C];2009年

4 羅丁三;;基于中醫(yī)藥視角下的腫瘤干細(xì)胞研究進(jìn)展[A];甘肅省中醫(yī)藥學(xué)會2013年學(xué)術(shù)年會論文集[C];2013年

5 陸士新;;腫瘤干細(xì)胞及其對腫瘤治療理念的影響[A];第三屆中國腫瘤內(nèi)科大會教育集暨論文集[C];2009年

6 湯永民;;腫瘤干細(xì)胞及其靶向治療[A];中國抗癌協(xié)會第七屆全國小兒腫瘤學(xué)術(shù)會議論文匯編[C];2007年

7 張宏權(quán);;腫瘤干細(xì)胞與腫瘤的侵襲與轉(zhuǎn)移[A];第九屆全國腫瘤轉(zhuǎn)移學(xué)術(shù)大會暨2011年黑龍江省醫(yī)學(xué)會腫瘤學(xué)年會報(bào)告集[C];2011年

8 吳沛宏;高飛;顧仰葵;;現(xiàn)代腫瘤微創(chuàng)治療進(jìn)展[A];中國(第七屆)腫瘤微創(chuàng)治療學(xué)術(shù)大會暨世界影像導(dǎo)引下腫瘤微創(chuàng)治療學(xué)會成立籌備大會論文匯編[C];2011年

9 周凱旋;艾軍;單保恩;;腫瘤干細(xì)胞研究:一個(gè)漫長且不尋常的旅程[A];第十四屆中國科協(xié)年會第17分會場：環(huán)境危害與健康防護(hù)研討會論文集[C];2012年

10 譚亞軍;侯啟明;張庶民;;腫瘤干細(xì)胞研究的問題和進(jìn)展[A];2012年中國藥學(xué)大會暨第十二屆中國藥師周論文集[C];2012年

相關(guān)重要報(bào)紙文章 前10條

1 潘文;腫瘤干細(xì)胞為癌癥治療帶來新曙光[N];中國醫(yī)藥報(bào);2006年

2 本版編輯邋海上飛魚 葛秋芳 王艷紅;揪出腫瘤的“元兇”——腫瘤干細(xì)胞[N];醫(yī)藥經(jīng)濟(jì)報(bào);2007年

3 潘文;腫瘤干細(xì)胞：為根治癌癥帶來新曙光[N];中國醫(yī)藥報(bào);2007年

4 記者 葉芳 通訊員 黃金娟;化療可刺激普通腫瘤細(xì)胞變腫瘤干細(xì)胞[N];廣東科技報(bào);2009年

5 記者 藍(lán)建中;滅腫瘤干細(xì)胞有望根治癌癥[N];新華每日電訊;2013年

6 香港麥迪信醫(yī)學(xué)出版有限公司供稿;腫瘤干細(xì)胞將成治癌新靶點(diǎn)[N];醫(yī)藥經(jīng)濟(jì)報(bào);2003年

7 記者 楊帆　實(shí)習(xí)生 楊周;“腫瘤干細(xì)胞研究”在渝實(shí)施[N];重慶日報(bào);2009年

8 何雷;“973”計(jì)劃腫瘤干細(xì)胞項(xiàng)目啟動[N];健康報(bào);2009年

9 記者 陳楓　通訊員 黃金娟 陳捚;廣東院士研究成果將影響癌癥治療策略[N];南方日報(bào);2009年

10 高凡;化療或是癌癥復(fù)發(fā)根源[N];科學(xué)導(dǎo)報(bào);2009年

相關(guān)博士學(xué)位論文 前10條

1 楊孟選;荷載腫瘤干細(xì)胞抗原的樹突細(xì)胞疫苗聯(lián)合糖脂類分子治療小鼠結(jié)腸癌的實(shí)驗(yàn)研究[D];復(fù)旦大學(xué);2014年

2 林鋮;人miR-489靶向p38α誘導(dǎo)腫瘤細(xì)胞自噬[D];浙江大學(xué);2015年

3 孫翠翠;雙聯(lián)芐類化合物Riccardin D的抗腫瘤作用及機(jī)制研究[D];山東大學(xué);2015年

4 孫蓉;納米載體同步輸送藥物用于腫瘤干細(xì)胞治療的研究[D];中國科學(xué)技術(shù)大學(xué);2015年

5 趙志舉;miR-221對正常乳腺和乳腺腫瘤干細(xì)胞調(diào)控的研究[D];中國科學(xué)技術(shù)大學(xué);2015年

6 蔡啟亮;CD44+腫瘤干/祖細(xì)胞在前列腺癌侵襲和轉(zhuǎn)移中的作用和機(jī)制研究[D];天津醫(yī)科大學(xué);2015年

7 劉紅;宮頸癌干細(xì)胞的分選及放療抵抗機(jī)制的研究[D];河北醫(yī)科大學(xué);2016年

8 侯春英;MET-PI3K-Akt信號通路介導(dǎo)miRNA-31調(diào)控肺腺癌腫瘤干細(xì)胞功能[D];北京協(xié)和醫(yī)學(xué)院;2016年

9 李文新;靶向腫瘤干細(xì)胞“Akt-Oct4”調(diào)控通路的小分子藥物初步研究[D];浙江大學(xué);2016年

10 葛春蕾;miR-942活化Wnt/β-catenin通路促進(jìn)ESCC腫瘤干細(xì)胞干性的作用研究[D];昆明醫(yī)科大學(xué);2015年

相關(guān)碩士學(xué)位論文 前10條

1 邱暢;CD44聯(lián)合Prpc作為胃癌干細(xì)胞的初步研究[D];中國人民解放軍醫(yī)學(xué)院;2015年

2 何文婷;載索拉非尼及蘿卜硫素介孔二氧化硅脂質(zhì)納米粒聯(lián)用體外抗腫瘤細(xì)胞與腫瘤干細(xì)胞作用研究[D];福建中醫(yī)藥大學(xué);2015年

3 毛驍麗;穿膜肽聯(lián)合鹽霉素磷脂膠束靶向腫瘤干細(xì)胞的實(shí)驗(yàn)研究[D];福建中醫(yī)藥大學(xué);2015年

4 王喜隆;~1H-MVS參數(shù)Cho/Cr與腫瘤干細(xì)胞標(biāo)記物關(guān)系研究[D];寧夏醫(yī)科大學(xué);2015年

5 譚燦亮;人甲狀腺癌中腫瘤干細(xì)胞樣細(xì)胞的分離培養(yǎng)與鑒定[D];南方醫(yī)科大學(xué);2015年

6 洪少馥;超聲輻照聯(lián)合紫杉醇對三維腫瘤球細(xì)胞毒性效果評價(jià)及其機(jī)制的研究[D];南方醫(yī)科大學(xué);2015年

7 張成龍;利用CD133~+腫瘤表面標(biāo)記物分離、鑒定和培養(yǎng)胃癌腫瘤干細(xì)胞的實(shí)驗(yàn)研究[D];昆明醫(yī)科大學(xué);2015年

8 尹曉龍;卵巢癌腫瘤干細(xì)胞的研究進(jìn)展[D];蚌埠醫(yī)學(xué)院;2015年

9 劉觀成;鼻咽癌中腫瘤干細(xì)胞標(biāo)記物的表達(dá)研究[D];桂林醫(yī)學(xué)院;2015年

10 徐望;5-氟尿嘧啶對人舌鱗癌Tca8113中腫瘤干細(xì)胞富集作用[D];重慶醫(yī)科大學(xué);2015年

，

本文編號：2052350