【摘要】：胚胎組織的微環(huán)境可通過(guò)表遺傳學(xué)機(jī)制使腫瘤細(xì)胞逆向轉(zhuǎn)化為表型正常的細(xì)胞，這一過(guò)程主要是通過(guò)抑制腫瘤細(xì)胞中不受調(diào)控的nodal信號(hào)蛋白的過(guò)度表達(dá)實(shí)現(xiàn)的。針對(duì)這樣的發(fā)現(xiàn)，有研究者提出在體外模擬該系統(tǒng)用于腫瘤治療的研究設(shè)想。為此，本研究采用胚胎細(xì)胞外基質(zhì)的主要成分透明質(zhì)酸為基本材料，將透明質(zhì)酸和IV型膠原中的活性肽段通過(guò)化學(xué)交聯(lián)的方法設(shè)計(jì)成可注射的水凝膠，來(lái)模擬胚胎發(fā)育的物理微環(huán)境，并將nodal受體cripto-1的封閉抗體接枝到水凝膠的骨架上，來(lái)模擬胚胎發(fā)育中逆轉(zhuǎn)腫瘤的生物學(xué)微環(huán)境。 通過(guò)對(duì)水凝膠材料流變學(xué)、孔隙率、顯微形貌的研究及腫瘤細(xì)胞三維培養(yǎng)后顯微形貌的觀察，該水凝膠系統(tǒng)能夠作為體外腫瘤逆轉(zhuǎn)研究的理想支架材料。我們選用人乳腺癌細(xì)胞系MCF-7細(xì)胞系作為快速增殖而不具有侵襲性代表，MDA-MB-231乳腺腫瘤細(xì)胞系作為侵襲和轉(zhuǎn)移性腫瘤細(xì)胞的代表。體外檢測(cè)該水凝膠系統(tǒng)對(duì)乳腺癌細(xì)胞惡性表型的影響。體外實(shí)驗(yàn)結(jié)果表明，水凝膠系統(tǒng)能有效逆轉(zhuǎn)腫瘤細(xì)胞的惡性表型，促進(jìn)線粒體膜電位下降、細(xì)胞凋亡，降低細(xì)胞的侵襲性。利用小動(dòng)物活體成像技術(shù)對(duì)于凝膠的體內(nèi)降解進(jìn)行了研究，表明該凝膠在體內(nèi)的降解持續(xù)10天。分別利用黑色素腫瘤細(xì)胞B16和MDA-MB-231制備了荷瘤鼠模型，并對(duì)水凝膠系用于荷瘤鼠腫瘤模型腫瘤逆轉(zhuǎn)治療的有效性進(jìn)行研究。液態(tài)凝膠可以注射到腫瘤部位，并在瘤體內(nèi)固化形成不溶的膠體，局部形成逆轉(zhuǎn)腫瘤的微環(huán)境。研究結(jié)果表明：該水凝膠系統(tǒng)能顯著減小MDA-MB-231腫瘤的體積，，并在注射后38天，實(shí)驗(yàn)組部分小鼠瘤體消失；并有效抑制惡性程度高的B16腫瘤的生長(zhǎng)。本課題研制出一種新型的生物活性水凝膠材料用于腫瘤的逆向轉(zhuǎn)化治療，為腫瘤的治療開(kāi)辟了新的途徑。
[Abstract]:The microenvironment of embryonic tissue can reverse transform tumor cells into normal phenotypic cells by epigenetic mechanism, which is mainly achieved by inhibiting the overexpression of uncontrolled nodal signal proteins in tumor cells. In response to these findings, some researchers proposed to simulate the system in vitro for tumor therapy. Therefore, hyaluronic acid, the main component of extracellular matrix of embryo, was used as the basic material. The active peptides of hyaluronic acid and IV collagen were chemically crosslinked to form injectable hydrogels. To simulate the physical microenvironment of embryonic development and graft the blocking antibody of nodal receptor cripto-1 onto the framework of hydrogel to simulate the biological microenvironment of tumor during embryonic development. The hydrogel system can be used as an ideal scaffold for tumor reversal in vitro by studying the rheology, porosity and morphology of hydrogel materials and observing the microscopic morphology of tumor cells after three-dimensional culture. The human breast cancer cell line MCF-7 cell line was chosen as the representative of rapid proliferation and not invasive, while the MDA-MB-231 breast cancer cell line was used as the representative of invasive and metastatic tumor cells. The effect of the hydrogel system on the malignant phenotype of breast cancer cells was detected in vitro. The results showed that the hydrogel system could effectively reverse the malignant phenotype of tumor cells, promote the decrease of mitochondrial membrane potential, apoptosis and decrease the invasiveness of tumor cells. The degradation of the gel in vivo was studied by using in vivo imaging of small animals, which showed that the degradation of the gel lasted for 10 days. The tumor-bearing mouse models were established by using melanoma cells B16 and MDA-MB-231, respectively, and the effectiveness of hydrogel system for tumor reversal therapy in tumor-bearing mice was studied. Liquid gel can be injected into the tumor site and solidified in the tumor body to form an insoluble colloid. The results showed that the hydrogel system could significantly reduce the volume of MDA-MB-231 tumor, and at 38 days after injection, the tumor of some mice in the experimental group disappeared, and the growth of B16 tumor with high malignancy was effectively inhibited. In this paper, a new bioactive hydrogel material was developed for reverse transformation therapy of tumor, which opened up a new way for tumor treatment.
【學(xué)位授予單位】：哈爾濱工業(yè)大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2012
【分類(lèi)號(hào)】：R318.08

【共引文獻(xiàn)】

相關(guān)期刊論文 前1條

1 孫凱;衛(wèi)立辛;吳孟超;;組織微環(huán)境對(duì)腫瘤發(fā)生發(fā)展的影響[J];第二軍醫(yī)大學(xué)學(xué)報(bào);2008年10期

相關(guān)博士學(xué)位論文 前4條

1 羅佐杰;微環(huán)境調(diào)控腎上腺皮質(zhì)癌干細(xì)胞CD44、CXCR4、CD133和ABCG2表達(dá)的實(shí)驗(yàn)研究[D];廣西醫(yī)科大學(xué);2010年

2 宋敏;DJ-1蛋白對(duì)肺癌微環(huán)境的調(diào)節(jié)作用及其與EGCG防癌的關(guān)系[D];中南大學(xué);2010年

3 董偉;胚胎干細(xì)胞在Lewis肺癌中的體內(nèi)外抗腫瘤作用研究[D];山東大學(xué);2013年

4 王魏;聚L-谷氨酸/殼聚糖材料在脂肪組織工程以及膽管癌三維培養(yǎng)模型中應(yīng)用的實(shí)驗(yàn)研究[D];山東大學(xué);2013年

相關(guān)碩士學(xué)位論文 前8條

1 郭寶平;SATB1基因與乳腺癌的關(guān)系研究[D];廣西醫(yī)科大學(xué);2011年

2 丁曉燕;小鼠胚胎體外侵襲人卵巢癌細(xì)胞HO8910PM機(jī)制研究[D];重慶醫(yī)科大學(xué);2011年

3 王天然;海藻酸鈉微囊包覆HEK293細(xì)胞緩釋lefty用于腫瘤逆轉(zhuǎn)治療的研究[D];哈爾濱工業(yè)大學(xué);2011年

4 丁雅明;中晚期小鼠胚胎與惡性腫瘤細(xì)胞H_（22）相互作用的研究[D];重慶醫(yī)科大學(xué);2008年

5 孫凱;胚胎肝細(xì)胞對(duì)二乙基亞硝胺誘發(fā)大鼠肝癌的過(guò)程的影響及其機(jī)制的研究[D];第二軍醫(yī)大學(xué);2009年

6 李凱;不同濃度透明質(zhì)酸水凝膠性能表征及其對(duì)骨髓間充質(zhì)干細(xì)胞三維培養(yǎng)生長(zhǎng)行為的影響[D];北京協(xié)和醫(yī)學(xué)院;2013年

7 李桐軍;重組人骨形態(tài)發(fā)生蛋白-2/珍珠層/聚乳酸羥基乙酸支架修復(fù)大鼠顱骨缺損的實(shí)驗(yàn)研究[D];福建醫(yī)科大學(xué);2013年

8 張龍;Nodal-Cripto-1信號(hào)分子用于黑色素瘤治療策略的研究[D];哈爾濱工業(yè)大學(xué);2013年

本文編號(hào)：2337129