本文關(guān)鍵詞： 視網(wǎng)膜母細(xì)胞瘤 腫瘤干細(xì)胞 細(xì)胞系 致瘤性 ABCG2 CD133 CD44　出處：《復(fù)旦大學(xué)》2011年博士論文　論文類型：學(xué)位論文

【摘要】：視網(wǎng)膜母細(xì)胞瘤(retinoblastoma, RB)是嬰幼兒最常見的眼內(nèi)惡性腫瘤,目前國際上針對RB開展了以化療為主結(jié)合局部治療的綜合療法,極大改善了患兒的生命預(yù)后,然而化療存在最大的問題就是腫瘤的復(fù)發(fā)和轉(zhuǎn)移。腫瘤化療失敗后復(fù)發(fā)的主要原因是腫瘤細(xì)胞對化療藥物產(chǎn)生耐藥性,而耐藥性的產(chǎn)生機制相當(dāng)復(fù)雜,主要包括多耐藥性蛋白的功能表達(dá)、靜息期細(xì)胞對化療不敏感以及腫瘤細(xì)胞凋亡耐受等,雖然在這些方面的研取得了一定的進(jìn)展,但在闡釋耐藥性機制及指導(dǎo)臨床應(yīng)用上并未取得根本性突破。 腫瘤干細(xì)胞(Cancer stem cells, CSCs)是一類極少的具有自我更新、不定潛能性并促使腫瘤形成的細(xì)胞,對腫瘤的生長、形成及轉(zhuǎn)移起到關(guān)鍵作用’,更為重要的是這部分腫瘤起始性細(xì)胞對化療藥物的敏感性較其它非致瘤性腫瘤細(xì)胞明顯降低。目前,臨床上化療很大程度上是針對大的非致瘤性腫瘤細(xì)胞組成的腫瘤塊,而不能有效殺滅或抑制腫瘤干細(xì)胞,導(dǎo)致了化療后腫瘤的復(fù)發(fā)和轉(zhuǎn)移。雖然不是所有惡性腫瘤的生物學(xué)特點都符合腫瘤干細(xì)胞理論,但CSCs假說為理解RB化療耐藥性提出一種更為合理的細(xì)胞水平的理論解釋。通過研究腫瘤干細(xì)胞,將有利于進(jìn)一步理解RB發(fā)生、發(fā)展及轉(zhuǎn)移的機制,可能為減少RB化療后復(fù)發(fā)和轉(zhuǎn)移提供新的治療策略。目前在多種實體瘤中均已證實有腫瘤干細(xì)胞存在,包括乳腺癌、腦腫瘤、胰腺癌、結(jié)腸癌、黑色素瘤、前列腺癌和卵巢癌等。然而和其他腫瘤研究相比,作為眼內(nèi)腫瘤的RB由于新鮮標(biāo)本獲取的困難性以及樣本的變異性使得其腫瘤干細(xì)胞的研究相對滯后。 本實驗通過對人RB腫瘤細(xì)胞體外采用無血清限定培養(yǎng)基長期培養(yǎng),分離得到了以腫瘤球方式生長的細(xì)胞系,并可以在連續(xù)傳代的同時保持了其自我更新、增殖及分化能力,同時通過化療耐藥性試驗及小鼠致瘤試驗評價其對化療藥物的反應(yīng)性及異體致瘤能力。同時文章第三部分還測定了表面標(biāo)志物ABCG2(ATP-binding cassette superfamily G member 2, ATP結(jié)合膜轉(zhuǎn)運蛋白2)、CD133和CD44在該群細(xì)胞中的表達(dá)情況,為進(jìn)一步研究視網(wǎng)膜母細(xì)胞瘤腫瘤干細(xì)胞(retinoblastoma cancer stem-like cell, RCSC)及其鑒定所需的表面標(biāo)志奠定了基礎(chǔ)。
[Abstract]:Retinoblastoma (RBB) is the most common intraocular malignant tumor in infants and young children. At present, a combination of chemotherapy and local therapy has been developed for RB in the world, which has greatly improved the life prognosis of children with retinoblastoma.The retinoblastoma (RBB) is one of the most common intraocular malignancies in infants. However, the biggest problem in chemotherapy is tumor recurrence and metastasis. The main reason for tumor recurrence after chemotherapy failure is that tumor cells develop resistance to chemotherapeutic drugs, and the mechanism of drug resistance is quite complex. These include the functional expression of multidrug resistance proteins, the insensitivity of resting cells to chemotherapy and the tolerance of tumor cells to apoptosis, although some progress has been made in these areas. However, no fundamental breakthrough has been made in explaining the mechanism of drug resistance and guiding clinical application. Tumor Stem Cell Cancer stem cells (CSCs) are a group of very few cells that have self-renewal, indeterminate potential, and promote tumorigenesis, the growth of tumors. Formation and metastasis play a key role. More importantly, the sensitivity of these tumor initiation cells to chemotherapeutic drugs is significantly lower than that of other non-tumorigenic tumor cells. Chemotherapeutic therapy is largely targeted at tumor blocks made up of large, non-tumorous tumor cells, rather than effectively killing or inhibiting tumor stem cells. Which leads to tumor recurrence and metastasis after chemotherapy. Although not all malignant tumors have biological characteristics consistent with cancer stem cell theory, However, the CSCs hypothesis provides a more reasonable theoretical explanation for understanding the chemoresistance of RB at cellular level. The study of tumor stem cells will be helpful to further understand the mechanism of RB occurrence, development and metastasis. It may provide new treatment strategies to reduce the recurrence and metastasis of RB after chemotherapy. Cancer stem cells have been confirmed in a variety of solid tumors, including breast cancer, brain tumor, pancreatic cancer, colon cancer, melanoma. However, compared with other tumor studies, RB, as an intraocular tumor, lags behind in the study of tumor stem cells due to the difficulty of obtaining fresh samples and the variability of samples. In this experiment, human RB tumor cells were cultured in serum-free medium for a long period of time, and the cell lines which grew in the form of tumor balls were isolated, and their ability of self-renewal, proliferation and differentiation were maintained at the same time of continuous passage. The reactivity to chemotherapeutic drugs and the ability of allogeneic tumorigenesis were evaluated by chemotherapeutic drug resistance test and mouse tumorigenicity test. The surface markers ABCG2(ATP-binding cassette superfamily G member 2 and ATP binding membrane transporter 2hmd CD133 were also determined in the third part of the paper. And the expression of CD44 in this group of cells, The results provide a basis for the further study of retinoblastoma cancer stem-like cells (RCSCs) and the surface markers needed for identification of retinoblastoma.
【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2011
【分類號】：R739.7

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本文編號：1549714