【摘要】：研究背景:卵巢癌(OC)是死亡率最高的婦科惡性腫瘤,其中最常見(jiàn)的是上皮性卵巢癌(EOC),約占卵巢癌的70%,在女性惡性腫瘤中死亡率居第五位[1]。由于臨床癥狀不明顯,患者在出現(xiàn)嚴(yán)重腹痛或消化道癥狀時(shí)才就診,初診患者中有2/3已屬晚期,其中超過(guò)70%已有盆腔轉(zhuǎn)移或淋巴結(jié)轉(zhuǎn)移。目前NCCN指南的晚期卵巢癌標(biāo)準(zhǔn)治療方案為“腫瘤細(xì)胞減滅術(shù)聯(lián)合鉑類(lèi)藥物化療”,卵巢癌的主要綜合治療化療方案是紫杉醇聯(lián)合鉑類(lèi)化療[2]。雖然外科手術(shù)技巧在不斷進(jìn)步,鉑類(lèi)為基礎(chǔ)的聯(lián)合化療也取得了新的進(jìn)展,但卵巢癌患者的5年生存率卻并沒(méi)有明顯提高。主要原因是卵巢腫瘤患者在化療過(guò)程中出現(xiàn)耐藥現(xiàn)象,嚴(yán)重影響化療效果�，F(xiàn)在常用的卵巢癌研究模型是細(xì)胞模型和細(xì)胞株移植模型,由于細(xì)胞模型的缺陷,如體外培養(yǎng)時(shí)間過(guò)長(zhǎng)導(dǎo)致難以避免的遺傳改變及生物學(xué)行為變化,難以真實(shí)模擬卵巢癌的異質(zhì)性和宿主微環(huán)境。因此我們迫切需要一個(gè)合適的臨床前模型來(lái)研究卵巢癌發(fā)生、發(fā)展、轉(zhuǎn)移的機(jī)制,研究化療治療及化療耐藥的機(jī)制,研究卵巢癌新的治療方案。本研究將建立人源化的卵巢癌鼠模型(Patient-derived xenograft model,PDX模型)并鑒定模型與原腫瘤組織的相似性,為卵巢癌的精準(zhǔn)治療提供合適的模型。目的:1.建立人源化的卵巢癌鼠模型,即卵巢癌PDX模型;2.鑒定卵巢癌PDX模型與原腫瘤組織的相似性,包括組織病理學(xué),分子特點(diǎn)的比較。方法:本研究已經(jīng)通過(guò)了倫理委員會(huì)的批準(zhǔn)1.收集了42例西京醫(yī)院婦產(chǎn)科術(shù)中經(jīng)冰凍證實(shí)且術(shù)后病理結(jié)果明確為卵巢惡性腫瘤的新鮮標(biāo)本移植到SCID鼠皮下建立P1代鼠模型;2.P1代成瘤后剝除移植瘤組織傳代到裸鼠皮下建立P2代鼠模型,成瘤后繼續(xù)傳代,分別命名為P3,P4,P5代;3.收集的臨床標(biāo)本記錄臨床資料,包括患者的年齡、臨床分期、組織學(xué)亞型、手術(shù)時(shí)間、有無(wú)腹水及復(fù)發(fā)時(shí)間,成瘤后統(tǒng)計(jì)分析成瘤率與臨床資料的相關(guān)性;4.成瘤入庫(kù)的緩凍組織復(fù)蘇檢測(cè)組織的活性,成瘤能力;5.原組織與移植瘤組織均留部分組織固定,做HE染色及CA125免疫組化染色;6.原組織與移植瘤組織提DNA,P53外顯子5-9基因測(cè)序分析。結(jié)果:1.卵巢癌PDX模型建模成功率35.7%(15/42),P2,P3代成瘤率100%,移植瘤均生長(zhǎng)良好;統(tǒng)計(jì)分析發(fā)現(xiàn)病人的年齡與成瘤率無(wú)關(guān)(P=0.137),與組織學(xué)亞型無(wú)明顯關(guān)系(P=0.461),與病人手術(shù)時(shí)間無(wú)關(guān)(P=0.694),與病人手術(shù)病理分期無(wú)關(guān)(P=0.222),但是與腹水有一定的相關(guān)性(P=0.047),與復(fù)發(fā)時(shí)間有相關(guān)性(P=0.001);2.復(fù)蘇檢測(cè)移植成功率100%,移植瘤均生長(zhǎng)良好;3.經(jīng)HE染色原組織與移植瘤組織病理學(xué)形態(tài)一致;4.CA125免疫組化染色原組織與移植瘤組織陽(yáng)性率一致;5.P53外顯子5-9基因測(cè)序結(jié)果表明原組織與移植瘤組織DNA序列一致。結(jié)論:1.本實(shí)驗(yàn)建模成功率35.7%(15/42),移植瘤均生長(zhǎng)良好,且移植瘤的成功率與惡性腹水的存在有關(guān),成瘤率或許可以作為卵巢癌患者預(yù)后的一項(xiàng)預(yù)測(cè)因素;2.經(jīng)鑒定移植瘤與原組織的組織病理學(xué)和分子特點(diǎn)相似,初步判定本研究的PDX模型可以為卵巢癌的精準(zhǔn)治療提供臨床前研究平臺(tái)。
[Abstract]:Background: Ovarian cancer (OC) is the most lethal gynecologic malignancy, the most common of which is epithelial ovarian cancer (EOC), accounting for 70% of ovarian cancer, and the fifth leading cause of mortality in female malignancies. At present, the standard treatment regimen for advanced ovarian cancer under NCCN guidelines is "cytoreductive surgery combined with platinum-based chemotherapy". The main combined chemotherapy regimen for ovarian cancer is paclitaxel plus platinum-based chemotherapy [2]. New progress has been made in combination chemotherapy, but the 5-year survival rate of patients with ovarian cancer has not been significantly improved. The main reason is that patients with ovarian cancer develop drug resistance during chemotherapy, which seriously affects the effectiveness of chemotherapy. It is difficult to simulate the heterogeneity and host microenvironment of ovarian cancer because of the unavoidable genetic and biological behavior changes caused by long incubation time in vitro. Therefore, we urgently need a suitable preclinical model to study the mechanism of ovarian cancer occurrence, development and metastasis, the mechanism of chemotherapy and chemotherapy resistance, and the ovarian cancer. This study will establish a humanized mouse model of ovarian cancer (PDX model) and identify the similarity between the model and the original tumor tissue, so as to provide a suitable model for accurate treatment of ovarian cancer. Methods: This study has been approved by the Ethics Committee. 42 fresh specimens of ovarian malignancies confirmed by frozen surgery in Xijing Hospital were transplanted into SCID mice to establish the P1 generation mouse model. The P2 generation mouse model was established by peeling off the transplanted tumor tissue and passing it to the nude mice subcutaneously, and then passing it on, named P3, P4 and P5, respectively. 3. The clinical data were collected and recorded, including age, clinical stage, histological subtype, operation time, ascites and recurrence time. Result: 1. PDX model of ovarian cancer was successfully established by 35.7% (P 53 exon 5-9 gene sequencing). 15/42, P 2, P 3 generation tumorigenesis rate was 100%, the transplanted tumors grew well; statistical analysis showed that the patient's age was not related to the tumorigenesis rate (P = 0.137), had no significant relationship with histological subtypes (P = 0.461), had no correlation with the operation time (P = 0.694), had no correlation with the operation pathological stage (P = 0.222), but had a certain correlation with ascites (P = 0.047), and had no correlation with the recurrence time (P = 0.047). Resuscitation test showed that the success rate of transplantation was 100%, and the transplanted tumors grew well. 3. HE staining was consistent with the histopathological morphology of the transplanted tumors. 4. The positive rate of CA125 immunohistochemical staining was consistent with that of the transplanted tumors. 5. P53 exon 5-9 gene sequencing showed that the DNA sequence of the original tissues was consistent with that of the transplanted tumors. Conclusion: 1. The success rate of this model was 35.7% (15/42), and the transplanted tumors grew well, and the success rate of transplanted tumors was related to the presence of malignant ascites. Tumor formation rate may be a predictor of the prognosis of ovarian cancer patients. 2. The transplanted tumors were identified to be similar to the histopathological and molecular characteristics of the original tissues, and the PDX model of this study was preliminarily determined. It can provide a preclinical research platform for precise treatment of ovarian cancer.
【學(xué)位授予單位】：第四軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2016
【分類(lèi)號(hào)】：R737.31;R-332

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