本文選題：肺鱗癌 + Notch��； 參考：《浙江大學(xué)》2016年博士論文

【摘要】：背景和目的：肺鱗癌是一種致死率很高的肺癌類型,在所有肺癌中,其發(fā)病率僅次于肺腺癌。因治療手段有限,晚期肺鱗癌的5年生存率不到15%。人類肺鱗癌的發(fā)生發(fā)展過程漫長,一般認(rèn)為：正常的支氣管黏膜假復(fù)層柱狀上皮細(xì)胞受慢性刺激和損傷,正常纖毛喪失,出現(xiàn)不同程度的支氣管上皮增生,隨后可能發(fā)生不典型增生,鱗狀上皮化生和發(fā)育不全,最后部分進(jìn)展為原位癌及浸潤性癌。提示若能阻止或逆轉(zhuǎn)肺鱗癌發(fā)生前任意一環(huán)節(jié)的良性病變,都將有可能阻止肺鱗癌的最終發(fā)生。目前肺鱗癌轉(zhuǎn)基因小鼠已逐漸應(yīng)用于人肺鱗癌的研究,已知的構(gòu)建方法主要有四種：Lkbl敲除/KrasGI2D過表達(dá),IKKa死亡激酶敲入,Lkbl/Pten同時敲除和Sox2過表達(dá)/Lkbl敲除。盡管這些小鼠能發(fā)生肺鱗癌,但卻存在肺癌類型混雜、潛伏期長、成瘤率低、僅能出現(xiàn)肺鱗癌卻缺失與人肺鱗癌發(fā)生前類似的階段性病理改變過程等缺點(diǎn)。并且,盡管肺鱗癌的發(fā)生與許多基因的同時突變有關(guān),但驅(qū)動正常肺組織進(jìn)展為肺鱗癌的啟動基因仍未明確。因此,本課題組選取了三個與人肺鱗癌密切相關(guān)的基因,構(gòu)建出轉(zhuǎn)基因小鼠模型,以期尋找肺鱗癌的啟動基因,并試圖通過在小鼠肺內(nèi)模擬與人肺鱗癌階段性病變類似的過程,幫助臨床肺鱗癌的診斷、治療和預(yù)防。另外,目前認(rèn)為,cytokeratin 5(K5)來源細(xì)胞是一類具有干細(xì)胞特性的細(xì)胞群,并可能與肺癌的發(fā)生有關(guān)。我們應(yīng)用Cre-loxP系統(tǒng),分別研究了K5特異性來源的細(xì)胞與非特異性來源的細(xì)胞在相同損傷及基因缺陷的背景下,是否都能在小鼠肺內(nèi)形成腫瘤及形成腫瘤的區(qū)別,從而探討K5來源細(xì)胞是否具有潛在的肺癌干細(xì)胞功能。方法：根據(jù)2012年Cancer Genome Atlas Research Network(TCCA)發(fā)布的178例人肺鱗癌標(biāo)本基因分析數(shù)據(jù)和本課題組小鼠體外氣道干細(xì)胞球氣液相體系培養(yǎng)的結(jié)果(未發(fā)表數(shù)據(jù)),我們選擇了NICD1,Lkb1和P53三個基因,利用Cre-loxP系統(tǒng),構(gòu)建出K5-CrePR;NICD1;P53;Lkbl轉(zhuǎn)基因小鼠模型。分別通過Ru486誘導(dǎo)K5細(xì)胞特異性Cre重組酶表達(dá)或直接應(yīng)用非細(xì)胞特異的Adenovirus Cre重組酶的方法,引起Notch通路重要因子NICD1的過度激活,并同時沉默抑癌基因Lkbl和P53在小鼠體內(nèi)的表達(dá)。此后對轉(zhuǎn)基因小鼠予以聚多卡醇肺損傷刺激,并長期觀察小鼠,當(dāng)小鼠出現(xiàn)異常狀態(tài)或體征后,處死小鼠留取肺組織標(biāo)本。首先,用HE染色的方法,篩查肺部腫瘤的形成情況及初步判斷肺部腫瘤的病理類型。隨后,對于篩選得到的肺部腫瘤標(biāo)本,用不同類型肺癌的特異性標(biāo)記抗體進(jìn)行免疫熒光染色,進(jìn)一步判斷肺部腫瘤的具體病理類型。最后,通過整理所有轉(zhuǎn)基因小鼠的數(shù)據(jù)：1.總結(jié)各基因型小鼠的肺部病理特點(diǎn),并分析各基因?qū)δ[瘤形成的作用；2.總結(jié)兩種來源Cre重組酶對小鼠肺部腫瘤形成的異同,并分析K5來源細(xì)胞在肺部腫瘤形成中的作用。另外,我們還在第一部分實(shí)驗(yàn)中,初步探討了K5來源細(xì)胞的干細(xì)胞功能：1.通過流式分選術(shù)及體外氣道干細(xì)胞成球氣液相體系培養(yǎng)的方法,觀察Trop-2+ITGA6+氣道干細(xì)胞(ABSCs)中是否富集K5來源干細(xì)胞。2.應(yīng)用K5-CrePR-YFP轉(zhuǎn)基因小鼠模型,通過K5-YFP+ve細(xì)胞的自身示蹤,追蹤K5來源細(xì)胞在博來霉素肺損傷小鼠肺組織中的動態(tài)變化。3.將K5-CrePR-YFP轉(zhuǎn)基因小鼠作為供體鼠,通過Frop-2+ITGA6+ABSCs的異體移植實(shí)驗(yàn),追蹤供體鼠K5-YFP+ve干細(xì)胞在博來霉素肺損傷受體鼠肺組織中的動態(tài)變化。結(jié)果：成功構(gòu)建了肺鱗癌轉(zhuǎn)基因小鼠模型,并在小鼠體內(nèi)觀察到類似人肺鱗癌發(fā)生前的不同程度的上皮異型增生。所有肺鱗癌均發(fā)生在NICD1雜合突變型小鼠(NICD1純合突變型小鼠均不能存活),提示NICD1可能作為肺鱗癌發(fā)生的驅(qū)動基因,在外在損傷刺激和P53及Lkbl共同缺陷的情況下,促使正常細(xì)胞轉(zhuǎn)變?yōu)榉西[癌細(xì)胞,從而參與肺鱗癌形成的過程。具體結(jié)果如下：(1)Ru486治療組小鼠出現(xiàn)肺鱗癌,提示K5來源細(xì)胞可能具有腫瘤干細(xì)胞功能,在損傷刺激及基因缺陷共同作用下轉(zhuǎn)變?yōu)榉西[癌細(xì)胞。在所有小鼠中：①NICD1野生型小鼠,均狀態(tài)如常。②NICD1純合突變型小鼠,均于出生后早夭或在母體內(nèi)流產(chǎn)。③NICD1雜合突變型小鼠,根據(jù)P53和Lkbl基因型的不同,表型明顯不同：NICD1+/fl;P53fl/fl、NICD1+/fl; Lkb1fl/fl和NICD1+/fl; P53+/fl; Lkb1fl/fl小鼠如常。而NICD1+/fl; P53+/fl; LKB1+/fl、NICD1+/fl; P53fl/fl/; LKB1+/fl和NICD1+/fl; P53fl/fl; LKBfl/fl/三種基因型小鼠,肺自發(fā)鱗癌形成,三組的成瘤小鼠數(shù)目分別為1只、2只和2只,成瘤率分別為25.0%、28.6%和33.3%,潛伏期為5-12月。所有肺癌標(biāo)本在免疫熒光染色后均強(qiáng)表達(dá)肺鱗癌標(biāo)記物K5,而肺鱗癌標(biāo)記物TTF1和cytokeratin 8(K8)表達(dá)缺失,經(jīng)免疫學(xué)證實(shí)為肺鱗癌。(2) Adeno virus Cre (AdenoCre)治療組小鼠出現(xiàn)肺鱗癌,且較Ru486治療組小鼠病變更為嚴(yán)重,提示除K5來源細(xì)胞外,可能存在其它具有腫瘤干細(xì)胞功能的細(xì)胞群,在損傷刺激及基因缺陷共同作用下與K5來源細(xì)胞協(xié)同,共同轉(zhuǎn)變?yōu)榉西[癌細(xì)胞。與Ru486治療組類似：①NICD1野生型小鼠,均狀態(tài)如常。②NICD1純合突變型小鼠,均于出生后早夭或在母體內(nèi)流產(chǎn)。③NICD1雜合突變型小鼠,根據(jù)P53和Lkbl基因型的不同,表型明顯不同：NICD1+/fl;P53fl/fl, NICDl+/fl; Lkb1fl/fl和NICDl+/fl; P53+/fl; Lkb1fl/fl小鼠如常。而NICD1+/fl; P53+/fl; LKB1+/fl, NICD1+/fl； P53fl/fl; LKB1+/fl和NICD1+/fl; P53fl/fl; LKB1fl/fl/三種基因型小鼠,肺部自發(fā)形成肺鱗癌,三組的成瘤小鼠均為1只,成瘤率均為100%,潛伏期為5-9月。所有肺癌標(biāo)本在免疫熒光染色后均強(qiáng)表達(dá)肺鱗癌標(biāo)記物K5,中等強(qiáng)度表達(dá)ProSPC,而肺鱗癌標(biāo)記物TTF1和K8表達(dá)缺失,經(jīng)免疫學(xué)證實(shí)為肺鱗癌。另外,我們還意外發(fā)現(xiàn)NICD1+/fl; P53fl/fl; LKB1fl/fl基因型小鼠在AdenoCre治療后,而不是在Ru486治療后,主氣道上皮K5細(xì)胞活躍增生,黏液明顯增多,正常纖毛丟失,Clara細(xì)胞消失。提示相同的損傷刺激和基因缺陷背景在近端大氣道和遠(yuǎn)端肺組織可引起截然不同的病理改變：近端大氣道的某些細(xì)胞(不包括K5來源細(xì)胞)可能過度分化為黏液分泌細(xì)胞,形成黏液增生性病變；而遠(yuǎn)端肺組織的某些細(xì)胞(包括K5來源細(xì)胞)可能轉(zhuǎn)變?yōu)槟[瘤細(xì)胞,參與肺鱗癌的形成。(3)Ru486治療組與AdenoCre治療組小鼠的主要區(qū)別有：①經(jīng)AdenoCre治療后的小鼠肺部腫瘤明顯較Ru486治療組小鼠肺部腫瘤多發(fā),體積大,異型性更為明顯。②經(jīng)AdenoCre治療后的小鼠明顯較Ru486治療組小鼠肺癌形成潛伏期短。③經(jīng)AdenoCre治療后的小鼠明顯較Ru486治療組小鼠成瘤率高。④相同基因背景的小鼠,經(jīng)AdenoCre治療后肺上皮增生和／或癌前病變的程度均較Ru486治療組嚴(yán)重。⑤經(jīng)AdenoCre治療后Cre+; NICDl+/fl; P53fl/fl; LKB1fl/fl小鼠支氣管黏液明顯增多,纖毛減少,而經(jīng)Ru486治療組小鼠未見類似改變。另外,在第一部分實(shí)驗(yàn)中,我們發(fā)現(xiàn)K5來源細(xì)胞具有自我更新和增殖分化能力,具有干細(xì)胞潛能,具體結(jié)果如下：(1)流式分選培養(yǎng)及免疫熒光結(jié)果示：Trop-2+ITGA6+ABSCs富集K5來源干細(xì)胞。(2)自身示蹤實(shí)驗(yàn)表明：K5來源細(xì)胞,而非K5+細(xì)胞在博來霉素肺損傷模型中增多,表現(xiàn)出向K8+祖細(xì)胞分化傾向,并可能參與損傷后肺新生血管及肺纖維化的形成。(3)異體移植實(shí)驗(yàn)表明：供體K5-YFP+ve細(xì)胞在博來霉素?fù)p傷受體鼠肺內(nèi)明顯增多,且表現(xiàn)出向K8+祖細(xì)胞分化傾向。結(jié)論：盡管目前已存在四種肺鱗癌轉(zhuǎn)基因小鼠模型,但這些模型存在形成腫瘤類型混雜,成瘤時間長,成瘤率低,小鼠肺鱗癌與人肺鱗癌病理特征之間差別大等缺點(diǎn),而我們成功構(gòu)建的K5-CrePR; NICD1; P53; Lkbl肺鱗癌轉(zhuǎn)基因小鼠模型在病理切片上呈現(xiàn)出氣道上皮輕度異型增生至肺鱗癌的各階段改變,更符合人肺鱗癌的發(fā)生發(fā)展過程。且具有形成肺癌類型單一,僅為肺鱗癌的優(yōu)點(diǎn)。因此,可為臨床人肺鱗癌的研究提供理想的工具鼠模型。另外,NICD1可能作為肺鱗癌發(fā)生的驅(qū)動基因在肺鱗癌的發(fā)生發(fā)展過程中起至關(guān)重要的作用,抑制Notch通路過度激活可能有助于預(yù)防肺鱗癌的發(fā)生。而K5來源細(xì)胞具有腫瘤干細(xì)胞的特征,抑制K5來源細(xì)胞的異常過度增生,可能為臨床肺鱗癌的預(yù)防治療提供新的思路。
[Abstract]:Background and objective: lung squamous cell carcinoma is a highly lethal type of lung cancer. In all lung cancers, the incidence of lung cancer is second only to that of lung adenocarcinoma. Because of limited treatment, the 5 year survival rate of advanced squamous cell carcinoma is less than 15%. human lung squamous cell carcinoma. It is generally believed that normal bronchial mucosa false stratified columnar epithelial cells are chronic. Irritation and injury, loss of normal cilia, the emergence of varying degrees of bronchial epithelial hyperplasia, and subsequent atypical hyperplasia, squamous metaplasia and dysplasia, and the last part of the carcinoma in situ and invasive carcinoma. It is suggested that lung squamous cell carcinoma may be prevented if it can prevent or reverse the benign lesions of any link before the occurrence of squamous carcinoma of the lung. At present, transgenic mice of lung squamous cell carcinoma have been gradually applied to the study of human lung squamous cell carcinoma. There are four known methods of Construction: Lkbl knockout /KrasGI2D overexpression, IKKa death kinase knocking, Lkbl/Pten knockout and Sox2 overexpression /Lkbl knockout. Although these mice can develop squamous cell carcinoma of the lung, there is a mixed type of lung cancer. However, the initiation of lung squamous cell carcinoma is still undefined. Therefore, three of them are selected in this group. The gene of human lung squamous cell carcinoma is closely related to the construction of a transgenic mouse model, in order to find the promoter gene of lung squamous cell carcinoma, and try to help the diagnosis, treatment and prevention of the clinical lung squamous cell carcinoma by simulating the similar process in the lung of the lung squamous cell carcinoma in the lungs of mice. In addition, the cytokeratin 5 (K5) source cell is a class of stem cells. Cell specific cell groups and may be associated with the occurrence of lung cancer. We used Cre-loxP system to investigate whether cells from K5 specific sources and non-specific sources can form tumors in mice and form tumors in the lungs of mice with the same damage and gene defects, so as to explore whether the K5 derived cells have a tumor or not. Methods: according to the genetic analysis data of 178 human lung squamous cell carcinoma specimens issued by Cancer Genome Atlas Research Network (TCCA) in 2012 and the results (unpublished data) of this group of mice in vitro, we chose the three genes of NICD1, Lkb1 and P53, using Cre-lox. P system, K5-CrePR; NICD1; P53; Lkbl transgenic mice model. The expression of K5 cell specific Cre recombinant enzyme was induced by Ru486 or the method of using non cell specific Adenovirus Cre recombinant enzyme to induce the excessive activation of NICD1 in Notch pathway, and the expression of silencing tumor suppressor gene and in mice in the same time. After that, the transgenic mice were stimulated by polycol lung injury, and the mice were observed for a long time. After the abnormal state or signs of the mice, the mice were sacrificed to leave the lung tissue specimens. First, the HE staining method was used to screen the formation of lung tumor and the pathological type of lung tumor. Then, the lung tumor was screened out. The specific marker antibody of different types of lung cancer was used to carry out immunofluorescence staining to further determine the specific pathological types of lung cancer. Finally, the data of all transgenic mice were collated. 1. the pathological characteristics of the lung were summarized, and the effect of each gene on the formation of the tumor was analyzed. 2. the two sources of Cre weight were summarized. The effects of the enzyme on the formation of lung tumor in mice were analyzed and the role of K5 derived cells in the formation of lung cancer was analyzed. In addition, in the first part of the experiment, we preliminarily discussed the stem cell function of the K5 derived cells: 1. the method of flow sorting and the culture of the gas liquid phase system of the extracorporeal airway stem cells was used to observe the Trop-2+ITGA6+ gas. Whether or not the stem cells (ABSCs) enriched K5 derived stem cells,.2. used K5-CrePR-YFP transgenic mice, and traced the dynamic changes of K5 source cells in the lung tissue of mice with bleomycin lung injury by the self tracing of K5-YFP+ve cells and.3. used K5-CrePR-YFP transgenic mice as donor mice by Frop-2+ITGA6+ABSCs allograft transplantation. The dynamic changes of the donor mouse K5-YFP+ve stem cells in the lung tissue of the bleomycin lung injury rat were traced. Results: a transgenic mouse model of lung squamous cell carcinoma was successfully constructed and the epithelial dysplasia of different degrees before the carcinogenesis of human lung squamous cell carcinoma was observed in the mice. All lung squamous cell carcinomas occurred in the NICD1 heterozygous mutant mice (N The ICD1 homozygous mutant mice could not survive), suggesting that NICD1 may be the driving gene of lung squamous cell carcinoma. In the case of external injury stimulation and common defects of P53 and Lkbl, the normal cells change into lung squamous cell carcinoma cells and participate in the formation of lung squamous cell carcinoma. The specific results are as follows: (1) lung squamous cell carcinoma in the Ru486 group of mice is presented. The K5 source cells may have the function of tumor stem cells and change into lung squamous cell carcinoma cells under the joint action of injury stimulation and gene defect. In all mice, the NICD1 wild type mice are all state as usual. (2) the NICD1 homozygous mutant mice were all aborted early or in the mother body. 3. NICD1 heterozygous mutant mice, according to P53 and Lk The phenotype of BL genotypes was distinct: NICD1+/fl; P53fl/fl, NICD1+/fl; Lkb1fl/fl and NICD1+/fl; P53+/fl; Lkb1fl/fl mice as usual. And NICD1+/fl; P53+/fl; LKB1+/fl, NICD1+/fl; three genotypes, spontaneous squamous cell carcinomas of the lungs, and the number of three groups of tumorigenic mice 1, 2 and 2 were 25%, 28.6% and 33.3%, respectively, and the incubation period was 5-12 months. All lung cancer specimens strongly expressed lung squamous cell carcinoma markers K5 after immunofluorescence staining, while lung squamous cell carcinoma markers TTF1 and cytokeratin 8 (K8) were expressed as lung squamous carcinoma. (2) Adeno virus Cre (AdenoCre) treatment group showed lung scale. Cancer, and more serious than that of the Ru486 treatment group, suggests that there may be other cell groups with tumor stem cell functions except the K5 source cells, which together with K5 derived cells under the joint action of injury stimulation and gene defects, together with the lung squamous cell carcinoma cells. It is similar to the Ru486 treatment group: (1) the NICD1 wild type mice are all as usual. (2) NICD1 homozygous mutant mice were aborted early or in the mother body after birth. 3. The phenotype of NICD1 heterozygous mutant mice was obviously different according to the P53 and Lkbl genotypes: NICD1+/fl; P53fl/fl, NICDl+/fl; Lkb1fl/fl and NICDl+/fl; P53+/fl; Lkb1fl/fl mice. LKB1+/fl and NICD1+/fl; P53fl/fl; LKB1fl/fl/ three genotypes mice, lung squamous cell carcinomas were spontaneously formed in the lungs, and 1 mice in the three group were all tumor forming mice, the tumor formation rate was 100% and the incubation period was 5-9 months. All lung cancer specimens strongly expressed K5 of lung squamous cell carcinoma markers after immunofluorescence staining, the medium intensity expressed ProSPC, and the markers of lung squamous cell carcinoma TTF1 and K8 table. In addition, we also found that NICD1+/fl; P53fl/fl; LKB1fl/fl genotype mice were treated with AdenoCre, but not after Ru486 treatment, K5 cells in the main airway epithelium were proliferated, mucus was markedly increased, normal cilium lost, and Clara cells disappeared. The same injury stimulation and gene defect back were suggested. The near terminal large airway and distal lung tissue can cause completely different pathological changes: some cells in the proximal large airway (not including K5 source cells) may excessively differentiate into mucous secretory cells to form mucous proliferative lesions; and some cells in the distal lung tissue (including K5 derived cells) may be transformed into tumor cells and participate in the lung scale. The formation of cancer. (3) the main differences between the Ru486 treatment group and the AdenoCre treatment group were as follows: (1) the lung tumor of the mice after the AdenoCre treatment was obviously more frequent than the Ru486 treatment group, the volume was large and the heteromorphy was more obvious. (2) the mice after the AdenoCre treatment were obviously shorter than the Ru486 treatment group. 3. AdenoC The mice after re treatment were significantly higher than those in the Ru486 treatment group. 4. The extent of lung epithelial hyperplasia and / or precancerous lesion after AdenoCre treatment in mice with the same gene background was more serious than that in the Ru486 treatment group. 5. After AdenoCre treatment, Cre+; NICDl+/fl; P53fl/fl; LKB1fl/fl rat bronchial mucus was significantly increased and cilia decreased, and Ru was reduced to Ru. In the 486 treatment group, no similar changes were found in the mice. In the first part of the experiment, we found that the K5 source cells have the ability of self renewal and proliferation and differentiation and have the potential of stem cells. The specific results are as follows: (1) flow cytometry and immunofluorescence results show that Trop-2+ITGA6+ ABSCs enriching K5 derived stem cells. (2) self tracer experiment showed that K 5 source cells, not K5+ cells in the bleomycin lung injury model, showed a tendency to differentiate into K8+ progenitor cells, and may participate in the formation of pulmonary neovascularization and pulmonary fibrosis after injury. (3) the allograft experiment showed that the donor K5-YFP+ve cells were significantly increased in the lungs of the injured mice in the bleomycin injury and displayed to the K8+ progenitor cells. Conclusion: Although there are four kinds of transgenic mice model of lung squamous cell carcinoma, these models have the disadvantages of forming tumor type mixed, long tumorigenesis, low tumor rate, large difference between lung squamous cell carcinoma and human lung squamous cell carcinoma, and we successfully constructed K5-CrePR; NICD1; P53; Lkbl transgenic mice model of lung squamous cell carcinoma The pathological sections show a slight dysplasia of the airway epithelium to the squamous cell carcinoma of the lung, which is more consistent with the development of human squamous cell carcinoma, and has the advantage of forming a single lung cancer type and only a squamous carcinoma of the lung. Therefore, it can provide an ideal tool mouse model for the study of human lung squamous cell carcinoma. In addition, NICD1 may be used as a squamous cell carcinoma of the lung. The induced gene plays a vital role in the development and development of lung squamous cell carcinoma. Inhibition of overactivation of Notch pathway may help prevent the occurrence of squamous cell carcinoma of the lung. K5 derived cells have the characteristics of tumor stem cells and inhibit abnormal hyperproliferation of K5 derived cells, which may provide a new idea for the prevention and treatment of lung squamous cell carcinoma.

【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】：R-332;R734.2

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