鼻咽纖維血管瘤血管內(nèi)皮細(xì)胞比正常血管內(nèi)皮細(xì)胞具有更強(qiáng)的遷移和侵襲能力
發(fā)布時間：2018-11-14 19:57
【摘要】：鼻咽纖維血管瘤,又稱青少年鼻咽纖維血管瘤(juvenile nasopharyngeal angiofibroma, JNA)是鼻咽部良性腫瘤中最常見的一種,約占總頭頸部腫瘤的0.5%,主要發(fā)生于14-25歲的青少年男性。盡管JNA組織學(xué)上呈良性表型,但其沒有包膜,而且具有局部侵襲和破壞性惡性表型,可以累及鼻腔、鼻咽部、鼻竇、翼腭窩、顳下窩、翼突以及前顱底組織等。 JNA沒有特異性的藥物治療手段,放射療法的使用尚存在爭議,外科手術(shù)切除仍然是目前最常用的治療方法。近年來,隨著耳鼻喉科臨床治療手段的長足進(jìn)步,特別是術(shù)前栓塞和鼻內(nèi)鏡技術(shù)的使用,使得大部分患者獲得了較好的預(yù)后,但是JNA術(shù)后高復(fù)發(fā)率(可高達(dá)50%)仍是一個極大的挑戰(zhàn)。目前關(guān)于JNA術(shù)后高復(fù)發(fā)的原因和相關(guān)的臨床預(yù)測指標(biāo)研究甚少,可能與JNA向周圍顱底骨質(zhì)侵襲,手術(shù)難以徹底切除有關(guān)。如能闡明引起JNA局部侵襲及術(shù)后復(fù)發(fā)的因素及其分子調(diào)節(jié)機(jī)制,將進(jìn)一步改善JNA患者的預(yù)后。 腫瘤血管生成與包括JNA在內(nèi)的多種腫瘤生長和局部侵襲密切相關(guān)。但是目前基于JNA血管生成及其分子機(jī)制研究不多,特別是針對內(nèi)皮細(xì)胞本身的功能研究更少,關(guān)鍵在于缺乏直接來源于腫瘤標(biāo)本并可用于體外培養(yǎng)的血管內(nèi)皮工具細(xì)胞。本課題首先分析血管內(nèi)皮標(biāo)記物CD105在JNA組織芯片(tissue microarray, TMA)微血管內(nèi)皮細(xì)胞中的表達(dá)及其臨床意義,進(jìn)一步通過免疫磁珠分選(magnetic activated cell sorting, MACS)人JNA的血管內(nèi)皮細(xì)胞進(jìn)行傳代培養(yǎng),檢測腫瘤血管內(nèi)皮細(xì)胞及正常血管內(nèi)皮細(xì)胞間的功能差異并探討其差異的分子機(jī)制,以期闡明導(dǎo)致JNA高復(fù)發(fā)的原因及可能機(jī)制,并以此尋找新的復(fù)發(fā)干預(yù)途徑,進(jìn)一步提高療效。 第一部分 血管內(nèi)皮標(biāo)記物CD105在鼻咽纖維血管瘤組織芯片微血管中的表達(dá)及其臨床意義 目的：通過構(gòu)建組織芯片并運用免疫組織化學(xué)染色的方法明確CD105蛋白在JNA微血管中的表達(dá),并分析其與JNA臨床病理特征以及復(fù)發(fā)之間的關(guān)系。 方法：通過免疫組織化學(xué)染色方法在一套獨立的組織芯片(包括70例JNA患者的腫瘤組織)中檢測了CD105的表達(dá)情況,進(jìn)行微血管計數(shù),并分析其與年齡、JNA手術(shù)史、手術(shù)方式、腫瘤分期、術(shù)中出血等臨床病理特征的關(guān)系,同時進(jìn)一步分析微血管密度(microvessel density, MVD)與JAN患者臨床病理參數(shù)及至復(fù)發(fā)時間(time to recurrence, TTR)的相關(guān)性。 結(jié)果：免疫組織化學(xué)檢測結(jié)果顯示,CD105僅表達(dá)于血管內(nèi)皮細(xì)胞中,在間質(zhì)中未見明顯表達(dá)�？ǚ綑z驗分析發(fā)現(xiàn)微血管數(shù)目高低與腫瘤復(fù)發(fā)顯著相關(guān)(P=0.013)。Kaplan-Meier生存分析和log-rank檢驗顯示,低微血管密度患者的TTR顯著高于高微血管密度患者(P=0.009)。多因素回歸模型結(jié)果也提示,微血管密度是一個決定JNA預(yù)后的獨立因素(P=0.01)。 結(jié)論：CD105染色的腫瘤微血管密度可以預(yù)測JNA患者術(shù)后復(fù)發(fā),提示血管生成在JNA發(fā)生發(fā)展進(jìn)程中可能起重要作用,有望成為JNA治療靶點和預(yù)后預(yù)測指標(biāo)。同時,為將CD105做為分離JNA血管內(nèi)皮細(xì)胞的表面標(biāo)記提供了臨床依據(jù)。 第二部分 人鼻咽纖維血管瘤血管內(nèi)皮細(xì)胞分選、鑒定與培養(yǎng) 目的：分選、鑒定及傳代培養(yǎng)人鼻咽纖維血管瘤血管內(nèi)皮細(xì)胞。 方法：采用抗CD105抗體交聯(lián)免疫磁珠,通過免疫磁珠分選法,對JNA組織進(jìn)行血管內(nèi)皮細(xì)胞分選；采用流式細(xì)胞術(shù)檢測陽性分選細(xì)胞的純度。通過細(xì)胞免疫化學(xué)法檢測von Willebrand factor (vWF,又稱Ⅷ因子)的表達(dá),并通過乙�；兔芏戎鞍讛z取實驗及小管生成實驗驗證陽性分選細(xì)胞是否具有血管內(nèi)皮細(xì)胞的功能。 結(jié)果：流式檢測陽性分選細(xì)胞的CD105表達(dá)高達(dá)99%以上；細(xì)胞免疫化學(xué)檢測顯示陽性分選細(xì)胞中Ⅷ因子表達(dá)為陽性,超過95%的陽性分選細(xì)胞乙酰化低密度脂蛋白攝取實驗陽性；分選細(xì)胞在基質(zhì)膠中可形成毛細(xì)管結(jié)構(gòu)。同時可將陽性分選細(xì)胞進(jìn)行傳代培養(yǎng)至10代以上,其內(nèi)皮細(xì)胞特性仍存在。 結(jié)論：通過免疫磁珠分選(MACS)法,我們成功分選獲得高純度的CD105陽性鼻咽纖維血管瘤血管內(nèi)皮細(xì)胞(CD105+ juvenile nasopharyngeal angiofibroma-derived endothelial cell, CD105+ JEC),并能夠成功傳代培養(yǎng),為后續(xù)研究提供了細(xì)胞平臺。 第三部分 鼻咽纖維血管瘤血管內(nèi)皮細(xì)胞與正常血管內(nèi)皮細(xì)胞的功能比較 目的：比較JNA組織中分離的CD105陽性內(nèi)皮細(xì)胞與人臍靜脈內(nèi)皮細(xì)胞(human umbilical vein endothelial cell, HUVEC)的功能差異。 方法：采用CyQUANT法增殖實驗、劃痕實驗及Transwell侵襲實驗對比觀察兩種細(xì)胞體外的增殖、侵襲和遷移能力的異同；通過免疫熒光觀察細(xì)胞骨架蛋白肌動蛋白纖維(F-actin)的表達(dá)和細(xì)胞內(nèi)定位分布的差異,運用Western blot檢測基質(zhì)金屬蛋白酶-2 (matrix metalloproteinase-2, MMP-2)及血管內(nèi)皮細(xì)胞生長因子受體(Vascular endothelial growth factor receptor, VEGFR)相關(guān)信號通路蛋白表達(dá)水平異同。 結(jié)果：增殖實驗發(fā)現(xiàn)CD105+JEC的增殖能力低于HUVEC；而劃痕實驗、侵襲實驗及F-actin熒光染色顯示CD105+JEC的遷移和侵襲能力高于HUVEC; Western blot結(jié)果顯示VEGFR1、p-MAPK、MMP-2在CD105+JNA血管內(nèi)皮細(xì)胞中的表達(dá)高于HUVEC,而VEGFR2、p-ERK的表達(dá)則相反。 結(jié)論：CD105+JEC比HUVEC具有更強(qiáng)的體外遷移、侵襲能力,其機(jī)制可能與VEGFR相關(guān)信號通路的差異性活化有關(guān)。
[Abstract]:Hemangioma of the nasopharynx, also known as the juvenile nasopharyngeal fibroma (JNA), is the most common one of the benign tumors of the nasopharynx, accounting for 0.5% of the total head and neck tumors, which mainly occurs in the 14-25-year-old male. Although the JNA is of a benign phenotype, it has no envelope and has a local attack and a destructive and malignant phenotype, which may involve the nasal cavity, the nasopharynx, the nose, the wing, the inferior fossa, the wing, and the anterior skull base tissue, and the like. JNA has no specific drug treatment means, the use of radiation therapy is still in dispute, and surgical resection is still the most commonly used treatment at present Methods: In recent years, with the rapid progress of the clinical treatment of otorhinolaryngology, especially the use of pre-operative embolization and nasal endoscopic technique, most patients have a good prognosis, but the high recurrence rate (up to 50%) after the operation of JNA is still a great Challenges. There are few studies on the causes of high recurrence and associated clinical predictors of postoperative high recurrence of JNA, which may be associated with the invasion of the surrounding base of the skull by the JNA, and the operation is difficult to complete with a complete resection. The factors of local invasion and post-operative recurrence of JNA and their molecular regulatory mechanisms will be further improved, which will further improve the JNA patients. Prognosis. Tumor angiogenesis and multiple tumor growth and local invasion, including JNA It is closely related to the attack, but at present, the research on the angiogenesis and molecular mechanism of the JNA is not much, especially for the function of the endothelial cell itself, the key point is the lack of a blood vessel which is directly derived from the tumor specimen and can be used for in-vitro culture. The expression of the vascular endothelial marker CD105 in the vascular endothelial cells of the tissue of the JNA tissue and its clinical significance were first analyzed. The vascular endothelial cells of the human JNA of the human JNA were further classified by the magnetic cell sorting (MACS). The functional difference between the endothelial cells of the tumor and the normal vascular endothelial cells was detected and the molecular mechanism of the difference was discussed, with a view to elucidating the causes and possible mechanisms of the high recurrence of JNA and finding a new way of recurrence intervention. step-up therapy Effect: The first part of the vascular endothelial marker CD105 is in the nasopharyngeal fibroma tissue chip. Expression of the blood vessel and its clinical significance: by constructing the tissue chip and using the immunohistochemical staining method, it is clear that the CD10 The expression of 5-protein in JNA microvessel and its interaction with JNA Methods: The expression of CD105 was detected in a set of independent tissue chips (including 70 JNA patients) by immunohistochemical staining. The microvessel counts were performed and their relationship with age was analyzed. The relationship between microvessel density (MVD) and clinical pathological parameters and time to re-recurrence in JAN patients was further analyzed. Correlation of currence, TTR). Results: The results of the immunohistochemistry showed that the CD105 only It was found that the number of microvessels was significantly correlated with the recurrence of the tumor (P = 0.013) in the vascular endothelial cells (P = 0.013). The Kaplan-Meier survival analysis and the log-rank test showed that the TTR of low microvessel density patients was significant. In patients with higher microvessel density (P = 0. 009), the multi-factor regression model results also suggest that the microvessel density is one The independent factor of the prognosis of JNA was determined (P = 0.01). Conclusion: The tumor microvessel density of CD105 can predict the postoperative recurrence of JNA, and it is suggested that angiogenesis can play a role in the development of JNA. It is expected to be a target for the treatment of JNA and to predict the prognosis of the prognosis. Separation of JN A clinical basis is provided for surface labeling of vascular endothelial cells. The classification, identification and identification of vascular endothelial cells in the second part of human nasopharyngeal fibroma in that method, the anti-CD105 antibody cross-linked immunomagnetic bead is adopted, The expression of von Willebrand factor (vWF, also called factor VIII) was detected by flow cytometry, and the low density of von Willebrand factor (vWF, also called factor VIII) was detected by cell immunochemical method. The results showed that the expression of CD105 in the flow-type test-positive sorted cells was higher than 99%, and the immunochemical test of the cells showed that the positive separation was fine. The expression of the factor VIII in the cell is positive, and more than 95% of the male is positive. Positive for low-density lipoprotein uptake in sex-sorted cells, and the ability of sorting cells to form a hair in a matrix gel It is concluded that by the method of immunomagnetic bead sorting (MACS), we have successfully sorted the vascular endothelial cells (CD105 + juvenile nasopharyngeal angio-derivedenthel) with high-purity CD105-positive nasopharyngeal fibroma. (c) ell, CD105 + JEC) and can be successfully subcultured, after The functional comparison of the vascular endothelial cells of the third part of the nasopharyngeal fibroma and the normal vascular endothelial cells is to compare the CD105-positive endothelial cells isolated from the JNA tissues with the human umbilical vein. Methods: The proliferation and invasion of two cells in vitro were observed by Cyquant method proliferation experiment, scratch test and Transwell invasion experiment. Western blot was used to detect the expression of the matrix metalloproteinases-2 (MMP-2) and the vascular endothelial growth factor receptor (Vasca). The results showed that the proliferation ability of CD105 + JEC was lower than that of HUVEC. The results showed that the proliferation ability of CD105 + JEC was lower than that of HUVEC. The results showed that the migration and invasion ability of CD105 + JEC was higher than that of HUVEC. Western blot showed that VEGFR1, p-M The expression of APK and MMP-2 in CD105 + JNA vascular endothelial cells was higher than that of HUVEC, while the expression of VEGFR2, p-ERK was opposite.
【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】：R739.63
本文編號：2332142
[Abstract]:Hemangioma of the nasopharynx, also known as the juvenile nasopharyngeal fibroma (JNA), is the most common one of the benign tumors of the nasopharynx, accounting for 0.5% of the total head and neck tumors, which mainly occurs in the 14-25-year-old male. Although the JNA is of a benign phenotype, it has no envelope and has a local attack and a destructive and malignant phenotype, which may involve the nasal cavity, the nasopharynx, the nose, the wing, the inferior fossa, the wing, and the anterior skull base tissue, and the like. JNA has no specific drug treatment means, the use of radiation therapy is still in dispute, and surgical resection is still the most commonly used treatment at present Methods: In recent years, with the rapid progress of the clinical treatment of otorhinolaryngology, especially the use of pre-operative embolization and nasal endoscopic technique, most patients have a good prognosis, but the high recurrence rate (up to 50%) after the operation of JNA is still a great Challenges. There are few studies on the causes of high recurrence and associated clinical predictors of postoperative high recurrence of JNA, which may be associated with the invasion of the surrounding base of the skull by the JNA, and the operation is difficult to complete with a complete resection. The factors of local invasion and post-operative recurrence of JNA and their molecular regulatory mechanisms will be further improved, which will further improve the JNA patients. Prognosis. Tumor angiogenesis and multiple tumor growth and local invasion, including JNA It is closely related to the attack, but at present, the research on the angiogenesis and molecular mechanism of the JNA is not much, especially for the function of the endothelial cell itself, the key point is the lack of a blood vessel which is directly derived from the tumor specimen and can be used for in-vitro culture. The expression of the vascular endothelial marker CD105 in the vascular endothelial cells of the tissue of the JNA tissue and its clinical significance were first analyzed. The vascular endothelial cells of the human JNA of the human JNA were further classified by the magnetic cell sorting (MACS). The functional difference between the endothelial cells of the tumor and the normal vascular endothelial cells was detected and the molecular mechanism of the difference was discussed, with a view to elucidating the causes and possible mechanisms of the high recurrence of JNA and finding a new way of recurrence intervention. step-up therapy Effect: The first part of the vascular endothelial marker CD105 is in the nasopharyngeal fibroma tissue chip. Expression of the blood vessel and its clinical significance: by constructing the tissue chip and using the immunohistochemical staining method, it is clear that the CD10 The expression of 5-protein in JNA microvessel and its interaction with JNA Methods: The expression of CD105 was detected in a set of independent tissue chips (including 70 JNA patients) by immunohistochemical staining. The microvessel counts were performed and their relationship with age was analyzed. The relationship between microvessel density (MVD) and clinical pathological parameters and time to re-recurrence in JAN patients was further analyzed. Correlation of currence, TTR). Results: The results of the immunohistochemistry showed that the CD105 only It was found that the number of microvessels was significantly correlated with the recurrence of the tumor (P = 0.013) in the vascular endothelial cells (P = 0.013). The Kaplan-Meier survival analysis and the log-rank test showed that the TTR of low microvessel density patients was significant. In patients with higher microvessel density (P = 0. 009), the multi-factor regression model results also suggest that the microvessel density is one The independent factor of the prognosis of JNA was determined (P = 0.01). Conclusion: The tumor microvessel density of CD105 can predict the postoperative recurrence of JNA, and it is suggested that angiogenesis can play a role in the development of JNA. It is expected to be a target for the treatment of JNA and to predict the prognosis of the prognosis. Separation of JN A clinical basis is provided for surface labeling of vascular endothelial cells. The classification, identification and identification of vascular endothelial cells in the second part of human nasopharyngeal fibroma in that method, the anti-CD105 antibody cross-linked immunomagnetic bead is adopted, The expression of von Willebrand factor (vWF, also called factor VIII) was detected by flow cytometry, and the low density of von Willebrand factor (vWF, also called factor VIII) was detected by cell immunochemical method. The results showed that the expression of CD105 in the flow-type test-positive sorted cells was higher than 99%, and the immunochemical test of the cells showed that the positive separation was fine. The expression of the factor VIII in the cell is positive, and more than 95% of the male is positive. Positive for low-density lipoprotein uptake in sex-sorted cells, and the ability of sorting cells to form a hair in a matrix gel It is concluded that by the method of immunomagnetic bead sorting (MACS), we have successfully sorted the vascular endothelial cells (CD105 + juvenile nasopharyngeal angio-derivedenthel) with high-purity CD105-positive nasopharyngeal fibroma. (c) ell, CD105 + JEC) and can be successfully subcultured, after The functional comparison of the vascular endothelial cells of the third part of the nasopharyngeal fibroma and the normal vascular endothelial cells is to compare the CD105-positive endothelial cells isolated from the JNA tissues with the human umbilical vein. Methods: The proliferation and invasion of two cells in vitro were observed by Cyquant method proliferation experiment, scratch test and Transwell invasion experiment. Western blot was used to detect the expression of the matrix metalloproteinases-2 (MMP-2) and the vascular endothelial growth factor receptor (Vasca). The results showed that the proliferation ability of CD105 + JEC was lower than that of HUVEC. The results showed that the proliferation ability of CD105 + JEC was lower than that of HUVEC. The results showed that the migration and invasion ability of CD105 + JEC was higher than that of HUVEC. Western blot showed that VEGFR1, p-M The expression of APK and MMP-2 in CD105 + JNA vascular endothelial cells was higher than that of HUVEC, while the expression of VEGFR2, p-ERK was opposite.
【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】：R739.63
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