上皮性卵巢肿瘤相关微淋巴管内皮细胞的体外培养及其特性研究
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摘要
第一部分上皮性卵巢肿瘤中微淋巴管内皮细胞的存在及其分布特点
目的研究上皮性卵巢肿瘤中微淋巴管内皮细胞的存在及其分布特点，探讨从上皮性卵巢肿瘤单细胞悬液中分离微淋巴管内皮细胞的可行性。方法(1)淋巴管内皮细胞标记分子D2-40相关免疫组织化学染色检测15例上皮性卵巢肿瘤(其中恶性10例，交界性5例)中微淋巴管的密度(1ymphatic vessels density，LVD)和微淋巴管所占的面积百分比(1ymphatic vessels area，LVA)；D2-40／Ki-67相结合双标免疫组织化学方法检测有无增生状态的微淋巴管内皮细胞。(2)流式细胞仪分别检测前述15例上皮性卵巢肿瘤新鲜组织，5例良性上皮性卵巢肿瘤和5例正常卵巢组织新鲜组织中淋巴管内皮透明质酸受体-1((lymphatic vessel endothelialHA receptor-1，LYVE-1)阳性细胞的比例。结果(1)交界性卵巢肿瘤中的LVD为(13．23±8．26)条／4HP，与恶性肿瘤(14．22±7．21)条／4HP相比无显著统计学差异(P＞0．05)。但是恶性上皮性肿瘤中LVA为(3．52±1．61)％较交界性卵巢肿瘤(2．21±1．42)％明显升高(P＜0．05)。Ki-67在D2-40(+)的淋巴管内皮细胞中无表达。(2)卵巢上皮肿瘤组织单细胞悬液中LYVE-1(+)细胞的比例为2-11％，恶性与交界性组织相比无显著统计学差异，但是比例较正常和良性卵巢肿瘤组织高(P＜0．05)。结论恶性和交界性卵巢肿瘤中存在微淋巴管内皮细胞，二者之间无显著差异。
第二部分体外分离，培养，鉴定上皮性卵巢肿瘤来源的微淋巴管内皮细胞及其一般生物学特点
目的从交界性和恶性上皮性卵巢肿瘤组织中分离微淋巴管内皮细胞，体外进行培养，鉴定和纯化，研究该细胞的一般生物学特性。方法(1)胶原酶消化26例新鲜卵巢肿瘤(其中交界性11例和恶性15例)组织得到单细胞悬液，免疫磁珠分选其中的LYVE-1(+)细胞体外贴壁进行二维和三维培养。(2)应用泛内皮细胞标记分子CD31和多种淋巴内皮细胞标记分子如Prox-1，D2-40，VEGFR-3和LYVE-1鉴定该细胞。(3)持续传代培养该细胞，尝试不同条件下的效果，探讨其生长的规律。(4)结合临床资料分析影响实验成功的因素。结果(1)应用免疫磁珠技术可以成功分离到上皮性卵巢肿瘤细胞中的LYVE-1(+)细胞并体外培养传代。(2)该细胞表达CD31，Prox-1，D2-40，VEGFR-3和LYVE-1，经联合鉴定其纯度在90％以上。(3)上皮性卵巢肿瘤来源的微淋巴管内皮细胞可以传6代以上并维持基本性状。(4)实验的成功率与患者年龄密切相关，年龄＜30岁者成功率显著升高(P＜0．05)。与病理类型无显著关联(P＞0．05)。结论应用免疫磁珠技术可以从卵巢肿瘤中分离培养微淋巴管内皮细胞，该细胞体外性状稳定，可以用于后续实验的研究。
第三部分上皮性卵巢肿瘤来源的微淋巴管内皮细胞及其在体外对肿瘤细胞CAOV-3的影响
目的研究上皮性卵巢肿瘤来源的微淋巴管内皮细胞在体外对卵巢癌细胞株增殖，侵袭和迁移能力的影响及其作用机制。方法(1)分别培养上皮性卵巢肿瘤来源的肿瘤相关微淋巴管内皮细胞(tumor associated1ymphatic endothelial cell，TLEC)和正常新生儿真皮来源的微淋巴管内皮细胞(normal lymphatic endothelial cell，NLEC)。并收集这两种细胞的上清得到相应的内皮细胞条件培养基。(2)分别用这两种条件培养基干预生长旺盛的卵巢癌细胞系CAOV-3，消化后苔盼蓝染色计数了解其对肿瘤细胞增值的影响，Transwell小室法检测干预后肿瘤细胞侵袭和迁移能力。(3)RT-PCR和荧光定量PCR检测分别受到两种条件培养基干预后CAOV-3细胞MMP-2．MMP-9，TIMP-1，TIMP-2和CXCR-4的表达水平。(4)明胶酶谱法检测TLEC和NLEC对肿瘤细胞CAOV-3分泌转移相关因子MMP-2和MMP-9的影响。结果(1)TLEC细胞条件培养基可以显著增强肿瘤细胞的侵袭和迁移能力。但是该细胞对肿瘤增殖有无影响尚难以确定。(2)PCR结果表明在mRNA水平受到TLEC干预的肿瘤细胞与受到NLEC干预的细胞相比其表达MMP-9的表达水平显著升高(P＜0．05)，同时TIMP-2的表达水平显著降低(P＜0．05)；而MMP-2、TIMP-1和CXCR4的表达无显著差异(P＞0．05)。(3)明胶酶谱法证实受到TLEC干预的CAOV-3细胞较受到NLEC干预者分泌MMP-9更多(P＜0．05)，而两者之间MMP-2的分泌无显著差异(P＞0．05)。结论上皮性肿瘤相关的微淋巴管内皮细胞可能通过激活MMP-9／TIMP-2途径增强卵巢肿瘤细胞株CAOV-3的侵袭与迁移能力。
PartⅠ
The existence and characters of tumor associated lymphaticendothelial cell in epithelial ovarian tumor
Objective To study the existence and distribution of lymphatic endothelialcells in epithelial ovarian tumor.Methods (1)Monoclonal lymphaticendothelial cell marker D2-40 antibody was used to immunistain thelymphatic microvessels in the paraffin sections of epithelial ovarian tumor(including 10 malignant and 5 borderline).Antibodies of D2-40 and Ki-67were used together by double immuohistchemistry to detect proliferation oflymphatic endothelial cells.Computer-assisted morph metric analysis wasused to quantitatively analyze lymphatic vessel density (LVD) and lymphaticvessel area (LVA) in epithelial ovarian tumor.(2) Polyclonal lymphatic vesselendothelial HA receptor- 1(LYVE-1) antibody was used to embark epithelialovarian tumor tissue (including 10 malignant,5 borderline,5 benign and 5control) single cell suspension for FCM detection.Results There was no significant difference between LVD in epithelial borderline ovarian tumorand malignant ovarian tumor ((13.23±8.26) vessels/4HP VS(14.22±7.21)vessels/4HP,P＞0.05).However,LVA in malignant ovarian tumor wassignificantly increased than that in borderline group ((3.52±1.61)% VS(2.21±1.42)%,P＜0.05).Lymphangiogenesis of epithelial ovarian cancer wasstill a pending question as the co-existence of D2-40 and Ki-67 was absenceby double immunohistchemostrity technique.LYVE-1 (+) cells can bedetected in both malignant and borderline tissue single cell suspension byFCM.Conclusion The existence of lymphatic endothelial cells in epithelialovarian tumor was sure.It's possible to isolate this cell from its single cellsuspension.
PartⅡ
The isolation,culture and identification of lymphatic endothelialcells from epithelial ovarian tumor and its biological characters incommon
Objective To study the feasibility of culture lymphatic endothelial cells(LECs) which were isolated from epithelial ovarian tumor in vitro,and offerbasic technology for researching development of epithelial ovarian tumor (including borderline and malignant ones).Methods (1) Epithelial ovariancancer single cell suspensions were obtained by digestion with collagenasefrom 26 cases (11 borderline and 15 malignant).LYVE-1 antibody was usedas LEC markers to isolate LEC by magnetic tosylactivated Macsbeads.LECswere culture in both two- and three-dimensional model in vitro.(2) Toidentify the cell by immunostain pan-endothelial cell marker CD31 andseveral LEC markers such as LYVE-1,D2-40,VEGFR-3(Flt-4),Prox-1.(3)LECs were subcultured consecutively until died,summarized the rule ofisolation and culture this new cell.Results (1) By magnetic beadstechnology LYVE-1(+) lymphatic endothelial cell can be harvested andculture successfully in vitro.Most of TLECs were from borderline tumor asthe age agent.(2) The identification purity of this cell by CD31 was 100%,Prox-1 was 99%,D2-40 was 95%,VEGFR-3 was 90%,LYVE-1 was 98%.(3)The most thriving one was cultured more than six passages.The success ratewas related to the age of the patient but other clinicopathologic variables,theyounger (＜30y),the better (P＜0.05).Conclusion By magnetic bead,highpurity lymphatic endothelial cell can be isolated and cultured from epithelialovarian tumor with stable characteristics for the future research.
PartⅢ
The effect of tumor associated lymphatic microvacsular endothelialcell from epithelial ovarian tumor on ovarian cancer cell lineCAOV-3
Objective The aim of this experiment was to detect the effects of LEC fromhuman epithelial ovarian tumor (EOT) on ovarian cancer cell line CAOV-3 invitro.Methods (1) Tumor associated lymphatic endothelial cell (TLEC) andnormal lymphatic endothelial cell (NLEC) were cultured in vitro respectively.Their serum free conditioned mediums were harvested.(2) CAOV-3 cellswere treated with these conditioned mediums;the cells were trypsinized,washed,stained with trypan blue solution and counted.Its ability of migrationand invasion was measured by Transwell.(3) Real-time PCR was used todetect MMPs/TIMPs of CAOV-3 treated by conditioned mediums from TLECand NLEC.(4) MMP-2 and MMP-9 excreted by ovarian tumor cell line whichtreated by conditioned mediums from TLEC and NLEC was detected bygelatin zymography.Results (1) Tumor associated lymphatic microvacsularendothelial cell from epithelial ovarian tumor enhanced migration andinvasion of ovarian cancer cell line CAOV-3 in vitro obviously (P＜0.05).However,the proliferation effect to CAOV-3 cell was still a pending problemas the method was simple.(2) The expression of MMP-9 and TIMP-2 mRNA of CAOV-3 changed obviously by influence of TLECs,the changes of MMPsalso demonstrated by gelatin zymography.Conclusion LECs from epithelialovarian tumor could enhance migration and invasion of human ovariancarcinoma cell line via activation MMP-9/TIMP-2 in vitro.
目的研究上皮性卵巢肿瘤中微淋巴管内皮细胞的存在及其分布特点，探讨从上皮性卵巢肿瘤单细胞悬液中分离微淋巴管内皮细胞的可行性。方法(1)淋巴管内皮细胞标记分子D2-40相关免疫组织化学染色检测15例上皮性卵巢肿瘤(其中恶性10例，交界性5例)中微淋巴管的密度(1ymphatic vessels density，LVD)和微淋巴管所占的面积百分比(1ymphatic vessels area，LVA)；D2-40／Ki-67相结合双标免疫组织化学方法检测有无增生状态的微淋巴管内皮细胞。(2)流式细胞仪分别检测前述15例上皮性卵巢肿瘤新鲜组织，5例良性上皮性卵巢肿瘤和5例正常卵巢组织新鲜组织中淋巴管内皮透明质酸受体-1((lymphatic vessel endothelialHA receptor-1，LYVE-1)阳性细胞的比例。结果(1)交界性卵巢肿瘤中的LVD为(13．23±8．26)条／4HP，与恶性肿瘤(14．22±7．21)条／4HP相比无显著统计学差异(P＞0．05)。但是恶性上皮性肿瘤中LVA为(3．52±1．61)％较交界性卵巢肿瘤(2．21±1．42)％明显升高(P＜0．05)。Ki-67在D2-40(+)的淋巴管内皮细胞中无表达。(2)卵巢上皮肿瘤组织单细胞悬液中LYVE-1(+)细胞的比例为2-11％，恶性与交界性组织相比无显著统计学差异，但是比例较正常和良性卵巢肿瘤组织高(P＜0．05)。结论恶性和交界性卵巢肿瘤中存在微淋巴管内皮细胞，二者之间无显著差异。
第二部分体外分离，培养，鉴定上皮性卵巢肿瘤来源的微淋巴管内皮细胞及其一般生物学特点
目的从交界性和恶性上皮性卵巢肿瘤组织中分离微淋巴管内皮细胞，体外进行培养，鉴定和纯化，研究该细胞的一般生物学特性。方法(1)胶原酶消化26例新鲜卵巢肿瘤(其中交界性11例和恶性15例)组织得到单细胞悬液，免疫磁珠分选其中的LYVE-1(+)细胞体外贴壁进行二维和三维培养。(2)应用泛内皮细胞标记分子CD31和多种淋巴内皮细胞标记分子如Prox-1，D2-40，VEGFR-3和LYVE-1鉴定该细胞。(3)持续传代培养该细胞，尝试不同条件下的效果，探讨其生长的规律。(4)结合临床资料分析影响实验成功的因素。结果(1)应用免疫磁珠技术可以成功分离到上皮性卵巢肿瘤细胞中的LYVE-1(+)细胞并体外培养传代。(2)该细胞表达CD31，Prox-1，D2-40，VEGFR-3和LYVE-1，经联合鉴定其纯度在90％以上。(3)上皮性卵巢肿瘤来源的微淋巴管内皮细胞可以传6代以上并维持基本性状。(4)实验的成功率与患者年龄密切相关，年龄＜30岁者成功率显著升高(P＜0．05)。与病理类型无显著关联(P＞0．05)。结论应用免疫磁珠技术可以从卵巢肿瘤中分离培养微淋巴管内皮细胞，该细胞体外性状稳定，可以用于后续实验的研究。
第三部分上皮性卵巢肿瘤来源的微淋巴管内皮细胞及其在体外对肿瘤细胞CAOV-3的影响
目的研究上皮性卵巢肿瘤来源的微淋巴管内皮细胞在体外对卵巢癌细胞株增殖，侵袭和迁移能力的影响及其作用机制。方法(1)分别培养上皮性卵巢肿瘤来源的肿瘤相关微淋巴管内皮细胞(tumor associated1ymphatic endothelial cell，TLEC)和正常新生儿真皮来源的微淋巴管内皮细胞(normal lymphatic endothelial cell，NLEC)。并收集这两种细胞的上清得到相应的内皮细胞条件培养基。(2)分别用这两种条件培养基干预生长旺盛的卵巢癌细胞系CAOV-3，消化后苔盼蓝染色计数了解其对肿瘤细胞增值的影响，Transwell小室法检测干预后肿瘤细胞侵袭和迁移能力。(3)RT-PCR和荧光定量PCR检测分别受到两种条件培养基干预后CAOV-3细胞MMP-2．MMP-9，TIMP-1，TIMP-2和CXCR-4的表达水平。(4)明胶酶谱法检测TLEC和NLEC对肿瘤细胞CAOV-3分泌转移相关因子MMP-2和MMP-9的影响。结果(1)TLEC细胞条件培养基可以显著增强肿瘤细胞的侵袭和迁移能力。但是该细胞对肿瘤增殖有无影响尚难以确定。(2)PCR结果表明在mRNA水平受到TLEC干预的肿瘤细胞与受到NLEC干预的细胞相比其表达MMP-9的表达水平显著升高(P＜0．05)，同时TIMP-2的表达水平显著降低(P＜0．05)；而MMP-2、TIMP-1和CXCR4的表达无显著差异(P＞0．05)。(3)明胶酶谱法证实受到TLEC干预的CAOV-3细胞较受到NLEC干预者分泌MMP-9更多(P＜0．05)，而两者之间MMP-2的分泌无显著差异(P＞0．05)。结论上皮性肿瘤相关的微淋巴管内皮细胞可能通过激活MMP-9／TIMP-2途径增强卵巢肿瘤细胞株CAOV-3的侵袭与迁移能力。
PartⅠ
The existence and characters of tumor associated lymphaticendothelial cell in epithelial ovarian tumor
Objective To study the existence and distribution of lymphatic endothelialcells in epithelial ovarian tumor.Methods (1)Monoclonal lymphaticendothelial cell marker D2-40 antibody was used to immunistain thelymphatic microvessels in the paraffin sections of epithelial ovarian tumor(including 10 malignant and 5 borderline).Antibodies of D2-40 and Ki-67were used together by double immuohistchemistry to detect proliferation oflymphatic endothelial cells.Computer-assisted morph metric analysis wasused to quantitatively analyze lymphatic vessel density (LVD) and lymphaticvessel area (LVA) in epithelial ovarian tumor.(2) Polyclonal lymphatic vesselendothelial HA receptor- 1(LYVE-1) antibody was used to embark epithelialovarian tumor tissue (including 10 malignant,5 borderline,5 benign and 5control) single cell suspension for FCM detection.Results There was no significant difference between LVD in epithelial borderline ovarian tumorand malignant ovarian tumor ((13.23±8.26) vessels/4HP VS(14.22±7.21)vessels/4HP,P＞0.05).However,LVA in malignant ovarian tumor wassignificantly increased than that in borderline group ((3.52±1.61)% VS(2.21±1.42)%,P＜0.05).Lymphangiogenesis of epithelial ovarian cancer wasstill a pending question as the co-existence of D2-40 and Ki-67 was absenceby double immunohistchemostrity technique.LYVE-1 (+) cells can bedetected in both malignant and borderline tissue single cell suspension byFCM.Conclusion The existence of lymphatic endothelial cells in epithelialovarian tumor was sure.It's possible to isolate this cell from its single cellsuspension.
PartⅡ
The isolation,culture and identification of lymphatic endothelialcells from epithelial ovarian tumor and its biological characters incommon
Objective To study the feasibility of culture lymphatic endothelial cells(LECs) which were isolated from epithelial ovarian tumor in vitro,and offerbasic technology for researching development of epithelial ovarian tumor (including borderline and malignant ones).Methods (1) Epithelial ovariancancer single cell suspensions were obtained by digestion with collagenasefrom 26 cases (11 borderline and 15 malignant).LYVE-1 antibody was usedas LEC markers to isolate LEC by magnetic tosylactivated Macsbeads.LECswere culture in both two- and three-dimensional model in vitro.(2) Toidentify the cell by immunostain pan-endothelial cell marker CD31 andseveral LEC markers such as LYVE-1,D2-40,VEGFR-3(Flt-4),Prox-1.(3)LECs were subcultured consecutively until died,summarized the rule ofisolation and culture this new cell.Results (1) By magnetic beadstechnology LYVE-1(+) lymphatic endothelial cell can be harvested andculture successfully in vitro.Most of TLECs were from borderline tumor asthe age agent.(2) The identification purity of this cell by CD31 was 100%,Prox-1 was 99%,D2-40 was 95%,VEGFR-3 was 90%,LYVE-1 was 98%.(3)The most thriving one was cultured more than six passages.The success ratewas related to the age of the patient but other clinicopathologic variables,theyounger (＜30y),the better (P＜0.05).Conclusion By magnetic bead,highpurity lymphatic endothelial cell can be isolated and cultured from epithelialovarian tumor with stable characteristics for the future research.
PartⅢ
The effect of tumor associated lymphatic microvacsular endothelialcell from epithelial ovarian tumor on ovarian cancer cell lineCAOV-3
Objective The aim of this experiment was to detect the effects of LEC fromhuman epithelial ovarian tumor (EOT) on ovarian cancer cell line CAOV-3 invitro.Methods (1) Tumor associated lymphatic endothelial cell (TLEC) andnormal lymphatic endothelial cell (NLEC) were cultured in vitro respectively.Their serum free conditioned mediums were harvested.(2) CAOV-3 cellswere treated with these conditioned mediums;the cells were trypsinized,washed,stained with trypan blue solution and counted.Its ability of migrationand invasion was measured by Transwell.(3) Real-time PCR was used todetect MMPs/TIMPs of CAOV-3 treated by conditioned mediums from TLECand NLEC.(4) MMP-2 and MMP-9 excreted by ovarian tumor cell line whichtreated by conditioned mediums from TLEC and NLEC was detected bygelatin zymography.Results (1) Tumor associated lymphatic microvacsularendothelial cell from epithelial ovarian tumor enhanced migration andinvasion of ovarian cancer cell line CAOV-3 in vitro obviously (P＜0.05).However,the proliferation effect to CAOV-3 cell was still a pending problemas the method was simple.(2) The expression of MMP-9 and TIMP-2 mRNA of CAOV-3 changed obviously by influence of TLECs,the changes of MMPsalso demonstrated by gelatin zymography.Conclusion LECs from epithelialovarian tumor could enhance migration and invasion of human ovariancarcinoma cell line via activation MMP-9/TIMP-2 in vitro.
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74. Fiedler U, Christian S, Koidl S, Kerjaschki D, Emmett MS, Bates DO, Christofori G, Augustin HG．The sialomucin CD34 is a marker of lymphatic endothelial cells in human tumors．Am J Pathol 2006；168：1045-53．
75，Zhuang Z，Jian P，Longjiang L，Bo H，Hongwei Z Identification of Oral Cancer Cell-Induced Changes in Gene Expression Profile of Lymphatic Endothelial Cell．Cancer Invest 2008； 26：1002-7．
76，魏军成激光捕获显微切割技术结合cDNA微距阵筛选乳腺癌相关淋巴管内皮细胞特异性表达基因及其所选靶点的功能研究。2008年博士毕业论文：32-37．
77，Shouhua Yang，Xiaowu Zhu，Liqiong Cai，Henghui Cheng，Hongbo Wang，Hong Zhao，Zehua Wang．Tumor associated lymphatic microvascular endothelial cell enhanced migration and invasion of ovarian cancer cell line via activation MMP-9/TIMP-2 in vitro．待发表