脉络膜黑色素瘤微循环模式及姜黄素联合内皮抑素对眼内移植瘤的影响
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摘要
目的
1.研究脉络膜黑色素瘤中不同微循环模式与临床病理参数及预后的关系;阐明其不同微循环模式中MMP-2、MMP-9、EphA2及VEGF的表达及意义。
2.探讨姜黄素联合内皮抑素对眼内黑色素移植瘤微循环模式及生长的抑制作用;研究其对MMP-2、MMP-9、EphA2及VEGF表达的影响,从而揭示二者从不同途径抑制肿瘤血管生成的相关分子机制,为临床恶性肿瘤的治疗提供新靶点,为寻求高效低毒的治疗药物提供实验依据。
方法
1.收集脉络膜黑色素瘤56例,复读HE染色切片,初步观察其微循环模式,利用电镜观察血管生成拟态的超微结构;采用CD34/PAS双重染色进一步确认脉络膜黑色素瘤中内皮依赖性血管(E)、马赛克血管(MV)、血管生成拟态(VM)三种微循环模式。根据有无VM分组。分别计数微血管密度(MVD)、MV及VM,以探讨其与病人临床病理指标之间的关系;使用单因素和多因素生存分析研究VM对预后的影响;免疫组化染色检测并比较MMP-2、MMP-9、EphA2及VEGF蛋白的表达,分析这些分子在VM形成中的作用。
2.C57/BL6小鼠72只,右眼视网膜下腔注射1×10~5B16黑色素瘤细胞悬液建立移植瘤模型。接种后第3天开始腹腔注射给药,持续18天;给予姜黄素(100mg/kg/日)和内皮抑素(10mg/kg/日)处理,依据处理方式不同分为4组:对照组、姜黄素组、内皮抑素组、姜黄素联合内皮抑素组。于取材前每组挑选2只进行活性炭示踪,以判断VM的功能;每组选2只,用于电镜观察VM结构;同时完整摘取脑、肺、肝、肾、脾,观察药物毒副作用及有无转移;用游标卡尺测量肿瘤体积,比较肿瘤的大小及生长速度;免疫组化法检测并比较移植瘤组织中MMP-9、MMP-2、EphA2及VEGF表达水平的差异;同时采用Real time RT-PCR技术检测并比较各组MMP-2、MMP-9、EphA2 mRNA表达量的差异。
结果
1.(1)VM与与性别、眼别、年龄无关(P=0.618,0.560,0.687),而与细胞类型、肿瘤最大直径(LTD)、转移有关,差异均有统计学意义。其中含有类上皮细胞患者瘤组织中的VM阳性率(91.67%)高于无类上皮细胞者(48.30%)(P=0.025);有转移者VM阳性率(81.80%)高于无肝转移病人(37.80%)(P=0.027);肿瘤最大直径＞12mm的患者VM阳性率(58.5%)高于=12mm者(47.8%)(P=0.021)。
(2)MVD与性别、眼别、年龄无关(P=0.266,0.430,0.316),而与细胞类型、肿瘤最大直径(LTD)及转移有关。并且有类上皮细胞的瘤组织中MVD(53.48±5.14)高于无类上皮细胞者(38.55±3.32)(P=0.017);肿瘤最大直径＞12mm者MVD(55.80±4.86)高于肿瘤最大直径=12mm的MVD(40.16±3.88)(P=0.014);有转移患者的MVD(64.27±8.16)高于无转移者MVD(41.18±3.08)(P=0.003)。
(3)VM组中MVD略微低于对照组MVD,但差异无统计学意义(P=0.082)。
(4)单因素生存显示,VM组患者生存时间与对照组相比较短(P=0.0076);肿瘤细胞类型、肿瘤最大直径、转移、MVD对患者预后有影响(P=0.0193,0.0231,0.0328,0.0321);而性别、年龄、眼别对预后无影响(P=0.662,0.278,0.885);多因素生存分析显示,肿瘤细胞类型、肿瘤最大直径及VM是影响CM患者预后的独立危险因素(P=0.005,0.000,0.003)。
(5)免疫组化染色结果:MMP-2、MMP-9在VM组中的阳性率分别为96.15%与100.0%高于对照组66.67%与80.00%,差异有统计学意义(P=0.000,0.002)。并且VM组MMP-2、MMP-9表达量增高,分别为(57.16±6.39)、(55.96±7.67)高于对照组表达量(36.18±4.55)(38.75±4.12),差异有统计学意义(P=0.000,0.000);EphA2在VM组中的阳性率92.31%高于对照组阳性率70.00%,表达量也随之增高(39.807±8.79),高于对照组表达量(33.36±4.86),差异具有统计学意义(P=0.002,0.002);VEGF在VM组与对照组的阳性率及表达量之间差异均无统计学意义(P=0.089,0.419)。
2.(1)免疫组化双重染色和电镜结果显示:眼内移植瘤微循环模式中三种微循环
2.(1)免疫组化双重染色和电镜结果显示:眼内移植瘤微循环模式中三种微循环模式共存。MVD及MV数目在各实验组瘤组织中明显降低(P＜0.05);MV数目仅在姜黄素组及联合组瘤组织中显著减少(P＜0.05)。
(2)活性炭示踪结果显示:移植瘤中VM结构中央区大量黑色炭颗粒出现,提示VM与内皮依赖性血管是相互连通的,以不同的方式维持肿瘤组织的血液供应。
(3)肿瘤体积测量及器官转移结果:各处理组肿瘤均较对照组生长缓慢(F=8.30,P＜0.05);其中,姜黄素组、联合组与对照组之间肿瘤平均生长体积差异有统计学意义(t=P＜0.05)。各实验组肺转移率5.6%低于对照组16.7%,但差异无统计学意义(P＞0.05)。
(4)免疫组化及实时荧光定量PCR结果:①MMP-9、MMP-2、EphA2胞浆阳性着色,棕黄色,肿瘤细胞阳性表达率从高到低依次为对照组、内皮抑素组、姜黄素组、联合组;VEGF阳性表达率内皮抑素组最低,对照组最高。而且MMP-2、MMP-9、EphA2及VEGF在各处理组中的表达与对照组比较,差异均有统计学意义(F=15.48,F=17.35,F=4.56,F=6.08,P＜0.05)。②MMP-2、MMP-9及EphA2mRNA在各处理组表达量也明显低于对照组(F=19.35,F=19.43,F=8.13,P＜0.05),其中MMP-2、MMP-9 mRNA在姜黄素组及联合组与对照组之间平均表达量差异有统计学意义(t=7.17,4.53,P＜0.05);EphA2 mRNA表达量在联合组瘤组织中明显降低(t=2.52,P＜0.05)。
结论
1.(1)在脉络膜黑色素瘤中,VM、MVD与肿瘤细胞类型、肿瘤最大直径及转移有关。
肿瘤体积越大,VM阳性率越高,且患者越易发生转移,有VM患者的生存时间明显短于无VM者;含有类上皮细胞的CM中VM阳性率增高。
(2)VM可作为判断脉络膜黑色素瘤患者预后的一项指标,是影响其预后的独立危险因素。
(3)VM阳性的脉络膜黑色素瘤中MMP-2、MMP-9及EphA2表达明显增高,而VEGF无显著升高,提示VM的形成机制不同于经典的内皮依赖性血管生成,MMP-2、MMP-9、EphA2是VM形成中的重要分子,VEGF不是影响VM的主要因素。
2.(1)眼内移植瘤组织并存有VM、马赛克血管和内皮依赖性血管三种微循环模式,并且VM与宿主血管相连,共同为肿瘤提供营养。
(2)姜黄素主要通过下调MMP-2、MMP-9及EphA2的表达,抑制VM的形成及肿瘤血管生成。内皮抑素主要通过下调VEGF的表达,抑制内皮依赖性血管生成,二者联合应用,具有协同增效作用。
(3)姜黄素联合内皮抑素将成为一种安全有效的抗肿瘤方法。
Objective:
1.To investigate the correlation between the different microcirculation patterns and clinicopathologic parameters and its prognosis;to evaluate thc cxprcssions of MMP-2, MMP-9,EphA2 and VEGF in different microcirculation of choroidal melanoma(CM) and its clinical significance.
2.To study curcumin and endostatin effect on intraocular melanoma model growth and microcirculation patterns;to examine curcumin and endostatin influcnce on the expressions of MMP-2,MMP-9,EphA2 and VEGF,and thereby reveal the molecular mechanism in suppressing angiogenesis and proliferation of melanoma cells in order to provide new targets and experimental data for the treatment of malignant tumors.
Methods:
1.56 cases of CM were collected and HE stainings were studied to check CM microcirculation patterns and the transelectron microscopy was used to observe the vasculogenic mimicry(VM)ultrastructure.Then PAS staining and CD34/PAS double staining were adopted to confirm three microcirculation patterns of CM.According to the presence of VM,All cases were divided into two groups,and also microvessel density(MVD),mosaic vessels and VM were counted to explore the correlation between CM and clinicopathologic parameters.Univariate and multivariate survival analysis were adopted to analyze VM effect upon prognosis,immunohistochemical staining was used to study the expression level of MMP-2,MMP-9,EphA2 and VEGF,and compare the difference between the VM group and the control group and analyze its role in the formation of VM and their correlation.
2.1×10~5B16 melanoma cell suspension was injected into the retinal subspace cavity of right eye for each of 72 C57/BL6 mice.72 mice wcrc randomly divided into 4 groups.3 days after inoculation,we administered intraperitoneally circumin at a dose of 100 mg/kg/day,endostatin at a dose of 10 mg/kg/day and circumin and endostatin at the same dose receptively in the treatment groups.We administered 0.9%NaCl solution to the control group.Injection continued 18 days.Animals were sacrificed on Day 21.30 minutes before the mice were sacrificed a diluted suspension of activated carbon was injected into the circulation of mice previously through the caudal veins to test the function of VM.2 models were chosen to observe the VM structure by the transelectron microscopy.At the same time,lung,liver,kidney,lien,brain were removed to observe side effect of the drug and the presence of metastasis.We measured tumor sizes with a vemier caliper and compared the sizes of the tumors. Immunohistochemical staining test was used to analyze the expression level of MMP-9,MMP-2,EphA2 and VEGF in the different groups.Real time RT-PCR test was used to detect MMP-2,MMP-9 and EphA2 mRNA level in the fresh tumor tissue in each group.
Results
1.(1)Statistical analysis found that VM was not related to gender,eye,and age(P=0.618,0.560,0.687),but was related to cell type,LTD and metastasis,and the differences were statistically significant.VM positive rate of the cases with epithelioid cells(91.67%)was higher compared with the control group (48.30%)(P=0.025);VM positive rate of the tumor with LTD＞12mm(58.5%)was higher than that of the tumor with LTD=12mm(47.8%)and the differences were statistically significant(P=0.021);VM positive rate of the patients with metastasis(81.80%)was higher compared with the control group(37.80%)(P=0.027).
(2)Similarly,MVD was not related to gender,eye,and age(P=0.266,0.430,0.316) but was related to celltype,LTD and metastasis.There were more MVD(53.48±5.14) with epithelioid cells MVD(38.55±3.32)compared with the control group(P=0.017). There were more MVD(55.80±4.86)with LTD＞12mm compared with the cases of LTD=12mm MVD(40.16±3.88)and the difference was statistically significant (P=0.014).MVD(64.27±8.16)of patients with metastasis was higher than that of patients without tumor metastasis(41.18±3.08)(P=0.003).
(3)The number of MVD in the VM group was slightly lower compared with that in the control group(P=0.082).
(4)Univariate survival analysis found that the survival rate for the patients with VM was significantly poorer than that for the patients without VM(P=0.000).Celltype, LTD,metastasis,MVD(average value 45.00),and VM had an effect on the prognosis(P=0.0193,0.0231,0.0328,0.0321,0.0076),while gender,age and eye, had no effect on it(P=0.662,0.278,0.885).
(5)Immunohistochemical staining result:The positive rates of MMP-2 and MMP-9 (96.15%,100.0%,respectively)in the VM group were higher than those in the control group(66.67%,80.00%,respectively)(P=0.000,0.002).The expression level of MMP-2 and MMP-9 in the VM group were increased(57.16±6.39,55.96±7.67 respectively)compared with the control group(36.18±4.55,38.75±4.12, respectively)(P=0.000,0.000).The positive rate and expression level for EphA2 (92.31%,39.807±8.79)were higher compared with the control group(70.00%, 33.36±4.86)and the difference was statistically significant(P=0.002).The difference in positive rates and expression level of VEGF between the VM group and the control group was not statistically significant(P=0.089,0.419).
2.(1)Immunohistochemical staining and transelectron microscopy showed that three blood supply patterns coexist in the intraocular malignant melanin transplanted tumor microcirculation patterns and the number of endothelium-dependent vessels,mosaic vessels and VM was obviously lower compared with the control group(P＜0.05).
(2)Activated-carbon tracing showed that numerous carbon grains appeared in the central area of VM structure and it suggested that VM and endothelium-dependent vessels are interconnected and that VM together with endothelium-dependent vessels and mosaic vessels provided blood to tumor tissue.
(3)Tumor size measurement showed that tumor growth in each treatment group was slower compared with the control group(F=8.30,P＜0.05).Tumors in curcumin group and in curcumin and endostatin group grew slower than in the control group(t =P＜0.05).Compared with the control group tumor metastasis in each treatment group was no significance(P＞0.05).
(4)①All of the melanoma cells were positive for MMP-2,MMP-9 and EphA2 as detected by immunohistochemical staining,and the cytoplasm of positive cells was dark brown.The positive rates went from high to low as follows:the control group, endostatin group,curcumin group,curcumin and endostatin group.The positive rate for VEGF was higher than the control group.The positive rates of MMP-2,MMP-9, EphA2 and VEGF in each treatment group were statistically different from the contro 1 group(F=15.48,F=17.35,F=4.56,F=6.08,P＜0.05).②Real time PCR demonstrated that the expressions of MMP-9,MMP-2 and EphA2 in the treatment group were lower compared with the control group(F=19.35, F=19.43,F=8.13,P＜0.05).The expression level of MMP-2,MMP-9 mRNA in curcumin group and in curcumin and endostatin group was lower compared with the control group(t=7.17,4.53,P＜0.05).The expression of EphA2 mRNA was decreased in the curcumin and endostatin group compared with the control group (t=2.52,P＜0.05).
Conclusion:
1.(1)MVD and VM are related to LTD,tumor celltype and tumor metastasis rate. Moreover,the larger the tumor,the higher the MVD and VM and the more tumor metastasis.The positive rate for VM with epithelioid cell was increased.(2)VM can be used as an indicator of poor prognosis of CM patients.The survival rate for the patients with VM was poorer compared with the control group.Tumor celltype,LTD, VM are important and independently prognostic factors for CM patients.(3)The expression level of MMP-2,MMP-9 and EphA2 in the VM group was increased obviously while VEGF remained low.MMP-2,MMP-9,EphA2 are necessary for the formation of VM in CM and are important enhancing factors whereas VEGF is not a major factor.This shows that the mechanism of VM formation is different from that of endothelium-dependent vessels formation.
2.(1)Three blood-supply patterns coexist in intraocular malignant melanin transplanted tumor microcirculation patterns.VM and host vessels are interconnected to supply tumor cells with nutrition.(2)Curcumin decreased MMP-2,MMP-9 and EphA2 expression,and inhibit the vasculogenic mimicry,mosaic vessel and endothelial dependent vessel formation.Endostatin decreased VEGF expression,and inhibit endothelial dependent vessel formation.The combination of curcumin and endostatin enhances the effect of anticancer.(3)Curcumin can decrease the activity of tumor cell proliferation and inhibit melanoma growth.
1.研究脉络膜黑色素瘤中不同微循环模式与临床病理参数及预后的关系;阐明其不同微循环模式中MMP-2、MMP-9、EphA2及VEGF的表达及意义。
2.探讨姜黄素联合内皮抑素对眼内黑色素移植瘤微循环模式及生长的抑制作用;研究其对MMP-2、MMP-9、EphA2及VEGF表达的影响,从而揭示二者从不同途径抑制肿瘤血管生成的相关分子机制,为临床恶性肿瘤的治疗提供新靶点,为寻求高效低毒的治疗药物提供实验依据。
方法
1.收集脉络膜黑色素瘤56例,复读HE染色切片,初步观察其微循环模式,利用电镜观察血管生成拟态的超微结构;采用CD34/PAS双重染色进一步确认脉络膜黑色素瘤中内皮依赖性血管(E)、马赛克血管(MV)、血管生成拟态(VM)三种微循环模式。根据有无VM分组。分别计数微血管密度(MVD)、MV及VM,以探讨其与病人临床病理指标之间的关系;使用单因素和多因素生存分析研究VM对预后的影响;免疫组化染色检测并比较MMP-2、MMP-9、EphA2及VEGF蛋白的表达,分析这些分子在VM形成中的作用。
2.C57/BL6小鼠72只,右眼视网膜下腔注射1×10~5B16黑色素瘤细胞悬液建立移植瘤模型。接种后第3天开始腹腔注射给药,持续18天;给予姜黄素(100mg/kg/日)和内皮抑素(10mg/kg/日)处理,依据处理方式不同分为4组:对照组、姜黄素组、内皮抑素组、姜黄素联合内皮抑素组。于取材前每组挑选2只进行活性炭示踪,以判断VM的功能;每组选2只,用于电镜观察VM结构;同时完整摘取脑、肺、肝、肾、脾,观察药物毒副作用及有无转移;用游标卡尺测量肿瘤体积,比较肿瘤的大小及生长速度;免疫组化法检测并比较移植瘤组织中MMP-9、MMP-2、EphA2及VEGF表达水平的差异;同时采用Real time RT-PCR技术检测并比较各组MMP-2、MMP-9、EphA2 mRNA表达量的差异。
结果
1.(1)VM与与性别、眼别、年龄无关(P=0.618,0.560,0.687),而与细胞类型、肿瘤最大直径(LTD)、转移有关,差异均有统计学意义。其中含有类上皮细胞患者瘤组织中的VM阳性率(91.67%)高于无类上皮细胞者(48.30%)(P=0.025);有转移者VM阳性率(81.80%)高于无肝转移病人(37.80%)(P=0.027);肿瘤最大直径＞12mm的患者VM阳性率(58.5%)高于=12mm者(47.8%)(P=0.021)。
(2)MVD与性别、眼别、年龄无关(P=0.266,0.430,0.316),而与细胞类型、肿瘤最大直径(LTD)及转移有关。并且有类上皮细胞的瘤组织中MVD(53.48±5.14)高于无类上皮细胞者(38.55±3.32)(P=0.017);肿瘤最大直径＞12mm者MVD(55.80±4.86)高于肿瘤最大直径=12mm的MVD(40.16±3.88)(P=0.014);有转移患者的MVD(64.27±8.16)高于无转移者MVD(41.18±3.08)(P=0.003)。
(3)VM组中MVD略微低于对照组MVD,但差异无统计学意义(P=0.082)。
(4)单因素生存显示,VM组患者生存时间与对照组相比较短(P=0.0076);肿瘤细胞类型、肿瘤最大直径、转移、MVD对患者预后有影响(P=0.0193,0.0231,0.0328,0.0321);而性别、年龄、眼别对预后无影响(P=0.662,0.278,0.885);多因素生存分析显示,肿瘤细胞类型、肿瘤最大直径及VM是影响CM患者预后的独立危险因素(P=0.005,0.000,0.003)。
(5)免疫组化染色结果:MMP-2、MMP-9在VM组中的阳性率分别为96.15%与100.0%高于对照组66.67%与80.00%,差异有统计学意义(P=0.000,0.002)。并且VM组MMP-2、MMP-9表达量增高,分别为(57.16±6.39)、(55.96±7.67)高于对照组表达量(36.18±4.55)(38.75±4.12),差异有统计学意义(P=0.000,0.000);EphA2在VM组中的阳性率92.31%高于对照组阳性率70.00%,表达量也随之增高(39.807±8.79),高于对照组表达量(33.36±4.86),差异具有统计学意义(P=0.002,0.002);VEGF在VM组与对照组的阳性率及表达量之间差异均无统计学意义(P=0.089,0.419)。
2.(1)免疫组化双重染色和电镜结果显示:眼内移植瘤微循环模式中三种微循环
2.(1)免疫组化双重染色和电镜结果显示:眼内移植瘤微循环模式中三种微循环模式共存。MVD及MV数目在各实验组瘤组织中明显降低(P＜0.05);MV数目仅在姜黄素组及联合组瘤组织中显著减少(P＜0.05)。
(2)活性炭示踪结果显示:移植瘤中VM结构中央区大量黑色炭颗粒出现,提示VM与内皮依赖性血管是相互连通的,以不同的方式维持肿瘤组织的血液供应。
(3)肿瘤体积测量及器官转移结果:各处理组肿瘤均较对照组生长缓慢(F=8.30,P＜0.05);其中,姜黄素组、联合组与对照组之间肿瘤平均生长体积差异有统计学意义(t=P＜0.05)。各实验组肺转移率5.6%低于对照组16.7%,但差异无统计学意义(P＞0.05)。
(4)免疫组化及实时荧光定量PCR结果:①MMP-9、MMP-2、EphA2胞浆阳性着色,棕黄色,肿瘤细胞阳性表达率从高到低依次为对照组、内皮抑素组、姜黄素组、联合组;VEGF阳性表达率内皮抑素组最低,对照组最高。而且MMP-2、MMP-9、EphA2及VEGF在各处理组中的表达与对照组比较,差异均有统计学意义(F=15.48,F=17.35,F=4.56,F=6.08,P＜0.05)。②MMP-2、MMP-9及EphA2mRNA在各处理组表达量也明显低于对照组(F=19.35,F=19.43,F=8.13,P＜0.05),其中MMP-2、MMP-9 mRNA在姜黄素组及联合组与对照组之间平均表达量差异有统计学意义(t=7.17,4.53,P＜0.05);EphA2 mRNA表达量在联合组瘤组织中明显降低(t=2.52,P＜0.05)。
结论
1.(1)在脉络膜黑色素瘤中,VM、MVD与肿瘤细胞类型、肿瘤最大直径及转移有关。
肿瘤体积越大,VM阳性率越高,且患者越易发生转移,有VM患者的生存时间明显短于无VM者;含有类上皮细胞的CM中VM阳性率增高。
(2)VM可作为判断脉络膜黑色素瘤患者预后的一项指标,是影响其预后的独立危险因素。
(3)VM阳性的脉络膜黑色素瘤中MMP-2、MMP-9及EphA2表达明显增高,而VEGF无显著升高,提示VM的形成机制不同于经典的内皮依赖性血管生成,MMP-2、MMP-9、EphA2是VM形成中的重要分子,VEGF不是影响VM的主要因素。
2.(1)眼内移植瘤组织并存有VM、马赛克血管和内皮依赖性血管三种微循环模式,并且VM与宿主血管相连,共同为肿瘤提供营养。
(2)姜黄素主要通过下调MMP-2、MMP-9及EphA2的表达,抑制VM的形成及肿瘤血管生成。内皮抑素主要通过下调VEGF的表达,抑制内皮依赖性血管生成,二者联合应用,具有协同增效作用。
(3)姜黄素联合内皮抑素将成为一种安全有效的抗肿瘤方法。
Objective:
1.To investigate the correlation between the different microcirculation patterns and clinicopathologic parameters and its prognosis;to evaluate thc cxprcssions of MMP-2, MMP-9,EphA2 and VEGF in different microcirculation of choroidal melanoma(CM) and its clinical significance.
2.To study curcumin and endostatin effect on intraocular melanoma model growth and microcirculation patterns;to examine curcumin and endostatin influcnce on the expressions of MMP-2,MMP-9,EphA2 and VEGF,and thereby reveal the molecular mechanism in suppressing angiogenesis and proliferation of melanoma cells in order to provide new targets and experimental data for the treatment of malignant tumors.
Methods:
1.56 cases of CM were collected and HE stainings were studied to check CM microcirculation patterns and the transelectron microscopy was used to observe the vasculogenic mimicry(VM)ultrastructure.Then PAS staining and CD34/PAS double staining were adopted to confirm three microcirculation patterns of CM.According to the presence of VM,All cases were divided into two groups,and also microvessel density(MVD),mosaic vessels and VM were counted to explore the correlation between CM and clinicopathologic parameters.Univariate and multivariate survival analysis were adopted to analyze VM effect upon prognosis,immunohistochemical staining was used to study the expression level of MMP-2,MMP-9,EphA2 and VEGF,and compare the difference between the VM group and the control group and analyze its role in the formation of VM and their correlation.
2.1×10~5B16 melanoma cell suspension was injected into the retinal subspace cavity of right eye for each of 72 C57/BL6 mice.72 mice wcrc randomly divided into 4 groups.3 days after inoculation,we administered intraperitoneally circumin at a dose of 100 mg/kg/day,endostatin at a dose of 10 mg/kg/day and circumin and endostatin at the same dose receptively in the treatment groups.We administered 0.9%NaCl solution to the control group.Injection continued 18 days.Animals were sacrificed on Day 21.30 minutes before the mice were sacrificed a diluted suspension of activated carbon was injected into the circulation of mice previously through the caudal veins to test the function of VM.2 models were chosen to observe the VM structure by the transelectron microscopy.At the same time,lung,liver,kidney,lien,brain were removed to observe side effect of the drug and the presence of metastasis.We measured tumor sizes with a vemier caliper and compared the sizes of the tumors. Immunohistochemical staining test was used to analyze the expression level of MMP-9,MMP-2,EphA2 and VEGF in the different groups.Real time RT-PCR test was used to detect MMP-2,MMP-9 and EphA2 mRNA level in the fresh tumor tissue in each group.
Results
1.(1)Statistical analysis found that VM was not related to gender,eye,and age(P=0.618,0.560,0.687),but was related to cell type,LTD and metastasis,and the differences were statistically significant.VM positive rate of the cases with epithelioid cells(91.67%)was higher compared with the control group (48.30%)(P=0.025);VM positive rate of the tumor with LTD＞12mm(58.5%)was higher than that of the tumor with LTD=12mm(47.8%)and the differences were statistically significant(P=0.021);VM positive rate of the patients with metastasis(81.80%)was higher compared with the control group(37.80%)(P=0.027).
(2)Similarly,MVD was not related to gender,eye,and age(P=0.266,0.430,0.316) but was related to celltype,LTD and metastasis.There were more MVD(53.48±5.14) with epithelioid cells MVD(38.55±3.32)compared with the control group(P=0.017). There were more MVD(55.80±4.86)with LTD＞12mm compared with the cases of LTD=12mm MVD(40.16±3.88)and the difference was statistically significant (P=0.014).MVD(64.27±8.16)of patients with metastasis was higher than that of patients without tumor metastasis(41.18±3.08)(P=0.003).
(3)The number of MVD in the VM group was slightly lower compared with that in the control group(P=0.082).
(4)Univariate survival analysis found that the survival rate for the patients with VM was significantly poorer than that for the patients without VM(P=0.000).Celltype, LTD,metastasis,MVD(average value 45.00),and VM had an effect on the prognosis(P=0.0193,0.0231,0.0328,0.0321,0.0076),while gender,age and eye, had no effect on it(P=0.662,0.278,0.885).
(5)Immunohistochemical staining result:The positive rates of MMP-2 and MMP-9 (96.15%,100.0%,respectively)in the VM group were higher than those in the control group(66.67%,80.00%,respectively)(P=0.000,0.002).The expression level of MMP-2 and MMP-9 in the VM group were increased(57.16±6.39,55.96±7.67 respectively)compared with the control group(36.18±4.55,38.75±4.12, respectively)(P=0.000,0.000).The positive rate and expression level for EphA2 (92.31%,39.807±8.79)were higher compared with the control group(70.00%, 33.36±4.86)and the difference was statistically significant(P=0.002).The difference in positive rates and expression level of VEGF between the VM group and the control group was not statistically significant(P=0.089,0.419).
2.(1)Immunohistochemical staining and transelectron microscopy showed that three blood supply patterns coexist in the intraocular malignant melanin transplanted tumor microcirculation patterns and the number of endothelium-dependent vessels,mosaic vessels and VM was obviously lower compared with the control group(P＜0.05).
(2)Activated-carbon tracing showed that numerous carbon grains appeared in the central area of VM structure and it suggested that VM and endothelium-dependent vessels are interconnected and that VM together with endothelium-dependent vessels and mosaic vessels provided blood to tumor tissue.
(3)Tumor size measurement showed that tumor growth in each treatment group was slower compared with the control group(F=8.30,P＜0.05).Tumors in curcumin group and in curcumin and endostatin group grew slower than in the control group(t =P＜0.05).Compared with the control group tumor metastasis in each treatment group was no significance(P＞0.05).
(4)①All of the melanoma cells were positive for MMP-2,MMP-9 and EphA2 as detected by immunohistochemical staining,and the cytoplasm of positive cells was dark brown.The positive rates went from high to low as follows:the control group, endostatin group,curcumin group,curcumin and endostatin group.The positive rate for VEGF was higher than the control group.The positive rates of MMP-2,MMP-9, EphA2 and VEGF in each treatment group were statistically different from the contro 1 group(F=15.48,F=17.35,F=4.56,F=6.08,P＜0.05).②Real time PCR demonstrated that the expressions of MMP-9,MMP-2 and EphA2 in the treatment group were lower compared with the control group(F=19.35, F=19.43,F=8.13,P＜0.05).The expression level of MMP-2,MMP-9 mRNA in curcumin group and in curcumin and endostatin group was lower compared with the control group(t=7.17,4.53,P＜0.05).The expression of EphA2 mRNA was decreased in the curcumin and endostatin group compared with the control group (t=2.52,P＜0.05).
Conclusion:
1.(1)MVD and VM are related to LTD,tumor celltype and tumor metastasis rate. Moreover,the larger the tumor,the higher the MVD and VM and the more tumor metastasis.The positive rate for VM with epithelioid cell was increased.(2)VM can be used as an indicator of poor prognosis of CM patients.The survival rate for the patients with VM was poorer compared with the control group.Tumor celltype,LTD, VM are important and independently prognostic factors for CM patients.(3)The expression level of MMP-2,MMP-9 and EphA2 in the VM group was increased obviously while VEGF remained low.MMP-2,MMP-9,EphA2 are necessary for the formation of VM in CM and are important enhancing factors whereas VEGF is not a major factor.This shows that the mechanism of VM formation is different from that of endothelium-dependent vessels formation.
2.(1)Three blood-supply patterns coexist in intraocular malignant melanin transplanted tumor microcirculation patterns.VM and host vessels are interconnected to supply tumor cells with nutrition.(2)Curcumin decreased MMP-2,MMP-9 and EphA2 expression,and inhibit the vasculogenic mimicry,mosaic vessel and endothelial dependent vessel formation.Endostatin decreased VEGF expression,and inhibit endothelial dependent vessel formation.The combination of curcumin and endostatin enhances the effect of anticancer.(3)Curcumin can decrease the activity of tumor cell proliferation and inhibit melanoma growth.
引文
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