人体黑色素瘤中LPPCN与VM的关系及其调控机制的初步研究
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摘要
目的
研究人体黑色素瘤组织中是否存在线形程序性坏死(linearly patterned programmed cell necrosis, LPPCN)及血管生成拟态(vasculogenic mimicry, VM)及其分布情况,分析它们的临床病理意义。研究70例人体黑色素瘤组织中LPPCN及VM阳性病例中的LPPCN、VM周围肿瘤细胞血.管内皮生长因子(VEGF)及其受体VEGFR1 (Flt-1)和VEGFR2 (Flk-1)的表达情况并研究VEGF与侵袭转移相关蛋白的相互作用,探讨它们在肿瘤血管生成中的作用以及与临床预后的关系。
方法
1、自1996-2007年天津医科大学附属肿瘤医院存档石蜡标本中挑选出符合实验要求(经手术切除、病理诊断明确且随访资料完整)的恶性黑色素瘤标本共70例,收集患者的性别、年龄、发病部位、肿瘤大小、手术日期、复发与转移和随访等临床资料。分析黑色素瘤患者的临床病理特征及其与预后的关系；
2、利用HE染色观察70例黑色素瘤组织中是否存在LPPCN及利用CD31/PAS双重染色的方法来观察这70例黑色素瘤组织中是否存在VM,并在显微镜下计数其各自的分布情况。运用相关检验法分析LPPCN、VM与MVD之间有无相关以探讨LPPCN与VM、内皮依赖性血管之间的关联性,并在此基础上进一步分析LPPCN、VM的存在与黑色素瘤患者的临床病理参数及预后间的关系；
3、应用免疫组织化学二步法,检测VEGF、Flt-1和Flk-1在距LPPCN及VM周围最近距离(1-3层)、中等距离(4-6层)及远距离(7-9层)的肿瘤细胞中的表达情况,以及侵袭与转移相关蛋白Twist1、MMP-2、MMP-9在LPPCN阳性组和LPPCN阴性组、VM阳性组和VM阴性组中的表达情况和他们在LPPCN周围肿瘤细胞中的表达情况,并进一步分析VEGF与这些蛋白的表达相关性和它们在VM形成过程中所起的作用。
结果
1、黑色素瘤组织中存在LPPCN及VM
对70例黑色素瘤组织进行HE染色可观察到其中有38例瘤组织中出现了胞质浓缩、胞核深染、细胞之间界限清楚的肿瘤细胞,呈线状或网络状分布,此即为LPPCN阳性。对70例黑色素瘤组织进行CD31/PAS双重染色可观察到其中有33例瘤组织中存在一些由CD31染色阴性的肿瘤细胞围成的管腔结构,其管腔壁上有PAS阳性物质,管腔内存在红细胞,周围没有出血坏死和炎症细胞浸润,此即为VM阳性。
2、LPPCN、VM与黑色素瘤患者临床病理参数及预后的关系
LPPCN和VM的发生与患者肿瘤体积的大小有关(P<0.05)而与患者的性别、年龄、肿瘤生长部位、有无复发与转移无关(P>0.05)。当肿瘤体积大于本实验中肿瘤体积的中位值20cm3的时候较易发生LPPCN和VM(P<0.05)。患者的生存率在LPPCN阳性组低于LPPCN阴性组(P<0.05),VM阳性组患者的生存率比VM阴性组低(P<0.05)。
3、VEGF、Flt-1及Flk-1在LPPCN和VM周围肿瘤细胞中的表达及与预后的关系
VEGF在LPPCN周围肿瘤细胞1-3层中的表达强于其外围肿瘤细胞(P<0.05),在外围4-6层与7-9层之间的表达差异无统计学意义(P>0.05)。F1k-1在LPPCN周围肿瘤细胞1-3层中的表达强于其外围肿瘤细胞(P<0.05),在外围4-6层与7-9层之间的表达差异无统计学意义(P>0.05)。而Flt-1在LPPCN周围肿瘤细胞1-3层、4-6层及7-9层之间的表达差异均无统计学意义。VEGF、Flt-1、Flk-1在VM周围肿瘤细胞1-3层、4-6层及7-9层之间的表达差异均无统计学意义(P>0.05)。Log-rank检验法比较显示在LPPCN周边VEGF阳性组患者的生存时间比LPPCN周边VEGF阴性组短,差异有统汁学意义(P<0.05)。LPPCN周边VEGF阳性组中,VM的阳性率高于LPPCN周边VEGF阴性组中VM的阳性率,差异有统计学意义(P<0.05)。
4、侵袭与转移相关蛋白Twist1、MMP-2、MMP-9的表达及与VEGF的相关性
Twist1蛋白在LPPCN阳性组中的表达高于LPPCN阴性组中的表达(P<0.05),其在VM阳性组中的表达也高于VM阴性组中的表达(P<0.05)。MMP-2蛋白在LPPCN阳性组中的表达高于LPPCN阴性组中的表达(P<0.05),其在VM阳性组中的表达也高于VM阴性组中的表达(P<0.05)。而MMP-9蛋白在LPPCN阳性组中的表达与LPPCN阴性组中的表达差异比较无统计学意义(P>0.05),但在VM阳性组中的表达高于VM阴性组中的表达(P<0.05)。
相关性分析结果显示,VEGF与MMP-2呈正相关关系(r=0.334,P=0.024); VEGF与MMP-9呈正相关关系(r=0.118,P=0.037); VEGF与Twist1的表达也呈正相关关系(r=0.526, P=0.003)。
结论
1、恶性黑色素瘤中确实存在LPPCN和VM,存在VM或/和LPPCN的黑色素瘤患者临床预后差。
2、LPPCN与黑色素瘤中的VM及内皮依赖性血管的形成有密切的关系,LPPCN区瘤细胞消融后形成的空间框架可能是VM及内皮依赖性血管形成的空间结构基础。
3、VEGF及其受体Flk-1在黑色索瘤组织中VM形成的早期可能起一定的作用。VEGF及其受体Flk-1的表达与黑色素瘤患者的临床预后有一定的关系。
4、侵袭与转移相关蛋白MMP-2、MMP-9及Twist1均在VM形成过程中起到了一定的作用,它们与VEGF协同参与了VM1的形成过程。
Objective:
To identify if LPPCN(linearly Patterned Programmed cell necrosis) and VM (Vasculogenic Mimicry) existing in human melanoma and to study the distribution of them by morphological observation and indicate the clinical and pathological significance in melanoma.To investigate the expression of VEGF and its receptors Flt-1 and Flk-1 in surrounding tumor cells of LPPCN-positive group and VM-positive group in 70 melanoma cases,and study the interactions between VEGF and invasion and metastasis-associated proteins,to investigate their roles in tumor novel vessel construction and their clinical significance.
Methods:
1、Seventy melanoma cases undergoing surgery in Tumor Hospital affiliated of Tianjin Medical University from 1996 to 2007,which meet the requirements of experiments (undergoing surgery with definite pathologic diagnosis and integrated follow-up document),were collected in this study.The information of samples including gender,age, location,tumor size, date of operation,recurrence and metastasis were collected and analyzed the relationship between the clinicopathologic character of patients and prognostic.
2、HE staining and CD31/PAS double staining was performed on the slides to confirm the existence of LPPCN and VM.Besides,to count the VM,LPPCN,MVD and analyze the relation among them in melanoma.Based on these,to explore the correlation between the existence of LPPCN,VM and clinicopathologic parameter clinical prognosis in the patients of melanoma.
3、Immunohistochemical method was used to detect the expression of VEGF and its receptors Flt-1 and Flk-1 in 1～3 layers,4～6 layers and 7～9 layers of melanoma cells surrounding LPPCN and VM in LPPCN-positive group and VM-positive group in 70 cases.At the same time, to detect the expression of invasion and metastasis-associated proteins Twist1、MMP-2、MMP-9 in LPPCN-positive group and LPPCN-negative group,VM-positive group and VM-negative group,and in melanoma cells surrounding LPPCN.Furthermore,to analysis the relevance between the expression of VEGF and invasion and metastasis-associated proteins, to investigate their roles in the formation of VM.
Results:
1、LPPCN and VM exists in melanoma
HE shows 38 cases existed LPPCN in 70 cases melanoma. The tumor cells undergoing LPPCN were a cluster of spindle cells with condensed cytoplasm and dark nuclei which were distributed in patterns of lines and networks in the HE staining. CD31/PAS double staining shows 33 cases existed VM. VM was tumor cells formed channel with CD31-negative,there was PAS-positive material separate tumor cells and red cells. Near these structures, there were no hemorrhage,necrosis and inflammatory cells infiltration.
2、The relation between LPPCN,VM and clinicopathologic data in melanoma
The melanoma was prone to generate VM and LPPCN when its volume exceed 20cm3 (P<0.05).The occurrence of VM and LPPCN was not correlated with gender,age, location,recurrence and metastasis (P>0.05). Kaplan-Meier survive plot shows the survive time of VM-positive group was shorter than VM-negative group, the survive time of LPPCN-positive group was shorter than LPPCN-negative group (P<0.05)
3、The expression of VEGF and its receptors Flt-1 and Flk-1 in surrounding LPPCN and VM tumor cells
The expression of VEGF and Flk-1 in 1-3 layers surrounding LPPCN was higher than those in 4-61ayers and 7-91ayers(P<0.05).The expression of Flt-1 had no statistical significance(P>0.05).The expression of VEGF,Flt-1 and Flk-1 surrounding VM also had no statistical significance (P>0.05).Kaplan-Meier survive plot showed that the survival time of VEGF-positive surrounding LPPCN group was shorter than VEGF-negative group (P<0.05).The positive rate of VM in VEGF-positive group was higher than that in VEGF-negative group (P<0.05)
4、The expression of Twistl,MMP-2,MMP-9 in melanoma and the relation between VEGF and them
The expression of Twistl in LPPCN-positive group was higher than LPPCN-negative group (P<0.05).The expression of Twistl in VM-positive group was higher than VM-negative group (P<0.05).The expression of MMP-2 and MMP-9 in VM-positive group was higher than VM-negative group (P<0.05).The expression of MMP-2 in LPPCN-positive group was higher than LPPCN-negative group (P<0.05).The expression of MMP-9 in LPPCN-positive group and in LPPCN-negative group had no statistical significance (P>0.05)
There is a highly positive correlation between VEGF and MMP-2(r=0.334, P=0.024).There is a positive correlation between VEGF and MMP-9(r=0.118, P=0.037).There is a highly positive correlation between VEGF and Twist1 (r=0.526,P=0.003).
Conclusion:
1、VM and LPPCN existed in melanoma and the patients with VM or/and LPPCN has worse clinical prognosis than those without VM and LPPCN.
2、LPPCN are closely related with the formation of VM and endothelium-dependent vessels in melanoma.Some tumor cells undergoing LPPCN can establish a special foundation for VM and endothelium-dependent vessels.
3, VEGF and Flk-1 can play critical roles in the early stage of formation of VM in melanoma and the expression of VEGF and its receptor Flk-1 are associated with clinical prognosis of the patients with melanoma.
4^ The proteins of MMP-2,MMP-9 and Twistl expressed by melanoma play a important role in the formation of VM.And them cooperate with VEGF in the formation of VM.
研究人体黑色素瘤组织中是否存在线形程序性坏死(linearly patterned programmed cell necrosis, LPPCN)及血管生成拟态(vasculogenic mimicry, VM)及其分布情况,分析它们的临床病理意义。研究70例人体黑色素瘤组织中LPPCN及VM阳性病例中的LPPCN、VM周围肿瘤细胞血.管内皮生长因子(VEGF)及其受体VEGFR1 (Flt-1)和VEGFR2 (Flk-1)的表达情况并研究VEGF与侵袭转移相关蛋白的相互作用,探讨它们在肿瘤血管生成中的作用以及与临床预后的关系。
方法
1、自1996-2007年天津医科大学附属肿瘤医院存档石蜡标本中挑选出符合实验要求(经手术切除、病理诊断明确且随访资料完整)的恶性黑色素瘤标本共70例,收集患者的性别、年龄、发病部位、肿瘤大小、手术日期、复发与转移和随访等临床资料。分析黑色素瘤患者的临床病理特征及其与预后的关系；
2、利用HE染色观察70例黑色素瘤组织中是否存在LPPCN及利用CD31/PAS双重染色的方法来观察这70例黑色素瘤组织中是否存在VM,并在显微镜下计数其各自的分布情况。运用相关检验法分析LPPCN、VM与MVD之间有无相关以探讨LPPCN与VM、内皮依赖性血管之间的关联性,并在此基础上进一步分析LPPCN、VM的存在与黑色素瘤患者的临床病理参数及预后间的关系；
3、应用免疫组织化学二步法,检测VEGF、Flt-1和Flk-1在距LPPCN及VM周围最近距离(1-3层)、中等距离(4-6层)及远距离(7-9层)的肿瘤细胞中的表达情况,以及侵袭与转移相关蛋白Twist1、MMP-2、MMP-9在LPPCN阳性组和LPPCN阴性组、VM阳性组和VM阴性组中的表达情况和他们在LPPCN周围肿瘤细胞中的表达情况,并进一步分析VEGF与这些蛋白的表达相关性和它们在VM形成过程中所起的作用。
结果
1、黑色素瘤组织中存在LPPCN及VM
对70例黑色素瘤组织进行HE染色可观察到其中有38例瘤组织中出现了胞质浓缩、胞核深染、细胞之间界限清楚的肿瘤细胞,呈线状或网络状分布,此即为LPPCN阳性。对70例黑色素瘤组织进行CD31/PAS双重染色可观察到其中有33例瘤组织中存在一些由CD31染色阴性的肿瘤细胞围成的管腔结构,其管腔壁上有PAS阳性物质,管腔内存在红细胞,周围没有出血坏死和炎症细胞浸润,此即为VM阳性。
2、LPPCN、VM与黑色素瘤患者临床病理参数及预后的关系
LPPCN和VM的发生与患者肿瘤体积的大小有关(P<0.05)而与患者的性别、年龄、肿瘤生长部位、有无复发与转移无关(P>0.05)。当肿瘤体积大于本实验中肿瘤体积的中位值20cm3的时候较易发生LPPCN和VM(P<0.05)。患者的生存率在LPPCN阳性组低于LPPCN阴性组(P<0.05),VM阳性组患者的生存率比VM阴性组低(P<0.05)。
3、VEGF、Flt-1及Flk-1在LPPCN和VM周围肿瘤细胞中的表达及与预后的关系
VEGF在LPPCN周围肿瘤细胞1-3层中的表达强于其外围肿瘤细胞(P<0.05),在外围4-6层与7-9层之间的表达差异无统计学意义(P>0.05)。F1k-1在LPPCN周围肿瘤细胞1-3层中的表达强于其外围肿瘤细胞(P<0.05),在外围4-6层与7-9层之间的表达差异无统计学意义(P>0.05)。而Flt-1在LPPCN周围肿瘤细胞1-3层、4-6层及7-9层之间的表达差异均无统计学意义。VEGF、Flt-1、Flk-1在VM周围肿瘤细胞1-3层、4-6层及7-9层之间的表达差异均无统计学意义(P>0.05)。Log-rank检验法比较显示在LPPCN周边VEGF阳性组患者的生存时间比LPPCN周边VEGF阴性组短,差异有统汁学意义(P<0.05)。LPPCN周边VEGF阳性组中,VM的阳性率高于LPPCN周边VEGF阴性组中VM的阳性率,差异有统计学意义(P<0.05)。
4、侵袭与转移相关蛋白Twist1、MMP-2、MMP-9的表达及与VEGF的相关性
Twist1蛋白在LPPCN阳性组中的表达高于LPPCN阴性组中的表达(P<0.05),其在VM阳性组中的表达也高于VM阴性组中的表达(P<0.05)。MMP-2蛋白在LPPCN阳性组中的表达高于LPPCN阴性组中的表达(P<0.05),其在VM阳性组中的表达也高于VM阴性组中的表达(P<0.05)。而MMP-9蛋白在LPPCN阳性组中的表达与LPPCN阴性组中的表达差异比较无统计学意义(P>0.05),但在VM阳性组中的表达高于VM阴性组中的表达(P<0.05)。
相关性分析结果显示,VEGF与MMP-2呈正相关关系(r=0.334,P=0.024); VEGF与MMP-9呈正相关关系(r=0.118,P=0.037); VEGF与Twist1的表达也呈正相关关系(r=0.526, P=0.003)。
结论
1、恶性黑色素瘤中确实存在LPPCN和VM,存在VM或/和LPPCN的黑色素瘤患者临床预后差。
2、LPPCN与黑色素瘤中的VM及内皮依赖性血管的形成有密切的关系,LPPCN区瘤细胞消融后形成的空间框架可能是VM及内皮依赖性血管形成的空间结构基础。
3、VEGF及其受体Flk-1在黑色索瘤组织中VM形成的早期可能起一定的作用。VEGF及其受体Flk-1的表达与黑色素瘤患者的临床预后有一定的关系。
4、侵袭与转移相关蛋白MMP-2、MMP-9及Twist1均在VM形成过程中起到了一定的作用,它们与VEGF协同参与了VM1的形成过程。
Objective:
To identify if LPPCN(linearly Patterned Programmed cell necrosis) and VM (Vasculogenic Mimicry) existing in human melanoma and to study the distribution of them by morphological observation and indicate the clinical and pathological significance in melanoma.To investigate the expression of VEGF and its receptors Flt-1 and Flk-1 in surrounding tumor cells of LPPCN-positive group and VM-positive group in 70 melanoma cases,and study the interactions between VEGF and invasion and metastasis-associated proteins,to investigate their roles in tumor novel vessel construction and their clinical significance.
Methods:
1、Seventy melanoma cases undergoing surgery in Tumor Hospital affiliated of Tianjin Medical University from 1996 to 2007,which meet the requirements of experiments (undergoing surgery with definite pathologic diagnosis and integrated follow-up document),were collected in this study.The information of samples including gender,age, location,tumor size, date of operation,recurrence and metastasis were collected and analyzed the relationship between the clinicopathologic character of patients and prognostic.
2、HE staining and CD31/PAS double staining was performed on the slides to confirm the existence of LPPCN and VM.Besides,to count the VM,LPPCN,MVD and analyze the relation among them in melanoma.Based on these,to explore the correlation between the existence of LPPCN,VM and clinicopathologic parameter clinical prognosis in the patients of melanoma.
3、Immunohistochemical method was used to detect the expression of VEGF and its receptors Flt-1 and Flk-1 in 1～3 layers,4～6 layers and 7～9 layers of melanoma cells surrounding LPPCN and VM in LPPCN-positive group and VM-positive group in 70 cases.At the same time, to detect the expression of invasion and metastasis-associated proteins Twist1、MMP-2、MMP-9 in LPPCN-positive group and LPPCN-negative group,VM-positive group and VM-negative group,and in melanoma cells surrounding LPPCN.Furthermore,to analysis the relevance between the expression of VEGF and invasion and metastasis-associated proteins, to investigate their roles in the formation of VM.
Results:
1、LPPCN and VM exists in melanoma
HE shows 38 cases existed LPPCN in 70 cases melanoma. The tumor cells undergoing LPPCN were a cluster of spindle cells with condensed cytoplasm and dark nuclei which were distributed in patterns of lines and networks in the HE staining. CD31/PAS double staining shows 33 cases existed VM. VM was tumor cells formed channel with CD31-negative,there was PAS-positive material separate tumor cells and red cells. Near these structures, there were no hemorrhage,necrosis and inflammatory cells infiltration.
2、The relation between LPPCN,VM and clinicopathologic data in melanoma
The melanoma was prone to generate VM and LPPCN when its volume exceed 20cm3 (P<0.05).The occurrence of VM and LPPCN was not correlated with gender,age, location,recurrence and metastasis (P>0.05). Kaplan-Meier survive plot shows the survive time of VM-positive group was shorter than VM-negative group, the survive time of LPPCN-positive group was shorter than LPPCN-negative group (P<0.05)
3、The expression of VEGF and its receptors Flt-1 and Flk-1 in surrounding LPPCN and VM tumor cells
The expression of VEGF and Flk-1 in 1-3 layers surrounding LPPCN was higher than those in 4-61ayers and 7-91ayers(P<0.05).The expression of Flt-1 had no statistical significance(P>0.05).The expression of VEGF,Flt-1 and Flk-1 surrounding VM also had no statistical significance (P>0.05).Kaplan-Meier survive plot showed that the survival time of VEGF-positive surrounding LPPCN group was shorter than VEGF-negative group (P<0.05).The positive rate of VM in VEGF-positive group was higher than that in VEGF-negative group (P<0.05)
4、The expression of Twistl,MMP-2,MMP-9 in melanoma and the relation between VEGF and them
The expression of Twistl in LPPCN-positive group was higher than LPPCN-negative group (P<0.05).The expression of Twistl in VM-positive group was higher than VM-negative group (P<0.05).The expression of MMP-2 and MMP-9 in VM-positive group was higher than VM-negative group (P<0.05).The expression of MMP-2 in LPPCN-positive group was higher than LPPCN-negative group (P<0.05).The expression of MMP-9 in LPPCN-positive group and in LPPCN-negative group had no statistical significance (P>0.05)
There is a highly positive correlation between VEGF and MMP-2(r=0.334, P=0.024).There is a positive correlation between VEGF and MMP-9(r=0.118, P=0.037).There is a highly positive correlation between VEGF and Twist1 (r=0.526,P=0.003).
Conclusion:
1、VM and LPPCN existed in melanoma and the patients with VM or/and LPPCN has worse clinical prognosis than those without VM and LPPCN.
2、LPPCN are closely related with the formation of VM and endothelium-dependent vessels in melanoma.Some tumor cells undergoing LPPCN can establish a special foundation for VM and endothelium-dependent vessels.
3, VEGF and Flk-1 can play critical roles in the early stage of formation of VM in melanoma and the expression of VEGF and its receptor Flk-1 are associated with clinical prognosis of the patients with melanoma.
4^ The proteins of MMP-2,MMP-9 and Twistl expressed by melanoma play a important role in the formation of VM.And them cooperate with VEGF in the formation of VM.
引文
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