膀胱移行细胞癌EphA2的表达及血管生成拟态的实验研究
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摘要
背景与目的：膀胱癌是泌尿系统最常见的恶性肿瘤，它的发病率占全身肿瘤的第8位，其中90％以上是移行细胞癌(transitionalcell carcinoma，TCC)，虽然，在初次就诊时55％～60％的膀胱癌为浅表的分化较好的乳头状癌，但治疗后易复发，复发的肿瘤中有20％～30％转变为病理和临床级别更高的侵袭性恶性肿瘤，预后不良。对于侵犯肌层的膀胱癌，有50％患者最终因广泛侵润和远处转移而导致死亡。临床分期和病理分级是公认的判定预后的依据，但哪些标记或结构能预测哪些膀胱癌有向更高恶性和侵袭性转变?这些生物学标记是否能为膀胱癌的生物治疗提供新靶向和新思路呢?这些问题已成为膀胱癌的研究热点。
EphA2(epithelial cell kinase，EphA2)是Eph酪氨酸激酶受体家族成员之一，最初是在成年人上皮细胞内发现的，虽然EphA2在正常细胞内的细胞学功能尚未被很好阐明，但在人类不同类型的肿瘤组织和细胞株中常常高表达，包括乳腺癌、恶性黑色素细胞瘤、前列腺癌、结肠癌和食管癌等，特别在高侵袭性的肿瘤中有更高水平的表达。对于一些肿瘤模型的研究也表明EphA2在调节细胞的生长、生存、迁移和血管发生中具有潜在的作用。近几年来，又发现它参与调控肿瘤血管生成拟态(vasculogenic mimicry VM)的形成。血管生成拟态最初是在1999年由Maniotis等提出的。他们发现在视网膜黑色素瘤内部可形成由恶性肿瘤细胞而非血管内皮细胞连接形成的、能为肿瘤提供血供的管网状结构。随后的进一步研究发现在其他一些高度恶性的肿瘤也中存在这种肿瘤微循环的新形式，这种由高度恶性肿瘤细胞通过细胞变形生成的被细胞外基质分割的微循环管道与恶性肿瘤的侵袭、转移和预后关系密切，也对以往认为肿瘤仅通过血管发生获得血流供应的机制提出了挑战。
目前，对肿瘤组织EphA2表达和血管生成拟态的研究，虽然在国内外有少量文献报道，但涉及到膀胱癌的报道极少。本实验通过测定膀胱移行细胞癌中EphA2蛋白、磷酸化EphA2蛋白及基因的表达，探讨EphA2与膀胱癌生物学特性的关系，并对EphA2表达的分子机制和调控机制进行初步研究。同时在膀胱癌中寻找是否存在血管生成拟态，探讨血管生成拟态与EphA2的相关性。本研究分2部分：
题目：EphA2在膀胱移行细胞癌中的表达情况及机制探讨
研究目的：研究EphA2与膀胱癌生物学特性的关系，初步探讨EphA2表达的分子调控机制。
研究方法：采用Western blotting和免疫沉淀技术分别测定20例膀胱移行细胞癌和10例正常膀胱粘膜EphA2蛋白和磷酸化EphA2蛋白的表达，应用RT-PCR技术对上述两组标本的EphA2 mRNA进行测定。
结果：EphA2蛋白在膀胱移行细胞癌中的表达明显高于正常膀胱粘膜(P＜0.001)，在膀胱移行细胞癌低分化组表达强于高分化组；磷酸化EphA2蛋白在正常膀胱粘膜中的表达高于膀胱移行细胞癌(P＜0.001)；EphA2 mRNA在膀胱移行细胞癌中的表达高于正常膀胱粘膜(P＜0.001)，与膀胱移行细胞癌的分化程度无关(P=0.295)。
题目：膀胱移行细胞癌中血管生成拟态及EphA2蛋白表达的实验分析
研究目的：寻找在膀胱癌中是否存在血管生成拟态(VM)，探讨VM、EphA2的生物学意义以及EphA2与VM、肿瘤微血管生成的相关性。
研究方法：对85例膀胱移行细胞癌存档石蜡标本采用过碘酸雪夫氏反应(periodic acid schiff，PAS)和CD31双重染色，寻找血管生成拟态，同时行微血管密度(microvessel density，MVD)计数。应用免疫组织化学技术检测85例膀胱移行细胞癌及10例正常膀胱粘膜中EphA2的表达。
结果：膀胱癌组织中大部分管道为内腔面有内皮细胞被覆的血管，这些血管呈现CD31、PAS染色阳性。在85例膀胱癌组织中有8例存在血管生成拟态，这些管道呈现PAS阳性、CD31阴性，其中2例为中分化膀胱癌，6例为低分化膀胱癌，包括T2期1例，T3期4例，T4期3例。8例中有6例出现淋巴结转移。在膀胱移行细胞癌中，EphA2表达阳性76例，阴性9例，阳性率为89.4％，在正常膀胱粘膜组，弱阳性4例，阴性6例，阳性率为40％。两组间差异有显著性意义(P＜0.01)；VM形成与EphA2表达程度有相关性(P＜0.05)，膀胱移行细胞癌EphA2阴性组与EphA2阳性组间肿瘤微血管密度(MVD)计数差异有显著性意义(P＜0.05)，EphA2不同阳性程度组之间MVD计数差异没有显著性意义(P＞0.05)。VM存在与否、EphA2表达程度与膀胱癌的病理分级、临床分期和淋巴结转移均有相关性(P＜0.05)；
结论：中低分化膀胱癌中存在血管生成拟态；EphA2与血管生成拟态、肿瘤血管生成均有相关性；VM和EphA2将成为判定膀胱癌恶性程度的指标和膀胱癌治疗的新靶向；EphA2 mRNA表达强度与EphA2蛋白表达强度不完全一致。提示转录后的调控机制干预了膀胱癌中EphA2的表达。
Background and objective: bladder carcinoma is the most common malignancy of urinary system, Approximately 90% of the urinary bladder cancers are transitional cell carcinomas that typically occur either as superficial (low-grade) or muscle-invasive (intermediate to high-grade) carcinoma. Superficial tumors can be surgically resected; however, local recurrence is common and 20% to 30% of recurrent lesions progress to higher grade or stage. Muscle-invasive cancers have the greatest propensity to metastasize and are fatal in～50% of the patients. Although the most reliable prognostic factors for recurrence and progression are tumor stage and grade. It is still necessary to search better prognostic markers, to improve clinical management of bladder carcinoma patients.
The Eph family of kinases constitutes the largest group of transmembrane receptor tyrosine kinases (RTKs). EphA2 is primarily found in adult human epithelial cells. Lower level of EphA2 expression in epithelial cells are observed, while high levels of EphA2 expression have been reported in different human tumor tissues and cell lines, including breast cancer, metastatic melanoma, prostate cancer, colon cancer, and esophagealcancer, specially with higher expression in some aggressive tumors. Increasing evidence indicates that EphA2 overexpression is a common event during the progression of cancer. The study on tumor-based models suggests potential roles for EphA2 in the regulation of cell growth, survival, migration, and angiogenesis. EphA2 has been recently identified as an important mediator of vasculogenie mimicry in vitro. The patterned microcirculation characteristic of vasculogenic mimicry was first described in uveal (intraocular) melanoma. The de novo generation of vascular channels by aggressive and metastatic tumor cells is not strictly a vasculogenic event, therefore the name "vasculogenic mimicry" is assigned to the process by which aggressive tumor cells generate non-endothelial cell-lined charnnels delimited by extracelhlar matrix. Recent researchs discover that other malignant tumors also can generate the characteristic of vasculogenic mimicry. Tumors with vaseulogenic mimicry have a high-grade malignancy, early blood metastasis and poor clinical prognosis. Bissell has further noted that vaseulogenic mimicry poses challenges to the practice of surgical pathology and provides opportunities for the development of new imaging techniques and cancer treatment strategies.
Although the researches about VM and EphA2 expression in tumor have been sporadically reported, the related study on bladder transitional cell carcinoma was seldom reported. We used Immunohistochemistry, Western blotting and immunoprecipitation to detect the expression of EphA2, EphA2-P and EphA2 mRNA in bladder transitional cell carcinoma and normal mucous membrane of urinary bladder; to investigate the relations between EphA2 and bladder transitional cell carcinoma biological characteristics;to explore the mechanism about EphA2 expression, at the same time, the possible vasculogenic mimicry(VM) presence in transitional cell carcinoma of bladder(TCCB) was investigated to explain the clinical significance of VM in bladder cancer. The relationship between Epha2 and VM, MVD was analysised.
Experiment part one: Expression and molecular regulation of EphA2 in transitional cell carcinoma of bladder.
Purpose: to study the relations between EphA2 and TCCB biological characteristics; to explore the molecular mechanism regulating EphA2 expression.
Methods: Western blotting and Immunoprecipitation were used to detect the protein expression of EphA2 and EphA2-P in 20 cases of TCCB and 10 cases of normal bladder. The expression of EphA2 mRNA in these cases was determined by RT-PCR.
Results: The EphA2 protein and EphA2 mRNA in TCCB were signigicantly higher expressed than those in normal mucous membrane of urinary bladder(P＜0.001). The EphA2 protein was highly expressed in poorly differentiated group than that in well differentiated group, the EphA2-P expression in normal mucous membrane of urinary bladder was signigicantly higher than that in TCCB(P＜0.001). The expression of EphA2 mRNA was not correlated with pathological grade of TCCB(P=0.295).
Experiment part two: Vasculogenic mimicry and expression of EphA2 protein in transitional cell carcinoma of bladder.
Purpose: to search whether vasculogenic mimicry(VM) exsits in TCCB, to explore the importment biological significances of VM and EphA2 in TCCB, to analyze the relations between EphA2 and VM, MVD in TCCB.
Methods: the results demonstrated that endothelium-lined vessels were stained positively for CD31 and PAS and were in the majority of the tumor microvasculature.PAS-positive pattern of VM were found in 8 BTCC specimens among 85 TCCB specimens,the 8 specimens belong toⅡ～Ⅲgrade and T2～T4 stage, 6 of them with lymphatic metastasis, the positive rate of EphA2 in TCCB and normal bladder group was 89.1% and 40% ,and was significantly different between the two groups(P＜0.01).VM correlate with the expression level of EphA2(P＜0.01).the MVD was significantly different between the EphA2 positive group and the EphA2 negative group in TCCB(P＜0.01), the MVD among the EphA2 positive groups was not different signigicantly (P＞0.05). VM and the expression of EphA2 correlate with clinic stage, histological grading and lymphatic metastasis(P＜0.01).
Conclusion: our results suggest that VM exists in some moderately /poorly differentiated TCCB; EphA2 correlates with VM and angiogenesis in TCCB; VM and EphA2 will be some good markers to monitor the malignant degree and some novel targets for therapeutic intervention against TCCB. The inconformity in expression of EphA2 mRNA and protein in TCCB indicate that the posttranscriptional mechanism may play an important role in the reglation of EphA2.
EphA2(epithelial cell kinase，EphA2)是Eph酪氨酸激酶受体家族成员之一，最初是在成年人上皮细胞内发现的，虽然EphA2在正常细胞内的细胞学功能尚未被很好阐明，但在人类不同类型的肿瘤组织和细胞株中常常高表达，包括乳腺癌、恶性黑色素细胞瘤、前列腺癌、结肠癌和食管癌等，特别在高侵袭性的肿瘤中有更高水平的表达。对于一些肿瘤模型的研究也表明EphA2在调节细胞的生长、生存、迁移和血管发生中具有潜在的作用。近几年来，又发现它参与调控肿瘤血管生成拟态(vasculogenic mimicry VM)的形成。血管生成拟态最初是在1999年由Maniotis等提出的。他们发现在视网膜黑色素瘤内部可形成由恶性肿瘤细胞而非血管内皮细胞连接形成的、能为肿瘤提供血供的管网状结构。随后的进一步研究发现在其他一些高度恶性的肿瘤也中存在这种肿瘤微循环的新形式，这种由高度恶性肿瘤细胞通过细胞变形生成的被细胞外基质分割的微循环管道与恶性肿瘤的侵袭、转移和预后关系密切，也对以往认为肿瘤仅通过血管发生获得血流供应的机制提出了挑战。
目前，对肿瘤组织EphA2表达和血管生成拟态的研究，虽然在国内外有少量文献报道，但涉及到膀胱癌的报道极少。本实验通过测定膀胱移行细胞癌中EphA2蛋白、磷酸化EphA2蛋白及基因的表达，探讨EphA2与膀胱癌生物学特性的关系，并对EphA2表达的分子机制和调控机制进行初步研究。同时在膀胱癌中寻找是否存在血管生成拟态，探讨血管生成拟态与EphA2的相关性。本研究分2部分：
题目：EphA2在膀胱移行细胞癌中的表达情况及机制探讨
研究目的：研究EphA2与膀胱癌生物学特性的关系，初步探讨EphA2表达的分子调控机制。
研究方法：采用Western blotting和免疫沉淀技术分别测定20例膀胱移行细胞癌和10例正常膀胱粘膜EphA2蛋白和磷酸化EphA2蛋白的表达，应用RT-PCR技术对上述两组标本的EphA2 mRNA进行测定。
结果：EphA2蛋白在膀胱移行细胞癌中的表达明显高于正常膀胱粘膜(P＜0.001)，在膀胱移行细胞癌低分化组表达强于高分化组；磷酸化EphA2蛋白在正常膀胱粘膜中的表达高于膀胱移行细胞癌(P＜0.001)；EphA2 mRNA在膀胱移行细胞癌中的表达高于正常膀胱粘膜(P＜0.001)，与膀胱移行细胞癌的分化程度无关(P=0.295)。
题目：膀胱移行细胞癌中血管生成拟态及EphA2蛋白表达的实验分析
研究目的：寻找在膀胱癌中是否存在血管生成拟态(VM)，探讨VM、EphA2的生物学意义以及EphA2与VM、肿瘤微血管生成的相关性。
研究方法：对85例膀胱移行细胞癌存档石蜡标本采用过碘酸雪夫氏反应(periodic acid schiff，PAS)和CD31双重染色，寻找血管生成拟态，同时行微血管密度(microvessel density，MVD)计数。应用免疫组织化学技术检测85例膀胱移行细胞癌及10例正常膀胱粘膜中EphA2的表达。
结果：膀胱癌组织中大部分管道为内腔面有内皮细胞被覆的血管，这些血管呈现CD31、PAS染色阳性。在85例膀胱癌组织中有8例存在血管生成拟态，这些管道呈现PAS阳性、CD31阴性，其中2例为中分化膀胱癌，6例为低分化膀胱癌，包括T2期1例，T3期4例，T4期3例。8例中有6例出现淋巴结转移。在膀胱移行细胞癌中，EphA2表达阳性76例，阴性9例，阳性率为89.4％，在正常膀胱粘膜组，弱阳性4例，阴性6例，阳性率为40％。两组间差异有显著性意义(P＜0.01)；VM形成与EphA2表达程度有相关性(P＜0.05)，膀胱移行细胞癌EphA2阴性组与EphA2阳性组间肿瘤微血管密度(MVD)计数差异有显著性意义(P＜0.05)，EphA2不同阳性程度组之间MVD计数差异没有显著性意义(P＞0.05)。VM存在与否、EphA2表达程度与膀胱癌的病理分级、临床分期和淋巴结转移均有相关性(P＜0.05)；
结论：中低分化膀胱癌中存在血管生成拟态；EphA2与血管生成拟态、肿瘤血管生成均有相关性；VM和EphA2将成为判定膀胱癌恶性程度的指标和膀胱癌治疗的新靶向；EphA2 mRNA表达强度与EphA2蛋白表达强度不完全一致。提示转录后的调控机制干预了膀胱癌中EphA2的表达。
Background and objective: bladder carcinoma is the most common malignancy of urinary system, Approximately 90% of the urinary bladder cancers are transitional cell carcinomas that typically occur either as superficial (low-grade) or muscle-invasive (intermediate to high-grade) carcinoma. Superficial tumors can be surgically resected; however, local recurrence is common and 20% to 30% of recurrent lesions progress to higher grade or stage. Muscle-invasive cancers have the greatest propensity to metastasize and are fatal in～50% of the patients. Although the most reliable prognostic factors for recurrence and progression are tumor stage and grade. It is still necessary to search better prognostic markers, to improve clinical management of bladder carcinoma patients.
The Eph family of kinases constitutes the largest group of transmembrane receptor tyrosine kinases (RTKs). EphA2 is primarily found in adult human epithelial cells. Lower level of EphA2 expression in epithelial cells are observed, while high levels of EphA2 expression have been reported in different human tumor tissues and cell lines, including breast cancer, metastatic melanoma, prostate cancer, colon cancer, and esophagealcancer, specially with higher expression in some aggressive tumors. Increasing evidence indicates that EphA2 overexpression is a common event during the progression of cancer. The study on tumor-based models suggests potential roles for EphA2 in the regulation of cell growth, survival, migration, and angiogenesis. EphA2 has been recently identified as an important mediator of vasculogenie mimicry in vitro. The patterned microcirculation characteristic of vasculogenic mimicry was first described in uveal (intraocular) melanoma. The de novo generation of vascular channels by aggressive and metastatic tumor cells is not strictly a vasculogenic event, therefore the name "vasculogenic mimicry" is assigned to the process by which aggressive tumor cells generate non-endothelial cell-lined charnnels delimited by extracelhlar matrix. Recent researchs discover that other malignant tumors also can generate the characteristic of vasculogenic mimicry. Tumors with vaseulogenic mimicry have a high-grade malignancy, early blood metastasis and poor clinical prognosis. Bissell has further noted that vaseulogenic mimicry poses challenges to the practice of surgical pathology and provides opportunities for the development of new imaging techniques and cancer treatment strategies.
Although the researches about VM and EphA2 expression in tumor have been sporadically reported, the related study on bladder transitional cell carcinoma was seldom reported. We used Immunohistochemistry, Western blotting and immunoprecipitation to detect the expression of EphA2, EphA2-P and EphA2 mRNA in bladder transitional cell carcinoma and normal mucous membrane of urinary bladder; to investigate the relations between EphA2 and bladder transitional cell carcinoma biological characteristics;to explore the mechanism about EphA2 expression, at the same time, the possible vasculogenic mimicry(VM) presence in transitional cell carcinoma of bladder(TCCB) was investigated to explain the clinical significance of VM in bladder cancer. The relationship between Epha2 and VM, MVD was analysised.
Experiment part one: Expression and molecular regulation of EphA2 in transitional cell carcinoma of bladder.
Purpose: to study the relations between EphA2 and TCCB biological characteristics; to explore the molecular mechanism regulating EphA2 expression.
Methods: Western blotting and Immunoprecipitation were used to detect the protein expression of EphA2 and EphA2-P in 20 cases of TCCB and 10 cases of normal bladder. The expression of EphA2 mRNA in these cases was determined by RT-PCR.
Results: The EphA2 protein and EphA2 mRNA in TCCB were signigicantly higher expressed than those in normal mucous membrane of urinary bladder(P＜0.001). The EphA2 protein was highly expressed in poorly differentiated group than that in well differentiated group, the EphA2-P expression in normal mucous membrane of urinary bladder was signigicantly higher than that in TCCB(P＜0.001). The expression of EphA2 mRNA was not correlated with pathological grade of TCCB(P=0.295).
Experiment part two: Vasculogenic mimicry and expression of EphA2 protein in transitional cell carcinoma of bladder.
Purpose: to search whether vasculogenic mimicry(VM) exsits in TCCB, to explore the importment biological significances of VM and EphA2 in TCCB, to analyze the relations between EphA2 and VM, MVD in TCCB.
Methods: the results demonstrated that endothelium-lined vessels were stained positively for CD31 and PAS and were in the majority of the tumor microvasculature.PAS-positive pattern of VM were found in 8 BTCC specimens among 85 TCCB specimens,the 8 specimens belong toⅡ～Ⅲgrade and T2～T4 stage, 6 of them with lymphatic metastasis, the positive rate of EphA2 in TCCB and normal bladder group was 89.1% and 40% ,and was significantly different between the two groups(P＜0.01).VM correlate with the expression level of EphA2(P＜0.01).the MVD was significantly different between the EphA2 positive group and the EphA2 negative group in TCCB(P＜0.01), the MVD among the EphA2 positive groups was not different signigicantly (P＞0.05). VM and the expression of EphA2 correlate with clinic stage, histological grading and lymphatic metastasis(P＜0.01).
Conclusion: our results suggest that VM exists in some moderately /poorly differentiated TCCB; EphA2 correlates with VM and angiogenesis in TCCB; VM and EphA2 will be some good markers to monitor the malignant degree and some novel targets for therapeutic intervention against TCCB. The inconformity in expression of EphA2 mRNA and protein in TCCB indicate that the posttranscriptional mechanism may play an important role in the reglation of EphA2.
引文
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