Cripto-1蛋白在乳腺癌中的表达和预后意义
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摘要
[目的]
乳腺癌是女性常见的一组恶性上皮性肿瘤,其特征为肿瘤浸润邻近的组织,和具有明显的远处转移倾向。目前的研究认为,上皮-间质转化(epithelial-mesenchymal transition,EMT)在肿瘤的侵袭和转移过程中发挥重要的作用。Cripto-1蛋白在肿瘤中能够促进EMT的发生,本研究旨在从Cripto-1蛋白的角度探讨它是如何通过EMT促进乳腺癌的浸润和转移的。
[方法]
采用免疫组织化学LSAB法检测组织芯片205例乳腺癌标本中Cripto-1蛋白、E-cadherin(E-CD)及β-catenin的表达情况,并分析它们与ER、PR、HER2/neu受体的表达情况、患者年龄、病理组织学分期、分级及淋巴结转移情况等主要临床病理学特征的关系。并且,进一步分析Cripto-1蛋白对乳腺癌复发、转移、生存时间等预后因素的影响。
[结果]
1.Cripto-1蛋白表达于癌细胞质,阳性表达率为82.9%(170／205例),其表达与肿瘤的病理组织学分期(r=0.418,P=0.000)、组织学分级(r=0.141,P=0.044)、HER2／neu状态(r=0.223,P=0.001)、淋巴结转移个数(r=0.293,P=0.000)、淋巴结外软组织癌浸润情况(r=0.206,P=0.003)及远处转移(r=0.273,P=0.000)呈正相关；而与ER, PR的表达及患者年龄无明显相关性。
2.E-CD表达于细胞膜,其表达下降率为54.1%(111／205),且与病理组织学分期(r=-0.165,P=0.018)、组织学分级(r=-0.151,P=0.031)、淋巴结转移个数(r=-0.154,P=0.027)、淋巴结外软组织癌浸润情况(r=-0.200,P=0.004)呈负相关；而与ER、PR、HER2/neu表达、患者的年龄、肿瘤大小及远处转移无明显相关性。
3.β-catenin同时表达于细胞膜、细胞质或细胞核,在EMT过程中P-catenin的表达由肿瘤细胞的胞膜转向胞质或胞核,其在肿瘤细胞中的异位表达率为67.3%(138／205),且与病理组织学分期(r=0.193,P=0.006)、淋巴结转移个数(r=0.153,P=0.028)呈正相关；而与ER、PR、HER2/neu表达、年龄、肿瘤大小组织学分级、淋巴结外软组织癌浸润情况及远处转移无明显相关性。
4.Cripto-1蛋白的表达与E-CD的表达呈明显负相关(r=-0.324,P=0.000),而与β-catenin在胞质或胞核中的异位表达呈明显正相关(r=0.412,P=0.000)；并且综合分析Cripto-1和E-CD、Cripto-1和β-catenin表达,将其分别分为三个表达水平：Cripto-1+/E-CD—、Cripto-1+/E-CD+/Cripto-1—/E-CD—、Cripto-1—/E-CD+；Cripto-1+/β-catenin+、Cripto-1+/β-catenin—/Cripto-1—/β-catenin+、Cripto-1—/β-catenin—。其中Cripto-1+/E-CD—与病理学分期(χ2=14.502,P=0.002)、淋巴结转移个数(χ2=12.858,P=0.005)、淋巴结外软组织癌浸润情况(χ2=9.275,P=0.002)及远处转移((χ2=4.654,P=0.045)呈明显正相关,而与ER、PR、HER2/neu表达、年龄、肿瘤大小、组织学分级及远处转移无明显相关性；Cripto-1+/β-catenin+与病理学分期(χ2=14.334,P=0.002)、淋巴结转移个数(χ2=8.734,P=0.033)及远处转移(χ2=5.400,P=0.020)呈正相关,而与ER、PR、HER2/neu表达、年龄、肿瘤大小、组织学分级及淋巴结外软组织癌浸润情况无明显相关性。
5.Kaplan-Meier生存分析显示Cripto-1蛋白的高表达与患者的生存率呈明显负相关(P<0.05),Cripto-1蛋白表达越强的病人其生存率越低；E-CD的高表达与患者的生存率呈明显的正相关(P<0.05)；β-catenin的异位表达与患者的生存率呈明显的负相关(P<0.05);Cripto-1+／E-CD—和Cripto-1+/β-catenin+的患者生存率明显下降(P<0.05)；Cox-Regression证明Cripto-1蛋白是乳腺癌独立的预后因素(HR,2.353)。
[结论]
1.Cripto-1蛋白可能是通过抑制E-CD的表达和促进β-catenin在细胞质或胞核中异位表达的EMT机制促进肿瘤的局部侵袭和远处转移的。
2.Cripto-1蛋白是乳腺癌的预后不良因素之一,可作为乳腺癌的独立预后因子。
3.Cripto-1蛋白为乳腺癌的个体化治疗提供了新的依据。
Objective
Breast cancer is a common cancer of women, which is a group of malignant epithelial tumors, characterized by tumor-infiltrating adjacent tissue, and an obvious tendency of distant metastasis. Our research was to study the significance of Cripto-1 which play an important role in Epithelial-Mesenchymal Transition(EMT) and its prognosis in breast cancer.
Methods
Immunohistochemical study for Cripto-1, E-CD and P-catenin were performed on 205 cases of breast cancer using LSAB methods. The relationship between Cripto-1, E-CD, P-catenin and various pathologic parameters (estrogen and progesterone receptor status, Her2/neu status,histologic grade, pathologic stage and lymph node metastasis etc.) in breast cancer was analyzed. And also analyzed the univariate Kaplan-Meier survival and Cox-regression survival.
Results
1. Cripto-1 was mainly expressed in the plasma of tumor cells. Upregulated Cripto-1 was found in 82.9%(170/205)cases. The expression of Cripto-1 was positively correlated with pathologic stage(r=0.357, P=0.000), histological grade(r=0.141, P=0.044), Her2/neu(r=0.223, P=0.001), lymph node metastasis(r=0.293, P=0.000), extranodal extension(r=0.206, P=0.003) and distant metastasis(r=0.273, P=0.000).
2. E-CD was expressed in the membrane of the breast cell, downregulated of E-CD was found in 54.1%(111/205) cases. The expression of E-CD was negatively correlated with pathologic stage(r=-0.165, P=0.018), histological grade(r=-0.151, P=0.031), lymph node metastasis(r=-0.154, P=0.027), extranodal extension(r=-0.200, P=0.004).
3. P-catenin was expressed in the cytoplasma and nuclear in EMT and was found in 67.3% (138/205) cases. The expression ofβ-catenin was positively correlated with pathologic stage(r=0.193, P=0.006), lymph node metastasis(r=0.153,P=0.028).
4. The expression of Cripto-1 was negatively correlated with E-CD(r=-0.324, P=0.000)and positively correlated with P-catenin(r=0.412, P=0.000). Combined evaluation Cripto-1/E-CD and Cripto-1/β-catenin, Cripto-1+/E-CD-was strongly associated with pathologic stage(χ2=14.502,P=0.002), lymph node metastasis(χ2=12.858, P=0.005), extranodal extension(χ2=9.275, P=0.002),distant metastasis((χ2=4.654, P=0.045), and Cripto-1+/β-catenin+ was strongly associated with pathologic stage(χ2=14.334, P=0.002), lymph node metastasis(χ2=8.734, P=0.033), distant metastasis(χ2=5.400,P=0.020).
5. Univariate Kaplan-Meier survival analysis reveals that patient with Cripto-1+, E-CD-orβ-catenin which localized in the cytoplasm showed lower survival rates than those with Cripto-1 -, E-CD+ orβ-catenin which localized in the membrane(P<0.05). When combined,evaluation of Cripto-1 and E-CD, Cripto-1 andβ-catenin, Cripto-1+/E-CD - and Cripto-1+/β-catenin+ indicated the worst survival(P<0.05). Cox-regression analysis indicated that the overexpression of Cripto-1 was an independent prognostic factor in breast cancer (HR,2.353).
Conclusion
1. Upregulation of Cripto-1, downregulation of E-CD and relocalization of P-catenin may play important roles in the invasion and metastasis of breast cancer.
2. overexpression of Cripto-1 was a significantly factor for prognosis.
3. Cripto-1 protein was a new target for the breast cancer treatment.
乳腺癌是女性常见的一组恶性上皮性肿瘤,其特征为肿瘤浸润邻近的组织,和具有明显的远处转移倾向。目前的研究认为,上皮-间质转化(epithelial-mesenchymal transition,EMT)在肿瘤的侵袭和转移过程中发挥重要的作用。Cripto-1蛋白在肿瘤中能够促进EMT的发生,本研究旨在从Cripto-1蛋白的角度探讨它是如何通过EMT促进乳腺癌的浸润和转移的。
[方法]
采用免疫组织化学LSAB法检测组织芯片205例乳腺癌标本中Cripto-1蛋白、E-cadherin(E-CD)及β-catenin的表达情况,并分析它们与ER、PR、HER2/neu受体的表达情况、患者年龄、病理组织学分期、分级及淋巴结转移情况等主要临床病理学特征的关系。并且,进一步分析Cripto-1蛋白对乳腺癌复发、转移、生存时间等预后因素的影响。
[结果]
1.Cripto-1蛋白表达于癌细胞质,阳性表达率为82.9%(170／205例),其表达与肿瘤的病理组织学分期(r=0.418,P=0.000)、组织学分级(r=0.141,P=0.044)、HER2／neu状态(r=0.223,P=0.001)、淋巴结转移个数(r=0.293,P=0.000)、淋巴结外软组织癌浸润情况(r=0.206,P=0.003)及远处转移(r=0.273,P=0.000)呈正相关；而与ER, PR的表达及患者年龄无明显相关性。
2.E-CD表达于细胞膜,其表达下降率为54.1%(111／205),且与病理组织学分期(r=-0.165,P=0.018)、组织学分级(r=-0.151,P=0.031)、淋巴结转移个数(r=-0.154,P=0.027)、淋巴结外软组织癌浸润情况(r=-0.200,P=0.004)呈负相关；而与ER、PR、HER2/neu表达、患者的年龄、肿瘤大小及远处转移无明显相关性。
3.β-catenin同时表达于细胞膜、细胞质或细胞核,在EMT过程中P-catenin的表达由肿瘤细胞的胞膜转向胞质或胞核,其在肿瘤细胞中的异位表达率为67.3%(138／205),且与病理组织学分期(r=0.193,P=0.006)、淋巴结转移个数(r=0.153,P=0.028)呈正相关；而与ER、PR、HER2/neu表达、年龄、肿瘤大小组织学分级、淋巴结外软组织癌浸润情况及远处转移无明显相关性。
4.Cripto-1蛋白的表达与E-CD的表达呈明显负相关(r=-0.324,P=0.000),而与β-catenin在胞质或胞核中的异位表达呈明显正相关(r=0.412,P=0.000)；并且综合分析Cripto-1和E-CD、Cripto-1和β-catenin表达,将其分别分为三个表达水平：Cripto-1+/E-CD—、Cripto-1+/E-CD+/Cripto-1—/E-CD—、Cripto-1—/E-CD+；Cripto-1+/β-catenin+、Cripto-1+/β-catenin—/Cripto-1—/β-catenin+、Cripto-1—/β-catenin—。其中Cripto-1+/E-CD—与病理学分期(χ2=14.502,P=0.002)、淋巴结转移个数(χ2=12.858,P=0.005)、淋巴结外软组织癌浸润情况(χ2=9.275,P=0.002)及远处转移((χ2=4.654,P=0.045)呈明显正相关,而与ER、PR、HER2/neu表达、年龄、肿瘤大小、组织学分级及远处转移无明显相关性；Cripto-1+/β-catenin+与病理学分期(χ2=14.334,P=0.002)、淋巴结转移个数(χ2=8.734,P=0.033)及远处转移(χ2=5.400,P=0.020)呈正相关,而与ER、PR、HER2/neu表达、年龄、肿瘤大小、组织学分级及淋巴结外软组织癌浸润情况无明显相关性。
5.Kaplan-Meier生存分析显示Cripto-1蛋白的高表达与患者的生存率呈明显负相关(P<0.05),Cripto-1蛋白表达越强的病人其生存率越低；E-CD的高表达与患者的生存率呈明显的正相关(P<0.05)；β-catenin的异位表达与患者的生存率呈明显的负相关(P<0.05);Cripto-1+／E-CD—和Cripto-1+/β-catenin+的患者生存率明显下降(P<0.05)；Cox-Regression证明Cripto-1蛋白是乳腺癌独立的预后因素(HR,2.353)。
[结论]
1.Cripto-1蛋白可能是通过抑制E-CD的表达和促进β-catenin在细胞质或胞核中异位表达的EMT机制促进肿瘤的局部侵袭和远处转移的。
2.Cripto-1蛋白是乳腺癌的预后不良因素之一,可作为乳腺癌的独立预后因子。
3.Cripto-1蛋白为乳腺癌的个体化治疗提供了新的依据。
Objective
Breast cancer is a common cancer of women, which is a group of malignant epithelial tumors, characterized by tumor-infiltrating adjacent tissue, and an obvious tendency of distant metastasis. Our research was to study the significance of Cripto-1 which play an important role in Epithelial-Mesenchymal Transition(EMT) and its prognosis in breast cancer.
Methods
Immunohistochemical study for Cripto-1, E-CD and P-catenin were performed on 205 cases of breast cancer using LSAB methods. The relationship between Cripto-1, E-CD, P-catenin and various pathologic parameters (estrogen and progesterone receptor status, Her2/neu status,histologic grade, pathologic stage and lymph node metastasis etc.) in breast cancer was analyzed. And also analyzed the univariate Kaplan-Meier survival and Cox-regression survival.
Results
1. Cripto-1 was mainly expressed in the plasma of tumor cells. Upregulated Cripto-1 was found in 82.9%(170/205)cases. The expression of Cripto-1 was positively correlated with pathologic stage(r=0.357, P=0.000), histological grade(r=0.141, P=0.044), Her2/neu(r=0.223, P=0.001), lymph node metastasis(r=0.293, P=0.000), extranodal extension(r=0.206, P=0.003) and distant metastasis(r=0.273, P=0.000).
2. E-CD was expressed in the membrane of the breast cell, downregulated of E-CD was found in 54.1%(111/205) cases. The expression of E-CD was negatively correlated with pathologic stage(r=-0.165, P=0.018), histological grade(r=-0.151, P=0.031), lymph node metastasis(r=-0.154, P=0.027), extranodal extension(r=-0.200, P=0.004).
3. P-catenin was expressed in the cytoplasma and nuclear in EMT and was found in 67.3% (138/205) cases. The expression ofβ-catenin was positively correlated with pathologic stage(r=0.193, P=0.006), lymph node metastasis(r=0.153,P=0.028).
4. The expression of Cripto-1 was negatively correlated with E-CD(r=-0.324, P=0.000)and positively correlated with P-catenin(r=0.412, P=0.000). Combined evaluation Cripto-1/E-CD and Cripto-1/β-catenin, Cripto-1+/E-CD-was strongly associated with pathologic stage(χ2=14.502,P=0.002), lymph node metastasis(χ2=12.858, P=0.005), extranodal extension(χ2=9.275, P=0.002),distant metastasis((χ2=4.654, P=0.045), and Cripto-1+/β-catenin+ was strongly associated with pathologic stage(χ2=14.334, P=0.002), lymph node metastasis(χ2=8.734, P=0.033), distant metastasis(χ2=5.400,P=0.020).
5. Univariate Kaplan-Meier survival analysis reveals that patient with Cripto-1+, E-CD-orβ-catenin which localized in the cytoplasm showed lower survival rates than those with Cripto-1 -, E-CD+ orβ-catenin which localized in the membrane(P<0.05). When combined,evaluation of Cripto-1 and E-CD, Cripto-1 andβ-catenin, Cripto-1+/E-CD - and Cripto-1+/β-catenin+ indicated the worst survival(P<0.05). Cox-regression analysis indicated that the overexpression of Cripto-1 was an independent prognostic factor in breast cancer (HR,2.353).
Conclusion
1. Upregulation of Cripto-1, downregulation of E-CD and relocalization of P-catenin may play important roles in the invasion and metastasis of breast cancer.
2. overexpression of Cripto-1 was a significantly factor for prognosis.
3. Cripto-1 protein was a new target for the breast cancer treatment.
引文
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