乳腺导管原位癌导管破口处细胞的形态学特征及其蛋白差异比较研究
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摘要
乳腺癌是人类癌症疾病中发病率最高的恶性疾病之一,我国乳腺癌发病率以每年3%的速度递增。研究表明,在乳腺导管原位癌阶段诊断出的患者经过治疗后复发率和死亡率都很低,说明导管原位癌不是威胁生命的疾病,然而浸润癌阶段或之后的阶段诊断出的患者,治疗结果很差,有高的复发率和死亡率。因此,提高乳腺癌早期阶段的诊断是有效防治乳腺癌的重要手段。但乳腺癌的临床病理学特征非常复杂,至今在原位癌的病理学分类上没有一个被普遍接受的统一标准。这使得乳腺癌的早期诊断率不高,对乳腺癌的控制非常困难。一般认为在乳腺原位癌阶段,病变导管管壁损坏出现破口是原位癌开始浸润的前提条件。有研究表明,在导管原位癌中,导管破口处分布的肿瘤细胞群在形态学和肿瘤相关表型上与相邻处同导管内其它肿瘤细胞相比有许多与肿瘤恶性特征相关的表型和基因的改变,如ER阴性、c-erb-B2表达上调、增生率低、基因不稳定性和基因的杂合性缺失等,提示这些细胞可能是原位癌中最早出现的具有浸润侵袭能力的肿瘤细胞。这些细胞可能代表乳腺浸润癌的前兆。之前的一系列研究一致显示位于导管破口处的肿瘤细胞簇与浸润、迁徙和不良预后显著相关,可以作为独立的预后因子。
为进一步研究分布于导管原位癌导管破口处的肿瘤细胞簇在超微结构和与基质降解、细胞粘附、运动以及蛋白质组学方面的特性。对3325例乳腺癌临床病理档案切片进行形态学观察分析,选取158例含有导管破口病变的石蜡包埋的导管原位癌病理标本转制超薄切片进行透射电镜观察发现,分布于乳腺导管破口处的肿瘤细胞在形态上与毗邻处同导管内其他的肿瘤细胞不同,细胞核成梭形或长杆状,核内电子密度高,胞质电子密度高,细胞之间没有紧密连接结构,但有狭窄的缝隙相隔,毗邻处的其他肿瘤细胞则显示核呈圆形或椭圆形、核内及胞质内电子密度低,细胞之间紧密连接,电子密度高。通过免疫组化染色发现,MMP-2和MMP-9在这些细胞簇的表达水平高于毗邻处其他的肿瘤细胞,TIMP-2的表达较毗邻处细胞亦升高。E-cadherin在这些细胞簇上表达异常,一是表达量高,二是表达部位不仅在胞膜,在胞质中也有高表达,而毗邻处的其他肿瘤细胞,E-cadherin仅在胞膜上表达。与癌旁正常乳腺导管相比,原位癌病变的导管中E-cadherin的表达低于癌旁正常乳腺导管。在含有原位癌和浸润癌混合病灶的标本中,E-cadherin在浸润癌的表达显著低于原位癌病变处的表达。FAK在导管原位癌病变处的表达低于癌旁正常乳腺导管,在含有导管破口的病变处,分布于导管破口处的肿瘤细胞上FAK表达量高于毗邻处其他的肿瘤细胞。与癌旁正常乳腺导管相比,talin、vinculin和integrinβ1的表达显著降低,但在浸润癌灶的表达却显著高于原位癌的表达。Vinculin在导管破口处细胞簇仅有少量弱表达(18%),其他部位的肿瘤细胞不表达。在纯导管原位癌中的肿瘤细胞不表达,仅表达于肌上皮细胞层。在浸润癌灶中显著高表达。这说明,原位癌中肿瘤细胞以E-cadherin为主的粘附关系在向浸润癌发展过程中逐渐丧失,浸润的肿瘤细胞通过以integrin为核心的黏着斑结构维持彼此的运动粘附关系。使用Qiagen公司的FFPE试剂盒提取分布于导管破口处肿瘤细胞和毗邻处同导管内其他肿瘤细胞的总蛋白,通过BeckMan公司的PF2D系统分离得到33个差异蛋白点,通过ESI-TOF MS/MS系统进行质谱分析及生物信息学分析得到140个差异蛋白。这些蛋白涉及细胞增殖、凋亡、代谢、运动等各个方面。随机选取两个蛋白,AKR1B10和DHRS7进行免疫组化验证,发现这两个蛋白在导管破口处分布的肿瘤细胞上的表达与毗邻处同导管内其他肿瘤细胞的表达有显著差异。在以往的研究中显示,AKR1B10和DHRS7在肿瘤中表达上调与不良预后相关。本研究结果显示,在导管破口处分布的肿瘤细胞上的表达水平高于同导管内毗邻处的其他肿瘤细胞,说明分布于原位癌中导管破口处的肿瘤细胞具有比纯导管原位癌细胞更高的恶性特征,是浸润癌的前兆,证明本研究的蛋白质组学分析结果可靠。
本研究成功获得了导管原位癌中导管破口处肿瘤细胞簇与同导管内毗邻的其它肿瘤细胞的蛋白质组差异。通过超微结构观察和免疫组化染色进一步证明了这些肿瘤细胞与肿瘤浸润、迁徙和不良预后的相关性。进一步证明了这些肿瘤细胞是乳腺癌浸润的前兆,可以作为独立的预后因子。获得的差异蛋白表达谱可以为乳腺癌早期诊断标志物的筛选提供基础数据,为临床治疗策略的选择提供依据。
Breast cancer is the top cancer in women both in the developed and the developing world. The incidence of breast cancer is increasing at a rate 3% in China. An follow up investigation shows that the recurrence rate of breast carcinoma in situ after surgical excision is low. But the recurrence rate of invasive carcinoma after surgical excision is high. Therefore, early detection in order to improve breast cancer outcome and survival remains the cornerstone of breast cancer control. The clinicopathological characteristics are complex. No single classification scheme has been universally accepted, and the mechanism of the processes from breast carcinoma in situ to invasive carcinoma remains unknown. This is the big obstacles to early detection and clinical treating strategy of breast carcinoma, so further research of the mechanism of the processes from breast carcinoma in situ to invasive carcinoma is significant for to find more diagnostic marks, to elevate early detection rate and provide more choices of clinical treating strategy.It is a commonly held belief that ductal carcinoma in situ is the precursor of the invasive breast carcinoma lesions. Some previous studies demonstrate that pre-invasive breast tumors have been found to be associated with focal myoepithelial cell layer disruptions and the cells overlaying focal myoepithelial cell layer disruptions are significant different from other adjacent tumor cells within the same duct, show more inmmuophenotypes and genetic mutations related to the tumor malignancy, such as ER nagitive, c-erb-B2 up-regulation, high proliferation rate, genetic instability, and loss of heterozygous. Based on these finding, it is speculated that these tumor cells may be the earliest cells with invasive and metasitic ability, may represent the precursor of invasive breast lesion. Previous series studies consistently shows that the cells overlaying ductal myoepithelial cell layer are associated with tumor invasion, metastasis and poor prognosis, and can be a indepent prognostic factor.
For further studding the ultrastructure and characteristics of stromal digestion, cell adhesion, cell motility and proteomics of the cells overlaying ductal wall disruption, we checked 3325 cases documents of breast cancer patients. Screening 158 cases performed formalin fixed, paraffin embedded tumor samples that harboring ductal wall disruptions transforming ultra-section. Under transmission electron microscope, it shows that the tumor cells overlying FMCLDs had darkly stained nuclei and cytoplasm, with elongated nuclei. Compared to these cells, the adjacent tumor cells within the same duct were rounded, with weakly stained nuclei and cytoplasm, with high electronic density at the regions of membrane contact. This demonstrated that the membrane junction was tight between in situ tumor cells Immuohistochemically, the expressions of MMP-2 and MMP-9 are higher in this cell cluster than adjacent tumor cells within same duct, and TIMP-2 same as this. E-cadherin, and focal adhesion kinase (FAK) in tumor cells overlying FMCLDs were higher than those within the corresponding duct. Integrinβ1 staining was detected only in a small number of the tumor cells overlying FMCLDs. Vinculin staining was weak (18%) or not detected (82%), and no expression was found in tumor cells within the corresponding duct or in pure isolated DCIS. By contrast, the expression levels of talin, vinculin and integrinβ1 in invasive tumors was distinctly higher than that in DCIS, and the expression of FAK and E-cadherin was lower. Under electron microscopy, the tight junctions between tumor cells overlying FMCLDs were reduced compared to the adjacent tumor cells in the lumen. These results indicate that the tumor cells overlying FMCLDs are likely to represent the specific precursors of invasive breast lesions. By PF 2D system, 33 differential protein points were identified. 140 candidate proteins were identified by ESI-TOF-MS/MS system. Random to choice two candidate proteins, AKR1B10 and DHRS7, performed Immunohistochemical staining, we found that these two proteins expression level in cell overlaying ductal wall disruption are significant different with the adjacent tumor cells within same duct. Previous same studies demonstrated the AKR1B10 and DHRS7 proteins over expression are associated with poor prognosis. Our finding demonstrated that the cells overlaying ductal wall disruption have more malignancy than the adjacent tumor cells within same duct, and confirm the proteomic results are trustworthy.
Our findings may also facilitate the identification of specific targets for further molecular profiling, which will more completely characterize this important cell population.
为进一步研究分布于导管原位癌导管破口处的肿瘤细胞簇在超微结构和与基质降解、细胞粘附、运动以及蛋白质组学方面的特性。对3325例乳腺癌临床病理档案切片进行形态学观察分析,选取158例含有导管破口病变的石蜡包埋的导管原位癌病理标本转制超薄切片进行透射电镜观察发现,分布于乳腺导管破口处的肿瘤细胞在形态上与毗邻处同导管内其他的肿瘤细胞不同,细胞核成梭形或长杆状,核内电子密度高,胞质电子密度高,细胞之间没有紧密连接结构,但有狭窄的缝隙相隔,毗邻处的其他肿瘤细胞则显示核呈圆形或椭圆形、核内及胞质内电子密度低,细胞之间紧密连接,电子密度高。通过免疫组化染色发现,MMP-2和MMP-9在这些细胞簇的表达水平高于毗邻处其他的肿瘤细胞,TIMP-2的表达较毗邻处细胞亦升高。E-cadherin在这些细胞簇上表达异常,一是表达量高,二是表达部位不仅在胞膜,在胞质中也有高表达,而毗邻处的其他肿瘤细胞,E-cadherin仅在胞膜上表达。与癌旁正常乳腺导管相比,原位癌病变的导管中E-cadherin的表达低于癌旁正常乳腺导管。在含有原位癌和浸润癌混合病灶的标本中,E-cadherin在浸润癌的表达显著低于原位癌病变处的表达。FAK在导管原位癌病变处的表达低于癌旁正常乳腺导管,在含有导管破口的病变处,分布于导管破口处的肿瘤细胞上FAK表达量高于毗邻处其他的肿瘤细胞。与癌旁正常乳腺导管相比,talin、vinculin和integrinβ1的表达显著降低,但在浸润癌灶的表达却显著高于原位癌的表达。Vinculin在导管破口处细胞簇仅有少量弱表达(18%),其他部位的肿瘤细胞不表达。在纯导管原位癌中的肿瘤细胞不表达,仅表达于肌上皮细胞层。在浸润癌灶中显著高表达。这说明,原位癌中肿瘤细胞以E-cadherin为主的粘附关系在向浸润癌发展过程中逐渐丧失,浸润的肿瘤细胞通过以integrin为核心的黏着斑结构维持彼此的运动粘附关系。使用Qiagen公司的FFPE试剂盒提取分布于导管破口处肿瘤细胞和毗邻处同导管内其他肿瘤细胞的总蛋白,通过BeckMan公司的PF2D系统分离得到33个差异蛋白点,通过ESI-TOF MS/MS系统进行质谱分析及生物信息学分析得到140个差异蛋白。这些蛋白涉及细胞增殖、凋亡、代谢、运动等各个方面。随机选取两个蛋白,AKR1B10和DHRS7进行免疫组化验证,发现这两个蛋白在导管破口处分布的肿瘤细胞上的表达与毗邻处同导管内其他肿瘤细胞的表达有显著差异。在以往的研究中显示,AKR1B10和DHRS7在肿瘤中表达上调与不良预后相关。本研究结果显示,在导管破口处分布的肿瘤细胞上的表达水平高于同导管内毗邻处的其他肿瘤细胞,说明分布于原位癌中导管破口处的肿瘤细胞具有比纯导管原位癌细胞更高的恶性特征,是浸润癌的前兆,证明本研究的蛋白质组学分析结果可靠。
本研究成功获得了导管原位癌中导管破口处肿瘤细胞簇与同导管内毗邻的其它肿瘤细胞的蛋白质组差异。通过超微结构观察和免疫组化染色进一步证明了这些肿瘤细胞与肿瘤浸润、迁徙和不良预后的相关性。进一步证明了这些肿瘤细胞是乳腺癌浸润的前兆,可以作为独立的预后因子。获得的差异蛋白表达谱可以为乳腺癌早期诊断标志物的筛选提供基础数据,为临床治疗策略的选择提供依据。
Breast cancer is the top cancer in women both in the developed and the developing world. The incidence of breast cancer is increasing at a rate 3% in China. An follow up investigation shows that the recurrence rate of breast carcinoma in situ after surgical excision is low. But the recurrence rate of invasive carcinoma after surgical excision is high. Therefore, early detection in order to improve breast cancer outcome and survival remains the cornerstone of breast cancer control. The clinicopathological characteristics are complex. No single classification scheme has been universally accepted, and the mechanism of the processes from breast carcinoma in situ to invasive carcinoma remains unknown. This is the big obstacles to early detection and clinical treating strategy of breast carcinoma, so further research of the mechanism of the processes from breast carcinoma in situ to invasive carcinoma is significant for to find more diagnostic marks, to elevate early detection rate and provide more choices of clinical treating strategy.It is a commonly held belief that ductal carcinoma in situ is the precursor of the invasive breast carcinoma lesions. Some previous studies demonstrate that pre-invasive breast tumors have been found to be associated with focal myoepithelial cell layer disruptions and the cells overlaying focal myoepithelial cell layer disruptions are significant different from other adjacent tumor cells within the same duct, show more inmmuophenotypes and genetic mutations related to the tumor malignancy, such as ER nagitive, c-erb-B2 up-regulation, high proliferation rate, genetic instability, and loss of heterozygous. Based on these finding, it is speculated that these tumor cells may be the earliest cells with invasive and metasitic ability, may represent the precursor of invasive breast lesion. Previous series studies consistently shows that the cells overlaying ductal myoepithelial cell layer are associated with tumor invasion, metastasis and poor prognosis, and can be a indepent prognostic factor.
For further studding the ultrastructure and characteristics of stromal digestion, cell adhesion, cell motility and proteomics of the cells overlaying ductal wall disruption, we checked 3325 cases documents of breast cancer patients. Screening 158 cases performed formalin fixed, paraffin embedded tumor samples that harboring ductal wall disruptions transforming ultra-section. Under transmission electron microscope, it shows that the tumor cells overlying FMCLDs had darkly stained nuclei and cytoplasm, with elongated nuclei. Compared to these cells, the adjacent tumor cells within the same duct were rounded, with weakly stained nuclei and cytoplasm, with high electronic density at the regions of membrane contact. This demonstrated that the membrane junction was tight between in situ tumor cells Immuohistochemically, the expressions of MMP-2 and MMP-9 are higher in this cell cluster than adjacent tumor cells within same duct, and TIMP-2 same as this. E-cadherin, and focal adhesion kinase (FAK) in tumor cells overlying FMCLDs were higher than those within the corresponding duct. Integrinβ1 staining was detected only in a small number of the tumor cells overlying FMCLDs. Vinculin staining was weak (18%) or not detected (82%), and no expression was found in tumor cells within the corresponding duct or in pure isolated DCIS. By contrast, the expression levels of talin, vinculin and integrinβ1 in invasive tumors was distinctly higher than that in DCIS, and the expression of FAK and E-cadherin was lower. Under electron microscopy, the tight junctions between tumor cells overlying FMCLDs were reduced compared to the adjacent tumor cells in the lumen. These results indicate that the tumor cells overlying FMCLDs are likely to represent the specific precursors of invasive breast lesions. By PF 2D system, 33 differential protein points were identified. 140 candidate proteins were identified by ESI-TOF-MS/MS system. Random to choice two candidate proteins, AKR1B10 and DHRS7, performed Immunohistochemical staining, we found that these two proteins expression level in cell overlaying ductal wall disruption are significant different with the adjacent tumor cells within same duct. Previous same studies demonstrated the AKR1B10 and DHRS7 proteins over expression are associated with poor prognosis. Our finding demonstrated that the cells overlaying ductal wall disruption have more malignancy than the adjacent tumor cells within same duct, and confirm the proteomic results are trustworthy.
Our findings may also facilitate the identification of specific targets for further molecular profiling, which will more completely characterize this important cell population.
引文
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