新辅助化疗前后宫颈癌组织中CD44V6、MUC1的表达及其意义
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摘要
背景与目的
宫颈癌是常见的妇科恶性肿瘤之一,发病率居妇科恶性肿瘤首位,近年来在我国发病率和死亡率有上升的趋势。新辅助化疗(neoadjuvant chemotherapy, NACT)自1982年由Frei提出后,越来越多地应用于临床,NACT不仅能使肿块缩小,增加手术机率,增强肿瘤细胞对放疗的敏感性；同时还能减少转移的发生,降低复发风险,提高患者生存率。目前其临床近期疗效已被多数研究所肯定,但仍有患者对化疗反应差,对这些化疗不敏感的患者实施NACT会导致其治疗延误。因此,寻找能准确预测宫颈癌患者化疗疗效的标志物意义重大。
CD44(eluster of differentiation 44,分化抗原簇44)指白细胞分化抗原分化簇第44号,是一种分布广泛的细胞表面跨膜糖蛋白,属于细胞粘附分子,分为：标准型CD44 (CD44s)和变异型CD44 (CD44V)。变异型中,与肿瘤关系较为密切的是CD44V6,高表达CD44V6的肿瘤细胞通过与细胞外基质(extracellular matrix, ECM)粘附,赋予肿瘤细胞很强的侵袭能力,从而构成肿瘤细胞的侵袭性和易转移性。粘蛋白1(MUC1)是一种高分子量糖蛋白,在正常上皮组织中起重要保护作用；在肿瘤组织中表达异常,在细胞膜大量表达且极性消失,造成整个肿瘤细胞表面粘附分子功能紊乱,能降低肿瘤细胞间的粘附力,并参与肿瘤细胞的侵袭及转移,与肿瘤的发生和发展关系密切。
细胞粘附是肿瘤侵袭和转移的始动因素,粘附分子异常表达与肿瘤侵袭转移密切相关。目前预测宫颈癌患者化疗疗效的研究大多集中于细胞增殖和细胞凋亡机制,而关于CD44V6、MUC1在这方面的研究较少。本文通过检测CD44V6、MUC1在宫颈癌NACT前后的表达,评价NACT疗效,探讨其与临床病理因素的相关性,以及其作为疗效预测标志物的可行性；并研究其在化疗前后的表达与患者预后的关系,以期能够筛选出预测宫颈癌NACT疗效的敏感指标,从而指导NACT在临床上的应用。
材料与方法
1.临床资料
所有标本均来自郑州大学第二附属医院病理科存档蜡块(2007年1月～2009年6月),所有病例均经病理证实且化疗前无其他治疗。收集化疗前宫颈活检组织及化疗后的手术标本蜡块40对(80例)。化疗方案为TC方案(紫杉醇+卡铂)。
2.实验方法
采用免疫组织化学方法检测NACT前后宫颈癌组织中CD44V6、MUC1的表达情况。
3.统计分析
实验数据采用SPSS10.0统计软件包进行统计分析,计数资料采用χ2检验及Fisher's精确概率检验,相关性分析采用Pearson相关分析,检验水准α=0.05。
结果
1.临床疗效
化疗总有效率85%,其中完全缓解(complete remission, CR)4例(10%),部分缓解(partial remission, PR)30例(75%),稳定(stable disease, SD)6例(15%),无进展(progressive disease, PD)病例,手术率100%,1例Ⅱa期患者术后病理检查为宫颈鳞状细胞原位癌。
2.CD44V6、MUC1的表达
NACT后CD44V6、MUC1在宫颈癌组织中的阳性表达显著低于NACT前其在宫颈癌组织中的阳性表达,差异有统计学意义(P<0.05)；NACT后临床有效组CD44V6、MUC1的阳性表达较化疗前显著下降,差异有统计学意义(P<0.05),临床无效组NACT前后CD44V6、MUC1的阳性表达差异无统计学意义(P>0.05)比较化疗前临床有效组和临床无效组宫颈癌组织中CD44V6、MUC1的阳性表达,差异无统计学意义(P>0.05)；化疗前淋巴结转移组宫颈癌组织中CD44V6、MUC1的阳性表达率明显高于无淋巴结转移组CD44V6、MUC1的阳性表达率,差异有统计学意义(P<0.05)；NACT前后CD44V6、MUC1阳性表达的变化值在不同病理类型、FIGO分期、组织学分级之间差异无统计学意义(P>0.05)。
3. CD44V6、MUC1在宫颈癌组织表达的相关性
化疗前在40例宫颈癌组织中CD44V6、MUC1共同表达阳性的有22例,共同表达阴性的有8例,两者之间存在正相关性(R<0.05,r=0.409);化疗后在40例宫颈癌组织中CD44V6、MUC1共同表达阳性的有10例,共同表达阴性的有18例,两者之间存在正相关性(P<0.05,r=0.354)。
结论
1.新辅助化疗TC方案对宫颈癌有较好的近期疗效,值得推广应用。
2.在化疗前检测宫颈癌组织中CD44V6和MUC1的表达,不能预测新辅助化疗的疗效。
3.在化疗后检测宫颈癌组织中CD44V6和MUC1的表达,可以较好的评估新辅助化疗疗效,化疗后表达有明显下降者,认为其临床有效。
4.宫颈癌组织中CD44V6和MUC1.之间存在正相关,两者联合检测能更好的评价新辅助化疗的疗效。
5.新辅助化疗后细胞粘附因子表达明显下降,有望对改善预后有积极意义。
Background and Objective
Cervical cancer, which is one of the common gynecological malignant tumors, has the first incidence rate. In our country the morbidity and mortality of cervical cancer shows an increasing trend in recent years. Since Frei proposed the program of Neoadjuvant Chemotherapy(NACT)in 1982, it has been used in clinic more and more. Not only can NACT reduce the size of the tumor, increase the operability, and enhance the sensitivity of the tumor sell to radiotherapy, but also can decrease the occurrence of metastasis, reduce the risk of recrudescence and enhance the survival rate. Now the clinical short-term curative effect of NACT has been well proved by most researches, but it still has some patients who have poor sensitivity to chemotherapy. Enforcing NACT to these patients can delay the best time for the other treatments. Therefore, it is of great significance to searching the index which can predict the effect of NACT exactly.
CD44, which calls eluster of differentiation 44, is a widespread transmembrane glycoprote on the cell surface.It belongs to cellular adhesion molecule. CD44 can be divided into:standard CD44(CD44S) and variant CD44(CD44V). In variant CD44, CD44V6 has a close relationship with the tumor. The tumor cell which has a high expression of CD44V6 can adhere to the extracellular matrix (ECM), give the tumor cell a high invasive ability, and compose the invasion and metastasis of the tumor cell thereby. Mucoprotein 1(MUC1)is a glucoprotein with high molecular mass. It plays an important role in protecting normal epithelial tissue. In tumor, MUC1 expresses abnormally. It expresses abundantly and the heteropolarity is disappeared. It disturbs the function of adhesion molecule of the whole tumor cell surface and reduces the adhesive ability between tumor cells. It takes part in the invasion and metastasis and has a close connection with the development of the tumor.
Cell adhesion is the initiating factor to the invasion and metastasis of tumor. The abnormal expression of cell adhesion molecules is closely related to the invasion and metastasis of tumor. So far, the researches about predicting the efficacy of NACT of cervical cancer mostly focus on the proliferation and apoptosis mechanisms of cells, but it is rarely reported about CD44V6 and MUC1 in this field. Through detecting the expression of CD44V6 and MUC1 before and after NACT of cervical cancer, this study evaluated the curative effect of NACT, discussed the correlation between the clinical effect and the clinical pathological factors, and explored the feasibility of CD44V6 and MUC1 being the index of effective prediction. The purpose of this study was to find out the sensitive index for predicting the effect of NACT, and provide guidance for the application of NACT in clinical practice.
Material and Methods
1. Clinical data
The paraffin section came from the department of pathology in the Second Affiliated Hospital of Zhengzhou University. All the cases were identified by histopathologic examination and had no other therapy before NACT. In this study we collected forty cervical biopsy specimens before NACT and forty surgical specimens after NACT. The chemotherapy plan was TC (Paclitaxel+Carboplatin) programe.
2. Experimental method
Immunohistochemical (IHC) staining was used to examine the expression of CD44V6 and MUC1 in cervical cancer before and after NACT.
3. Statistics analysis
Statistical analysis was executed by statistical package SPSS version 10.0 software. The statistic data were analyzed with Chi-square tests and Fisher's exact probability test. Pearson correlation analysis was used to analyze correlation between CD44V6 and MUC1, and a value less than 0.05 was considered as significance.
Results
1. Clinical effect
The overall response rate of NACT was 85%, including CR group 4(10%), PR group 30(75%) and SD group 6(5%). There was no PD samples, and 100% of patients had operation.1 case with stageⅡwas confirmed as cervical squamous cell carcinomas in situ by pathological examination after the surgery.
2. The expression of CD44V6 and MUC1
The positive expression of CD44V6 and MUC1 in cervical cancer after NACT was significantly lower than that before NACT. There was significant difference between the two groups (P<0.05). In clinical effective group the positive expression of CD44V6 and MUC1 after NACT was significantly lower than that before NACT, and the difference had statistical significance (P<0.05); The positive expression of CD44V6 and MUC1 before and after NACT in clinical invalid group had no obvious contrast(P>0.05). The contrast of the positive expression of CD44V6 and MUC1 between the clinical effective and invalid groups before NACT had no statistical sense (P>0.05). Before NACT the metastatic rate of lymph nodes in group with CD44V6 and MUC1 positive expression was significantly higher than those in the negative group (P<0.05). In cervical cancer tissues with different pathologic type, clinical stage and histological grade, the change of positive expression of CD44V6 and MUC1 before and after NACT has no significance (P>0.05).
3. The correlation between CD44V6 and MUC1 in cervical cancer
In the expression of CD44V6 and MUC1 before NACT in 40 cervical cancer tissues, the positive co-expression had 22 cases, and the negative co-expression had 8 cases. There was positive correlation between the two groups (P<0.05, r=0.409). In the expression of CD44V6 and MUC1 after NACT in 40 cervical cancer tissues, the positive co-expression had 10 cases, and the negative co-expression had 18 cases. There was positive correlation between the two groups (P<0.05, r=0.354).
Conclusions
1. The neoadjuvant chemotherapy TC program has good short-term curative effect on cervical cancer, and it is worthwhile for extensive application.
2. Detecting the expression of CD44V6 and MUC1 before NACT in the cervical cancer tissues can not predict the curative effect of NACT.
3. Detecting the expression of CD44V6 and MUC1 after NACT in the cervical cancer tissues can better evaluate the curative effect of NACT. It can be considered as clinical effective group if the expression of CD44V6 and MUC1 had obvious declined after NACT.
4. In cervical cancer tissues, there is positive correlation between CD44V6 and MUC1. The combined detection of CD44V6 and MUC1 can evaluate the effect of NACT better.
5. The expression of cellular adhesive molecular decline obviously after NACT. It may have positive effects on improving the prognosis of cervical cancer.
宫颈癌是常见的妇科恶性肿瘤之一,发病率居妇科恶性肿瘤首位,近年来在我国发病率和死亡率有上升的趋势。新辅助化疗(neoadjuvant chemotherapy, NACT)自1982年由Frei提出后,越来越多地应用于临床,NACT不仅能使肿块缩小,增加手术机率,增强肿瘤细胞对放疗的敏感性；同时还能减少转移的发生,降低复发风险,提高患者生存率。目前其临床近期疗效已被多数研究所肯定,但仍有患者对化疗反应差,对这些化疗不敏感的患者实施NACT会导致其治疗延误。因此,寻找能准确预测宫颈癌患者化疗疗效的标志物意义重大。
CD44(eluster of differentiation 44,分化抗原簇44)指白细胞分化抗原分化簇第44号,是一种分布广泛的细胞表面跨膜糖蛋白,属于细胞粘附分子,分为：标准型CD44 (CD44s)和变异型CD44 (CD44V)。变异型中,与肿瘤关系较为密切的是CD44V6,高表达CD44V6的肿瘤细胞通过与细胞外基质(extracellular matrix, ECM)粘附,赋予肿瘤细胞很强的侵袭能力,从而构成肿瘤细胞的侵袭性和易转移性。粘蛋白1(MUC1)是一种高分子量糖蛋白,在正常上皮组织中起重要保护作用；在肿瘤组织中表达异常,在细胞膜大量表达且极性消失,造成整个肿瘤细胞表面粘附分子功能紊乱,能降低肿瘤细胞间的粘附力,并参与肿瘤细胞的侵袭及转移,与肿瘤的发生和发展关系密切。
细胞粘附是肿瘤侵袭和转移的始动因素,粘附分子异常表达与肿瘤侵袭转移密切相关。目前预测宫颈癌患者化疗疗效的研究大多集中于细胞增殖和细胞凋亡机制,而关于CD44V6、MUC1在这方面的研究较少。本文通过检测CD44V6、MUC1在宫颈癌NACT前后的表达,评价NACT疗效,探讨其与临床病理因素的相关性,以及其作为疗效预测标志物的可行性；并研究其在化疗前后的表达与患者预后的关系,以期能够筛选出预测宫颈癌NACT疗效的敏感指标,从而指导NACT在临床上的应用。
材料与方法
1.临床资料
所有标本均来自郑州大学第二附属医院病理科存档蜡块(2007年1月～2009年6月),所有病例均经病理证实且化疗前无其他治疗。收集化疗前宫颈活检组织及化疗后的手术标本蜡块40对(80例)。化疗方案为TC方案(紫杉醇+卡铂)。
2.实验方法
采用免疫组织化学方法检测NACT前后宫颈癌组织中CD44V6、MUC1的表达情况。
3.统计分析
实验数据采用SPSS10.0统计软件包进行统计分析,计数资料采用χ2检验及Fisher's精确概率检验,相关性分析采用Pearson相关分析,检验水准α=0.05。
结果
1.临床疗效
化疗总有效率85%,其中完全缓解(complete remission, CR)4例(10%),部分缓解(partial remission, PR)30例(75%),稳定(stable disease, SD)6例(15%),无进展(progressive disease, PD)病例,手术率100%,1例Ⅱa期患者术后病理检查为宫颈鳞状细胞原位癌。
2.CD44V6、MUC1的表达
NACT后CD44V6、MUC1在宫颈癌组织中的阳性表达显著低于NACT前其在宫颈癌组织中的阳性表达,差异有统计学意义(P<0.05)；NACT后临床有效组CD44V6、MUC1的阳性表达较化疗前显著下降,差异有统计学意义(P<0.05),临床无效组NACT前后CD44V6、MUC1的阳性表达差异无统计学意义(P>0.05)比较化疗前临床有效组和临床无效组宫颈癌组织中CD44V6、MUC1的阳性表达,差异无统计学意义(P>0.05)；化疗前淋巴结转移组宫颈癌组织中CD44V6、MUC1的阳性表达率明显高于无淋巴结转移组CD44V6、MUC1的阳性表达率,差异有统计学意义(P<0.05)；NACT前后CD44V6、MUC1阳性表达的变化值在不同病理类型、FIGO分期、组织学分级之间差异无统计学意义(P>0.05)。
3. CD44V6、MUC1在宫颈癌组织表达的相关性
化疗前在40例宫颈癌组织中CD44V6、MUC1共同表达阳性的有22例,共同表达阴性的有8例,两者之间存在正相关性(R<0.05,r=0.409);化疗后在40例宫颈癌组织中CD44V6、MUC1共同表达阳性的有10例,共同表达阴性的有18例,两者之间存在正相关性(P<0.05,r=0.354)。
结论
1.新辅助化疗TC方案对宫颈癌有较好的近期疗效,值得推广应用。
2.在化疗前检测宫颈癌组织中CD44V6和MUC1的表达,不能预测新辅助化疗的疗效。
3.在化疗后检测宫颈癌组织中CD44V6和MUC1的表达,可以较好的评估新辅助化疗疗效,化疗后表达有明显下降者,认为其临床有效。
4.宫颈癌组织中CD44V6和MUC1.之间存在正相关,两者联合检测能更好的评价新辅助化疗的疗效。
5.新辅助化疗后细胞粘附因子表达明显下降,有望对改善预后有积极意义。
Background and Objective
Cervical cancer, which is one of the common gynecological malignant tumors, has the first incidence rate. In our country the morbidity and mortality of cervical cancer shows an increasing trend in recent years. Since Frei proposed the program of Neoadjuvant Chemotherapy(NACT)in 1982, it has been used in clinic more and more. Not only can NACT reduce the size of the tumor, increase the operability, and enhance the sensitivity of the tumor sell to radiotherapy, but also can decrease the occurrence of metastasis, reduce the risk of recrudescence and enhance the survival rate. Now the clinical short-term curative effect of NACT has been well proved by most researches, but it still has some patients who have poor sensitivity to chemotherapy. Enforcing NACT to these patients can delay the best time for the other treatments. Therefore, it is of great significance to searching the index which can predict the effect of NACT exactly.
CD44, which calls eluster of differentiation 44, is a widespread transmembrane glycoprote on the cell surface.It belongs to cellular adhesion molecule. CD44 can be divided into:standard CD44(CD44S) and variant CD44(CD44V). In variant CD44, CD44V6 has a close relationship with the tumor. The tumor cell which has a high expression of CD44V6 can adhere to the extracellular matrix (ECM), give the tumor cell a high invasive ability, and compose the invasion and metastasis of the tumor cell thereby. Mucoprotein 1(MUC1)is a glucoprotein with high molecular mass. It plays an important role in protecting normal epithelial tissue. In tumor, MUC1 expresses abnormally. It expresses abundantly and the heteropolarity is disappeared. It disturbs the function of adhesion molecule of the whole tumor cell surface and reduces the adhesive ability between tumor cells. It takes part in the invasion and metastasis and has a close connection with the development of the tumor.
Cell adhesion is the initiating factor to the invasion and metastasis of tumor. The abnormal expression of cell adhesion molecules is closely related to the invasion and metastasis of tumor. So far, the researches about predicting the efficacy of NACT of cervical cancer mostly focus on the proliferation and apoptosis mechanisms of cells, but it is rarely reported about CD44V6 and MUC1 in this field. Through detecting the expression of CD44V6 and MUC1 before and after NACT of cervical cancer, this study evaluated the curative effect of NACT, discussed the correlation between the clinical effect and the clinical pathological factors, and explored the feasibility of CD44V6 and MUC1 being the index of effective prediction. The purpose of this study was to find out the sensitive index for predicting the effect of NACT, and provide guidance for the application of NACT in clinical practice.
Material and Methods
1. Clinical data
The paraffin section came from the department of pathology in the Second Affiliated Hospital of Zhengzhou University. All the cases were identified by histopathologic examination and had no other therapy before NACT. In this study we collected forty cervical biopsy specimens before NACT and forty surgical specimens after NACT. The chemotherapy plan was TC (Paclitaxel+Carboplatin) programe.
2. Experimental method
Immunohistochemical (IHC) staining was used to examine the expression of CD44V6 and MUC1 in cervical cancer before and after NACT.
3. Statistics analysis
Statistical analysis was executed by statistical package SPSS version 10.0 software. The statistic data were analyzed with Chi-square tests and Fisher's exact probability test. Pearson correlation analysis was used to analyze correlation between CD44V6 and MUC1, and a value less than 0.05 was considered as significance.
Results
1. Clinical effect
The overall response rate of NACT was 85%, including CR group 4(10%), PR group 30(75%) and SD group 6(5%). There was no PD samples, and 100% of patients had operation.1 case with stageⅡwas confirmed as cervical squamous cell carcinomas in situ by pathological examination after the surgery.
2. The expression of CD44V6 and MUC1
The positive expression of CD44V6 and MUC1 in cervical cancer after NACT was significantly lower than that before NACT. There was significant difference between the two groups (P<0.05). In clinical effective group the positive expression of CD44V6 and MUC1 after NACT was significantly lower than that before NACT, and the difference had statistical significance (P<0.05); The positive expression of CD44V6 and MUC1 before and after NACT in clinical invalid group had no obvious contrast(P>0.05). The contrast of the positive expression of CD44V6 and MUC1 between the clinical effective and invalid groups before NACT had no statistical sense (P>0.05). Before NACT the metastatic rate of lymph nodes in group with CD44V6 and MUC1 positive expression was significantly higher than those in the negative group (P<0.05). In cervical cancer tissues with different pathologic type, clinical stage and histological grade, the change of positive expression of CD44V6 and MUC1 before and after NACT has no significance (P>0.05).
3. The correlation between CD44V6 and MUC1 in cervical cancer
In the expression of CD44V6 and MUC1 before NACT in 40 cervical cancer tissues, the positive co-expression had 22 cases, and the negative co-expression had 8 cases. There was positive correlation between the two groups (P<0.05, r=0.409). In the expression of CD44V6 and MUC1 after NACT in 40 cervical cancer tissues, the positive co-expression had 10 cases, and the negative co-expression had 18 cases. There was positive correlation between the two groups (P<0.05, r=0.354).
Conclusions
1. The neoadjuvant chemotherapy TC program has good short-term curative effect on cervical cancer, and it is worthwhile for extensive application.
2. Detecting the expression of CD44V6 and MUC1 before NACT in the cervical cancer tissues can not predict the curative effect of NACT.
3. Detecting the expression of CD44V6 and MUC1 after NACT in the cervical cancer tissues can better evaluate the curative effect of NACT. It can be considered as clinical effective group if the expression of CD44V6 and MUC1 had obvious declined after NACT.
4. In cervical cancer tissues, there is positive correlation between CD44V6 and MUC1. The combined detection of CD44V6 and MUC1 can evaluate the effect of NACT better.
5. The expression of cellular adhesive molecular decline obviously after NACT. It may have positive effects on improving the prognosis of cervical cancer.
引文
[1]汤钊猷.现代肿瘤学第一版[M].上海：上海医科大学出版社,2000,899-900.
[2]章文华,李楠,吴令英等.重视宫颈癌患者年轻化的趋势[J].浙江肿瘤,2000,6(2)：112-114.
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