趋化因子SDF-1及其受体CXCR4在乳腺癌中的表达和意义
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摘要
【目的】
具有高度淋巴结转移能力和不良预后的乳腺浸润性微小乳头状癌(Invasivemicropapillary carcinoma,IMPC)是研究高转移乳腺癌的良好模型,本研究旨在明确趋化因子SDF(stromal cell-derived factor)-1及其受体CXCR4在这种高淋巴结转移的特殊类型乳腺癌中的表达方式、强度及定位,及其与淋巴结转移的关系:通过对比SDF-1/CXCR4在乳腺浸润性微小乳头状癌和髓样癌(medullarycarcinoma,MC)中的表达及其与肿瘤微环境中淋巴细胞浸润的关系,初步探讨不同类型乳腺癌微环境中淋巴细胞浸润的原因及意义;并分析SDF-1/CXCR4在浸润性乳腺癌中的表达与其相关临床病理指标及淋巴结转移之间的关系,验证在特殊类型乳腺癌IMPC中得出的相关结论在其它类型浸润性乳腺癌中的普遍意义。
【方法】
采用免疫组织化学方法检测103例IMPC(包括IMPC相应淋巴结、对照组96例浸润性导管癌)、34例典型MC及120例浸润性乳腺癌(其中包括上述96例浸润性导管癌及其他类型浸润性乳腺癌)中SDF-1/CXCR4蛋白的表达情况;采用地高辛标记的寡核苷酸探针进行原位杂交以检测SDF-1和CXCR4 mRNA的表达;观察各类乳腺癌组织间质淋巴细胞浸润、淋巴结转移情况等病理学特征,分析SDF-1/CXCR4的表达与各病理学特征之间的关系。
【结果】
1.IMPC成分在肿瘤中所占比例与淋巴结转移程度无显著相关性(P=0.407);73例淋巴结阳性的混合型IMPC中,与淋巴结转移灶中的其它肿瘤成分相比,IMPC成分是主要的转移成分(P＜0.001)。
2.免疫组化及原位杂交显示SDF-1的蛋白及mRNA均主要定位于肿瘤细胞(96%),肿瘤间质细胞也有较弱的表达(14%),且上述两部位的表达均与IMPC淋巴结转移正相关(P＜0.05)。
3.罕见SDF-1 mRNA表达的脉管内皮却可见SDF-1蛋白的表达,其表达程度与肿瘤细胞SDF-1胞质着色正相关(P=0.001)。其中淋巴管内皮SDF-1的着色与淋巴结转移程度正相关(P=0.001);血管内皮SDF-1的着色与肿瘤环境中的淋巴细胞浸润正相关(P=0.024),且同时伴有较多淋巴细胞浸润(+/++)及SDF-1血管内皮着色(+)的病例,其淋巴结的转移程度分别高于仅有上述条件之一或二者均不具备的各组病例(P＜0.05)。
4.上述免疫组化显示SDF-1阳性的各着色部位中,肿瘤细胞胞质和脉管内皮SDF-1的表达高于IDC组(P=0.001;P=0.019)。
5.51例伴有DCIS的IMPC病例中DCIS成分的SDF-1胞膜着色程度明显高于IMPC成分(P=0.009);而胞质SDF-1的着色在两种成分中的表达差异无统计学意义(P＞0.05)。
6.CXCR4在IMPC中主要表达于肿瘤细胞的胞核及胞质,仅有胞质的表达与淋巴结受累程度正相关(P=0.008),并且高于IDC组胞质CXCR4的表达(P=0.049)。
7.淋巴结转移成分中包含IMPC成分的84例IMPC中,CXCR4在IMPC原发部位胞核和胞质的表达均高于转移淋巴结(P＜0.001)。
8.混合型IMPC中IMPC成分肿瘤细胞SDF-1及CXCR4的表达高于内对照(伴随的其他类型的浸润性癌)肿瘤细胞的表达(P=0.003;P=0.001)。
9.伴较多淋巴细胞浸润(+/++)的IMPC(n=54),其淋巴结转移程度、SDF-1在肿瘤细胞胞质及间质脉管内皮的表达、CXCR4在肿瘤细胞核的表达均高于MC组(P＜0.01);SDF-1在肿瘤细胞胞膜的表达、CXCR4在肿瘤细胞胞质的表达与MC组差异无统计学意义(P＞0.05)。
10.SDF-1在浸润性乳腺癌中主要表达于肿瘤细胞(包括胞质与胞膜);肿瘤细胞胞质SDF-1的表达在淋巴结阳性组高于阴性组(P＜0.05),且其表达程度与淋巴结受累数目、病理学分期、组织学分级、肿瘤大小及ER表达等指标呈正相关(P＜0.05)。
11.CXCR4在浸润性乳腺癌中也主要表达于肿瘤细胞(包括胞质与胞核);肿瘤细胞胞质CXCR4的表达在淋巴结阳性组高于阴性组(P＜0.01),且其表达程度与淋巴结受累数目、病理学分期、组织学分级、肿瘤大小及HER-2表达等呈正相关(P＜0.05),而胞核的表达仅与PR的表达情况呈正相关(P＜0.001)。
12.肿瘤细胞胞质CXCR4与SDF-1的表达呈正相关(P＜0.01)。
【结论】
1.IMPC的生物学行为并不取决于肿瘤中IMPC成分的多少。
2.SDF-1/CXCR4可能是IMPC结构的分子特征之一,并可能为IMPC高淋巴结转移的原因之一。
3.SDF-1和CXCR4在肿瘤组织中的多种定位和不同的表达方式中,SDF-1和CXCR4在肿瘤细胞胞质的表达、SDF-1在脉管内皮的着色可能是引起IMPC高度淋巴结转移的关键因素。
4.大量淋巴细胞浸润在乳腺IMPC和MC两种癌中的意义不同。
5.IMPC肿瘤微环境中与SDF-1表达相关的淋巴细胞浸润可能促进了其淋巴结转移。
6.均伴较多淋巴细胞浸润的IMPC与MC中SDF-1的表达差异可能是二者预后差异的关键因素。
7.SDF-1/CXCR4在肿瘤细胞胞质的表达与浸润性乳腺癌的淋巴结转移等多项临床病理指标之间密切相关,可能作为预测乳腺癌淋巴结转移及预后的免疫病理学指标。
Objective:
Invasive micropapillary carcinoma(IMPC)of the breast is a newly recognized subtype of breast cancer characterized by a high propensity for lymph node metastasis.The purpose of this study is to investigate the relationship between the features of location,expression pattern and intensity of SDF-1/CXCR4 and lymph node metastasis in IMPC of the breast;To explore the reason and the significance of the lymphocytes infiltration in different tumor microenvironment by comparing SDF-1 expression and its relationship with lymphocytes infiltration in IMPC with that in MC of the breast.To investigate the reason of some IMPC in which dense lymphocyte infiltrating but with poor prognosis;To explore the expression of SDF-1/CXCR4 and their association with clinic-pathological features and lymph node metastasis in human invasive breast carcinoma.
Methods:
Immunohistochemistry and in situ hybridization were performed to analyze the expression of SDF-1/CXCR4 in IMPC(including primary tumor and lymph nodes of IMPC,and 96 cases of IDC as control group),34 of MC and 120 cases of invasive breast cancer.Pathological features,lymphocytes infiltration and status of lymph node metastasis were examined by microscopic analysis.
Results:
1.The percentage of IMPC component in the whole tumor was not significantly associated with the extent of lymph node metastasis(P=0.067).In 73 cases of mixed-IMPC,IMPC component are the main source for lymph node metastasis compared with other components in the primary tumor(P＜0.001).
2.SDF-1 was mainly expressed in tumor cells(96%)and also in stromal cells (14%),staining scores of which were both correlated with the extent of lymph node metastasis in IMPC(P＜0.05).
3.Although SDF-1 mRNA was rarely detected in the endothelial cells,SDF-1 immunostaining on lymphatic vessels(36%of IMPCs)was also associated with nodal involvement(P=0.001)and that on blood vessels(34%)correlated with stromal lymphocyte infiltration in IMPC(P=0.024).
4.Cytoplasmic SDF-1 expression in tumor cells and SDF-1 staining on vessels in IMPCs were higher than IDCs(P=0.001;P=0.019).
5.51 of the 103 IMPCs contained DCIS as or as a part of nonmicropapillary components,in which significantly higher membranous(P=0.009)but similar cytoplasmic SDF-1 staining(P＞0.05)was found compared with IMPC component.
6.CXCR4 was detected in either cytoplasm or nucleus of tumor cells,but only cytoplasmic expression in IMPC was correlated with nodal involvement (P=0.008)and higher than IDC group(P=0.049).
7.The degree of cytoplasmic and nuclear CXCR4 expression in primary tumor was significantly higher than that in metastatic foci of the same case(P＜0.001).
8.SDF-1 and CXCR4 expression in IMPC component were higher than the internal control in mixed-IMPC(P=0.003;P=0.001).
9.In the cases of IMPC with abundant infiltrating lymphocytes(+/++)(n=54),the degree of lymph node metastasis,SDF-1 staining in tumor cell cytoplasma and on vessels,CXCR4 nuclear staining were higer than that in MC group(P＜0.01); No difference of SDF-1 membrane staining and CXCR4 cytoplasmic staining was found between the two.groups(P＞0.05).
10.SDF-1 was mainly expressed in tumor cells(both membrane and cytoplasm); Cytoplasmic SDF-1 expression in lymph node-positive group was higher than that in node-negative group,and the level of which was correlated with the number of nodal involvement,TNM stages,histological grades,tumor diameter and ER status(P＜0.05).
11.CXCR4 was also mainly expressed in tumor cells(both nuclei and cytoplasm); Cytoplasmic SDF-1 expression in lymph node-positive group was higher than that in node-negative group,and the level of which was correlated with the number of nodal involvement,TNM stages,histological grade,tumor diameter and HER-2 status(P＜0.05),but the nuclear expression was only correlated with PR status(P＜0.001).
12.The cytoplasmic CXCR4 was correlated with SDF-1 expression positively (P＜0.01).
Conclusion:
1.The biological behavior of IMPC is not dependent on the percentage of IMPC components in the whole tumor.
2.High expression of SDF-1/CXCR4 might be one of the molecular characteristics of IMPC and facilitate lymphatic metastasis.
3.SDF-1 located in tumor cells and on vessels,cytoplasmic staining pattern of SDF-1 and CXCR4 may be the key factors that influence the extent of lymph node metastasis in IMPC.
4.The significance of lymphocyte infiltrating for prognosis might be different.
5.Abundant infiltrating lymphocytes which associated with SDF-1 expression in tumor microenvironment of IMPC might he a factor promoting lymph node metastasis.
6.The difference of SDF-1 expression in the two types of breast carcinoma might be the key factor leading to their different prognosis.
7.The potential value of SDF-1 and CXCR4 as biomarkers for diagnosis and for predicting lymph node metastasis and a potential therapeutic target in invasive breast carcinoma,but different location in tumor microenvironment and staining patterns may signify different features of tumors.
具有高度淋巴结转移能力和不良预后的乳腺浸润性微小乳头状癌(Invasivemicropapillary carcinoma,IMPC)是研究高转移乳腺癌的良好模型,本研究旨在明确趋化因子SDF(stromal cell-derived factor)-1及其受体CXCR4在这种高淋巴结转移的特殊类型乳腺癌中的表达方式、强度及定位,及其与淋巴结转移的关系:通过对比SDF-1/CXCR4在乳腺浸润性微小乳头状癌和髓样癌(medullarycarcinoma,MC)中的表达及其与肿瘤微环境中淋巴细胞浸润的关系,初步探讨不同类型乳腺癌微环境中淋巴细胞浸润的原因及意义;并分析SDF-1/CXCR4在浸润性乳腺癌中的表达与其相关临床病理指标及淋巴结转移之间的关系,验证在特殊类型乳腺癌IMPC中得出的相关结论在其它类型浸润性乳腺癌中的普遍意义。
【方法】
采用免疫组织化学方法检测103例IMPC(包括IMPC相应淋巴结、对照组96例浸润性导管癌)、34例典型MC及120例浸润性乳腺癌(其中包括上述96例浸润性导管癌及其他类型浸润性乳腺癌)中SDF-1/CXCR4蛋白的表达情况;采用地高辛标记的寡核苷酸探针进行原位杂交以检测SDF-1和CXCR4 mRNA的表达;观察各类乳腺癌组织间质淋巴细胞浸润、淋巴结转移情况等病理学特征,分析SDF-1/CXCR4的表达与各病理学特征之间的关系。
【结果】
1.IMPC成分在肿瘤中所占比例与淋巴结转移程度无显著相关性(P=0.407);73例淋巴结阳性的混合型IMPC中,与淋巴结转移灶中的其它肿瘤成分相比,IMPC成分是主要的转移成分(P＜0.001)。
2.免疫组化及原位杂交显示SDF-1的蛋白及mRNA均主要定位于肿瘤细胞(96%),肿瘤间质细胞也有较弱的表达(14%),且上述两部位的表达均与IMPC淋巴结转移正相关(P＜0.05)。
3.罕见SDF-1 mRNA表达的脉管内皮却可见SDF-1蛋白的表达,其表达程度与肿瘤细胞SDF-1胞质着色正相关(P=0.001)。其中淋巴管内皮SDF-1的着色与淋巴结转移程度正相关(P=0.001);血管内皮SDF-1的着色与肿瘤环境中的淋巴细胞浸润正相关(P=0.024),且同时伴有较多淋巴细胞浸润(+/++)及SDF-1血管内皮着色(+)的病例,其淋巴结的转移程度分别高于仅有上述条件之一或二者均不具备的各组病例(P＜0.05)。
4.上述免疫组化显示SDF-1阳性的各着色部位中,肿瘤细胞胞质和脉管内皮SDF-1的表达高于IDC组(P=0.001;P=0.019)。
5.51例伴有DCIS的IMPC病例中DCIS成分的SDF-1胞膜着色程度明显高于IMPC成分(P=0.009);而胞质SDF-1的着色在两种成分中的表达差异无统计学意义(P＞0.05)。
6.CXCR4在IMPC中主要表达于肿瘤细胞的胞核及胞质,仅有胞质的表达与淋巴结受累程度正相关(P=0.008),并且高于IDC组胞质CXCR4的表达(P=0.049)。
7.淋巴结转移成分中包含IMPC成分的84例IMPC中,CXCR4在IMPC原发部位胞核和胞质的表达均高于转移淋巴结(P＜0.001)。
8.混合型IMPC中IMPC成分肿瘤细胞SDF-1及CXCR4的表达高于内对照(伴随的其他类型的浸润性癌)肿瘤细胞的表达(P=0.003;P=0.001)。
9.伴较多淋巴细胞浸润(+/++)的IMPC(n=54),其淋巴结转移程度、SDF-1在肿瘤细胞胞质及间质脉管内皮的表达、CXCR4在肿瘤细胞核的表达均高于MC组(P＜0.01);SDF-1在肿瘤细胞胞膜的表达、CXCR4在肿瘤细胞胞质的表达与MC组差异无统计学意义(P＞0.05)。
10.SDF-1在浸润性乳腺癌中主要表达于肿瘤细胞(包括胞质与胞膜);肿瘤细胞胞质SDF-1的表达在淋巴结阳性组高于阴性组(P＜0.05),且其表达程度与淋巴结受累数目、病理学分期、组织学分级、肿瘤大小及ER表达等指标呈正相关(P＜0.05)。
11.CXCR4在浸润性乳腺癌中也主要表达于肿瘤细胞(包括胞质与胞核);肿瘤细胞胞质CXCR4的表达在淋巴结阳性组高于阴性组(P＜0.01),且其表达程度与淋巴结受累数目、病理学分期、组织学分级、肿瘤大小及HER-2表达等呈正相关(P＜0.05),而胞核的表达仅与PR的表达情况呈正相关(P＜0.001)。
12.肿瘤细胞胞质CXCR4与SDF-1的表达呈正相关(P＜0.01)。
【结论】
1.IMPC的生物学行为并不取决于肿瘤中IMPC成分的多少。
2.SDF-1/CXCR4可能是IMPC结构的分子特征之一,并可能为IMPC高淋巴结转移的原因之一。
3.SDF-1和CXCR4在肿瘤组织中的多种定位和不同的表达方式中,SDF-1和CXCR4在肿瘤细胞胞质的表达、SDF-1在脉管内皮的着色可能是引起IMPC高度淋巴结转移的关键因素。
4.大量淋巴细胞浸润在乳腺IMPC和MC两种癌中的意义不同。
5.IMPC肿瘤微环境中与SDF-1表达相关的淋巴细胞浸润可能促进了其淋巴结转移。
6.均伴较多淋巴细胞浸润的IMPC与MC中SDF-1的表达差异可能是二者预后差异的关键因素。
7.SDF-1/CXCR4在肿瘤细胞胞质的表达与浸润性乳腺癌的淋巴结转移等多项临床病理指标之间密切相关,可能作为预测乳腺癌淋巴结转移及预后的免疫病理学指标。
Objective:
Invasive micropapillary carcinoma(IMPC)of the breast is a newly recognized subtype of breast cancer characterized by a high propensity for lymph node metastasis.The purpose of this study is to investigate the relationship between the features of location,expression pattern and intensity of SDF-1/CXCR4 and lymph node metastasis in IMPC of the breast;To explore the reason and the significance of the lymphocytes infiltration in different tumor microenvironment by comparing SDF-1 expression and its relationship with lymphocytes infiltration in IMPC with that in MC of the breast.To investigate the reason of some IMPC in which dense lymphocyte infiltrating but with poor prognosis;To explore the expression of SDF-1/CXCR4 and their association with clinic-pathological features and lymph node metastasis in human invasive breast carcinoma.
Methods:
Immunohistochemistry and in situ hybridization were performed to analyze the expression of SDF-1/CXCR4 in IMPC(including primary tumor and lymph nodes of IMPC,and 96 cases of IDC as control group),34 of MC and 120 cases of invasive breast cancer.Pathological features,lymphocytes infiltration and status of lymph node metastasis were examined by microscopic analysis.
Results:
1.The percentage of IMPC component in the whole tumor was not significantly associated with the extent of lymph node metastasis(P=0.067).In 73 cases of mixed-IMPC,IMPC component are the main source for lymph node metastasis compared with other components in the primary tumor(P＜0.001).
2.SDF-1 was mainly expressed in tumor cells(96%)and also in stromal cells (14%),staining scores of which were both correlated with the extent of lymph node metastasis in IMPC(P＜0.05).
3.Although SDF-1 mRNA was rarely detected in the endothelial cells,SDF-1 immunostaining on lymphatic vessels(36%of IMPCs)was also associated with nodal involvement(P=0.001)and that on blood vessels(34%)correlated with stromal lymphocyte infiltration in IMPC(P=0.024).
4.Cytoplasmic SDF-1 expression in tumor cells and SDF-1 staining on vessels in IMPCs were higher than IDCs(P=0.001;P=0.019).
5.51 of the 103 IMPCs contained DCIS as or as a part of nonmicropapillary components,in which significantly higher membranous(P=0.009)but similar cytoplasmic SDF-1 staining(P＞0.05)was found compared with IMPC component.
6.CXCR4 was detected in either cytoplasm or nucleus of tumor cells,but only cytoplasmic expression in IMPC was correlated with nodal involvement (P=0.008)and higher than IDC group(P=0.049).
7.The degree of cytoplasmic and nuclear CXCR4 expression in primary tumor was significantly higher than that in metastatic foci of the same case(P＜0.001).
8.SDF-1 and CXCR4 expression in IMPC component were higher than the internal control in mixed-IMPC(P=0.003;P=0.001).
9.In the cases of IMPC with abundant infiltrating lymphocytes(+/++)(n=54),the degree of lymph node metastasis,SDF-1 staining in tumor cell cytoplasma and on vessels,CXCR4 nuclear staining were higer than that in MC group(P＜0.01); No difference of SDF-1 membrane staining and CXCR4 cytoplasmic staining was found between the two.groups(P＞0.05).
10.SDF-1 was mainly expressed in tumor cells(both membrane and cytoplasm); Cytoplasmic SDF-1 expression in lymph node-positive group was higher than that in node-negative group,and the level of which was correlated with the number of nodal involvement,TNM stages,histological grades,tumor diameter and ER status(P＜0.05).
11.CXCR4 was also mainly expressed in tumor cells(both nuclei and cytoplasm); Cytoplasmic SDF-1 expression in lymph node-positive group was higher than that in node-negative group,and the level of which was correlated with the number of nodal involvement,TNM stages,histological grade,tumor diameter and HER-2 status(P＜0.05),but the nuclear expression was only correlated with PR status(P＜0.001).
12.The cytoplasmic CXCR4 was correlated with SDF-1 expression positively (P＜0.01).
Conclusion:
1.The biological behavior of IMPC is not dependent on the percentage of IMPC components in the whole tumor.
2.High expression of SDF-1/CXCR4 might be one of the molecular characteristics of IMPC and facilitate lymphatic metastasis.
3.SDF-1 located in tumor cells and on vessels,cytoplasmic staining pattern of SDF-1 and CXCR4 may be the key factors that influence the extent of lymph node metastasis in IMPC.
4.The significance of lymphocyte infiltrating for prognosis might be different.
5.Abundant infiltrating lymphocytes which associated with SDF-1 expression in tumor microenvironment of IMPC might he a factor promoting lymph node metastasis.
6.The difference of SDF-1 expression in the two types of breast carcinoma might be the key factor leading to their different prognosis.
7.The potential value of SDF-1 and CXCR4 as biomarkers for diagnosis and for predicting lymph node metastasis and a potential therapeutic target in invasive breast carcinoma,but different location in tumor microenvironment and staining patterns may signify different features of tumors.
引文
[1]Borresen-Dale AL.TP53 and breast cancer[J].Human Mutation,2003,21:292-300.
[2]李湘鸣,刘秀梵.乳腺癌发病率与动物性食物的相关性及死亡队列研究[J].实用肿瘤杂志,2003,18(6):485-488.
[3]Tavassoli FA,Devilee P.WHO classification of tumours.Pathology &genetics,tumours of the breast and female genital organs[M].Lyon:IARC Press,2003:10.
[4]付丽,松山郁生,付笑影,等.乳腺浸润性微乳头状癌的形态学与生物学行为关系的研究[J].中华病理学杂志,2004,33:21-25.
[5]Luna-More S,Gonzalez B,Acedo C,et al.Invasive micropapillary carcinoma of the breast.A new special type of invasive mammary carcinoma[J].Patho Res Pract,1994,190:668-674.
[6]Tsumagari K,Sakamoto G,Akiyama F,et al.The pathological diagnosis and clicical significance of invasive micropapillary carcinoma of the breast[J].Jpn J Breast Cancer,2001,16:441-447.
[7]Pettinato G,Manivel CJ,Panico L,et al.Invasive micropapillary carcinoma of the breast:clinicopathologic study of 62 cases of a poorly recognized variant with highly aggressive behavior[J].Am J Clin Pathol,2004,121:857-866.
[8]De La Cruz C,Moriya T,Endoh M,et al.Invasive micropapillary carcinoma of the breast:Clinicopathological and immunohistochemical study[J].Pathol Int,2004,54:90-96.
[9]付丽.重视乳腺浸润性微乳头状癌的诊断[J].中华病理学杂志,2004,33:305-307.
[10]Salvucci O,Bouchard A,Baccarelli A,et al.The role of CXCR4 receptor expression in breast cancer:a large tissue microarray study[J].Breast Cancer Res Treat.2006,97(3):275-283.
[11]Zou W,Machelon V,Coulomb-L'Hermin A,et al.Stromal derived factor-1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells [J]. Nat Med,2001,7(12): 1339 - 1346.
[12]Bachelder RE, Wendt MA, Mercurio AM. Vascular endothelial growth factor promotes breast carcinoma invasion in an autocrine manner by regulating the chemokine receptor CXCR4 [J]. Cancer Res, 2002, 62:7203-7206.
[13]Kang H, Watkins G, Parr C, et al. Stromal cell derived factor-1: its influence on invasiveness and migration of breast cancer cells in vitro, and its association with prognosis and survival in human breast cancer [J]. Breast Cancer Res, 2005,7:R402-R410.
[14]Barbero S, Bonavia R, Bajetto A, et al. Stromal cell-derived factor 1 alpha stimulates human glioblastoma cell growth through the activation of both extracellular signal-regulated kinases 1/2 and Akt [J]. Cancer Res, 2003, 63:1969-1974.
[15]Koshiba T, Hosotani R, Miyamoto Y, et al. Expression of stromal cell-derived factor 1 and CXCR4 ligand receptor system in pancreatic cancer: A possible role for tumor progression [J]. Clin Cancer Res, 2000, 6:3530-3535.
[16] Singh S, Singh UP, Grizzle WE, et al. CXCL12-CXCR4 interactions modulate prostate cancer cell migration, metalloproteinase expression and invasion [J]. Laboratory Investigation, 2004, 84:1666-1676.
[17] Hall JM, Korach KS. Stromal cell-derived factor 1, a novel target of estrogen receptor action, mediates the mitogenic effects of estradiol in ovarian and breast cancer cells [J]. Mol Endocrinol,2003,17(5): 792-803.
[18]Hartmann TN, Burger JA, Glodek A, et al. CXCR4 chemokine receptor and integrin signaling co-operate in mediating adhesion and chemoresistance in small cell lung cancer (SCLC) cells [J]. Oncogene, 2005, 24(27): 4462-4471.
[19]Santiaqo B, Baleux F, Palao G, et al.CXCL12 is displayed by rheumatoid endothelial cells through its basic amino-terminal motif on heparan sulfate proteoglycans [J]. Arthritis Res Ther, 2006, 8(2):R43.
[20] Muller A, Homey B, Soto H, et al. Involvement of chemokine receptors in breast cancer metastasis [J]. Nature,2001,410(6824):50-56.
[21]Schmid BC, Rudas M, Rezniczek GA, et al. CXCR4 is expressed in ductal carcinoma in situ of the breast and in atypical ductal hyperplasia [J]. Breast Cancer Res Treat, 2004, 84(3): 247-250.
[22]Kato M, Kitayama J, Kazama S, et al. Expression pattern of CXC chemokine receptor-4 is correlated with lymph node metastasis in human invasive ductal carcinoma [J]. Breast Cancer Res, 2003,5(5): R144-R50.
[23]Salvucci O, Bouchard L, Baccarelli A, et al. The role of CXCR4 receptor expression in breast cancer: a large tissue microarray study [J]. Breast Cancer Res Treat, 2006,97(3): 275-283.
[24] Walsh MM, Bleiweiss IJ. Invasive micropapillary carcinoma of the breast: Eighty cases of an underrecognized entity [J]. Hum Pathol, 2001, 32(6): 583-589.
[25]Guo XJ, Chen L, Lang RG, et al. Invasive micropapillary carcinoma of the breast - Association of pathologic features with lymph node metastasis [J]. Am J Clin Pathol, 2006,126(5): 740-746.
[26]Paterakos M, Watkin WG, Edgerton SM, et al. Invasive micropapillary carcinoma of the breast: A prognostic study [J]. Hum Pathol, 1999, 30(12): 1459-1463.
[27]Nassar H, Wallis T, Andea A, et al. Clinicopathologic analysis of invasive micropapillary differentiation in breast carcinoma [J]. Mod Pathol, 2001, 14(9): 836-841.
[28]Zekioglu O, Erhan Y, Ciris M, et al. Invasive micropapillary carcinoma of the breast: high incidence of lymph node metastasis with extranodal extension and its immunohistochemical profile compared with invasive ductal carcinoma [J]. Histopathology, 2004,44(1): 18-23.
[29] Li YS, Kaneko M, Amatya VJ, et al. Expression of vascular endothelial growth factor-C and its receptor in invasive micropapillary carcinoma of the breast [J]. Pathol Int, 2006,56(5): 256-261.
[30] Li Y-s, Kaneko M, Sakamoto DG, et al. The reversed apical pattern of MUC1 expression is characteristics of invasive micropapillary carcinoma of the breast [J]. Breast Cancer, 2006,13(1): 58-63.
[31]Tarasova NI, Stauber RH, Michejda CJ. Spontaneous and ligand-induced trafficking of CXC-chemokine receptor 4 [J]. J Bio Chem, 1998, 273:15883-15886.
[32]Amara A, Lorthioir 0, Valenzuela A, et al. Stromal cell-derived factor-1 alpha associates with heparan sulfates through the first beta-strand of the chemokine [J]. J Bio Chem, 1999,274:23916-23925.
[33] De La Luz Sierra M, Yang F, Narazaki M, et al. Differential processing of stromal-derived factor-lalpha and stromal-derived factor-1beta explains functional diversity [J]. Blood, 2004,103:2452-2459.
[34] Campbell JJ, Hedrick J, Zlotnik A, et al. Chemokines and the arrest of lymphocytes rolling under flow conditions [J]. Science, 1998,279:381-384.
[35]Shamri R, Grabovsky V, Gauguet JM, et al, Lymphocyte arrest requires instantaneous induction of an extended LFA-1 conformation mediated by endothelium-bound chemokines [J]. Nature Immunol, 2005, 6:497-506.
[36]Tsuta K, Ishii G, Kim E, et al. Primary lung adenocarcinoma with massive lymphocyte infiltration [J]. Am J Clin Pathol, 2005,123(4): 547-552.
[37]Canna K, McArdle PA, McMillan DC, et al. The relationship between tumour T-lymphocyte infiltration, the systemic inflammatory response and survival in patients undergoing curative resection for colorectal cancer [J]. Brit J Cancer, 2005, 92(4): 651-654.
[38]Hansen MH, Nielsen HV, Ditzel HJ. Translocation of an intracellular antigen to the surface of medullary breast cancer cells early in apoptosis allows for an antigen-driven antibody response elicited by tumor-infiltrating B cells [J]. J Immunol, 2002,169(5): 2701-2711.
[39]Zou LH, Barnett B, Safah H, et al. Bone marrow is a reservoir for CD4(+)CD25(+) regulatory T cells that traffic through CXCL12/CXCR4 signals [J]. Cancer Res, 2004, 64:8451-8455.
[40] Vermi W, Bonecchi R, Facchetti F, Bianchi D, Sozzani S, Festa S, Berenzi A, Cella M, Colonna M: Recruitment of immature plasmacytoid dendritic cells (plasmacytoid monocytes) and myeloid dendritic cells in primary cutaneous melanomas [J]. J Pathol, 2003,200:255-268.
[41]Orimo A, Gupta PB, Sgroi DC, et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion [J]. Cell, 2005,121(3): 335-348.
[42]Orimo A, Weinberg RA. Stromal fibroblasts in cancer - A novel tumor-promoting cell type [J]. Cell Cycle, 2006,5(15): 1597-601.
[43] Shim H, Lau SK, Devi S et al.Lower expression of CXCR4 in lymph node metastases than in primary breast cancers: potential regulation by ligand-dependent degradation and HIF-lalpha [J]. Biochem Biophys Res Commun, 2006,346(1):252-258.
[1]Rapin V,Contesso G,Mouriesse H,et al.Medullary breast carcinoma.A reevaluation of 95 cases of breast cancer with inflammatory stroma[J].Cancer,1998,61:2503-2510.
[2]Nzula S,Going JJ,Stott DI.Antigen driven clonal proliferation,somatic hypermutation,and selection of B lymphocytes infiltrating human ductal breast carcinomas[J].Cancer Res,2003,63:3275-3280.
[3]郭晓静,陈凌,郎荣刚,等.乳腺浸润性微乳头状癌的病理学特征与淋巴结转移的关系[J].中华病理学杂志,2006,35:8-12.
[4]Tavassoli FA,Devilee P.WHO classification of tumours.Pathology & genetics,tumours of the breast and female genital organs[M].Lyon:IARC Press,2003:10.
[5]Guo XJ,Chen L,Lang RG,et al.Invasive micropapillary carcinoma of the breast -Association of pathologic features with lymph node metastasis[J].Am J Clin Pathol,2006,126:740-746.
[6]Salvucci O,Bouchard L,Baccarelli A,et al.The role of CXCR4 receptor expression in breast cancer:a large tissue microarray study[J].Breast Cancer Res Treat,2006,97:275-283.
[7]Tashiro K,Tada H,Heilker R,et al.SIGNAL SEQUENCE TRAP-A CLONING STRATEGY FOR SECRETED PROTEINS AND TYPE-I MEMBRANE-PROTEINS[J].Science,1993,261:600-603.
[8]Zou WP,Machelon V,Coulomb-L'Hermin A,et al.Stromal-derived factor-1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells[J].Nature Med,2001,7:1339-1346.
[9]Middleton J,Neil S,Wintle J,et al.Transcytosis and surface presentation of IL-8ky venular endothelial cells[J].Cell,1997,91:385-395.
[10]Amara A,Lorthioir O,Valenzuela A,et al.Stromal cell-derived factor-1 alpha associates with heparan sulfates through the first beta-strand of the chemokine[J].J Bio Chem,1999,274:23916-23925.
[11]De La Luz Sierra M,Yang F,Narazaki M,et al.Differential processing of stromal-derived factor-lalpha and stromal-derived factor-lbeta explains functional diversity [J]. Blood, 2004,103:2452-2459.
[12] Campbell JJ, Hedrick J, Zlotnik A, et al. Chemokines and the arrest of lymphocytes rolling under flow conditions [J]. Science, 1998,279:381-384.
[13]Shamri R, Grabovsky V, Gauguet JM, et al. Lymphocyte arrest requires instantaneous induction of an extended LFA-1 conformation mediated by endothelium-bound chemokines [J]. Nature Immunol, 2005, 6:497-506.
[14]Zou LH, Barnett B, Safah H, et al. Bone marrow is a reservoir for CD4(+)CD25(+) regulatory T cells that traffic through CXCL12/CXCR4 signals [J]. Cancer Res, 2004,64:8451-8455.
[15] Vermi W, Bonecchi R, Facchetti F, et al. Recruitment of immature plasmacytoid dendritic cells (plasmacytoid monocytes) and myeloid dendritic cells in primary cutaneous melanomas [J]. J Pathol, 2003,200:255-268.
[16] Muller A, Homey B, Soto H, et al. Involvement of chemokine receptors in breast cancer metastasis [J]. Nature, 2001,410:50-56.
[17] Liang ZX, Wu T, Lou H, et al. Inhibition of breast cancer metastasis by selective synthetic polypeptide against CXCR4 [J]. Cancer Res, 2004,64:4302-4308.
[18] Liang ZX, Yoon YH, Votaw J, et al. Silencing of CXCR4 blocks breast cancer metastasis [J]. Cancer Res, 2005,65:967-971.
[1] Tavassoli FA, Devilee P. WHO classification of tumours. Pathology and genetics, tumours of the breast and female genital organs [M]. Lyon: IARC Press, 2003:10.
[2] Salvucci 0, Bouchard A, Baccarelli A, et al. The role of CXCR4 receptor expression in breast cancer: a large tissue microarray study [J]. Breast Cancer Res Treat, 2006, 97(3):275-283.
[3] Hartmann TN, Burger JA, Glodek A, et al. CXCR4 chemokine receptor and integrin signaling co-operate in mediating adhesion and chemoresistance in small cell lung cancer (SCLC) cells [J]. Oncogene, 2005, 24: 4462 - 4471.
[4] Marchesi F, Monti P, Leone BE, et al. Increased survival, proliferation, and migration in metastatic human pancreatic tumor cells expressing functional CXCR4 [J]. Cancer Res, 2004, 64: 8420 - 8427.
[5] Campbell JJ, Hedrick J, Zlotnik A, et al. Chemokines and the arrest of lymphocytes rolling under flow conditions [J]. Science, 1998,279:381-384.
[6] Shamri R, Grabovsky V, Gauguet JM, et al. Lymphocyte arrest requires instantaneous induction of an extended LFA-1 conformation mediated by endothelium-bound chemokines [J]. Nature Immunology, 2005, 6:497-506.
[7] Zou LH, Barnett B, Safah H, et al. Bone marrow is a reservoir for CD4(+)CD25(+) regulatory T cells that traffic through CXCL12/CXCR4 signals [J]. Cancer Research, 2004,64:8451-8455.
[8] Vermi W, Bonecchi R, Facchetti F, Bianchi D, Sozzani S, Festa S, Berenzi A, Cella M, Colonna M: Recruitment of immature plasmacytoid dendritic cells (plasmacytoid monocytes) and myeloid dendritic cells in primary cutaneous melanomas [J]. Journal of Pathology 2003,200:255-268.
[9] Hall JM, Korach KS. Stromal cell-derived factor 1, a novel target of estrogen receptor action, mediates the mitogenic effects of estradiol in ovarian and breast cancer cells [J]. Mol Endocrinol, 2003,17: 792 - 803.
[10]Li YM, Pan Y, Wei Y, et al. Upregulation of CXCR4 is essential for HER2-mediated tumor metastasis [J]. Cancer Cell, 2004, Nov; 6(5): 459-469.
[11]Cabioglu N, Yazici MS, Arun B, et al. CCR7 and CXCR4 as novel biomarkers predicting axillary lymph node metastasis in T1 breast cancer [J]. Clin Cancer Res, 2005,11(16): 5686-5693.
[1] Tashiro K, Tada H, Heilker R, et al. Signal sequence trap: a cloning strategy for secreted proteins and type I membrane proteins [J]. Science, 1993, 261(5121): 600-603.
[2] Murdoch C. CXCR4: chemokine receptor extraordinaire [J]. Immunol Rev, 2000,177: 175-184.
[3] Bums JM, Summers BC, Wang Y, et al. A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development [J].J Exp Med, 2006,203(9): 2201-2213.
[4] Grunewald M, Avraham I, Dor Y, et al. VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells [J]. Cell, 2006,124(1): 175-189.
[5] Katayama Y, Battista M, Kao WM, et al. Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow [J]. Cell, 2006,124(2): 407-421.
[6] Zou W, Machelon V, Coulomb-L'Hermin A, et al. Stromal derived factor-1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells [J]. Nat Med, 2001,7(12): 1339-1346.
[7] Kang H, Watkins G, Parr C,et al. Stromal cell derived factor-1: its influence on invasiveness and migration of breast cancer cells in vitro, and its association with prognosis and survival in human breast cancer [J]. Breast Cancer Res, 2005,7(4): R402-R410.
[8] Barbero S, Bonavia R, Bajetto A,et al. Stromal cell-derived factor-1α stimulates human glioblastoma cell growth through the activation of both extracellular signal-regulated kinases 1/2 and Akt [J]. Cancer Res, 2003, 63(8): 1969-1974.
[9] Marchesi F, Monti P, Leone BE,et al. Increased survival, proliferation, and migration in metastatic human pancreatic tumor cells expressing functional CXCR4 [J]. Cancer Res, 2004,64(22): 8420-8427.
[10]Darash-Yahana M, Pikarsky E, Abramovitch R, et al. Role of high expression levels of CXCR4 in tumor growth, vascularization, and metastasis [J]. FASEB J,2004,18(11):1240-1242.
[11] Singh S, Singh UP, Grizzle WE, et al. CXCL12-CXCR4 interactions modulate prostate cancer cell migration, metalloproteinase expression and invasion [J]. Lab Invest, 2004,84(12):1666-1676.
[12]Orimo A, Weinberg RA.Stromal fibroblasts in cancer: a novel tumor-promoting cell type [J]. Cell Cycle, 2006,5(15): 1597-1601.
[13]Orimo A, Gupta PB, Sgroi DC,et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion [J]. Cell, 2005,121(3): 335-348.
[14]Allinen M, Beroukhim R, Cai L, et al. Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell,2004,6(1): 17-32.
[15]Zou L, Barnett B, Safah H, et al. Bone marrow is a reservoir for CD4+ CD25+regulatory T cells that traffic through CXCL12/CXCR4 signals [J]. Cancer Res, 2004,64(22): 8451-8455.
[16]Kryczek I, Lange A, Mottram P,et al. CXCL12 and vascular endothelial growth factor synergistically induce neoangiogenesis in human ovarian cancers [J]. Cancer Res, 2005,65(2): 465-472.
[17] Aghi M,Cohen KS,Klein RJ,et al. Tumor Stromal-Derived Factor-1 Recruits Vascular Progenitors to Mitotic Neovasculature, where Microenvironment Influences Their Differentiated Phenotypes [J]. Cancer Res, 2006, 66(18):9054-9064.
[18]Curiel TJ, Cheng P, Mottram P,et al. Dendritic cell subsets differentially regulate angiogenesis in human ovarian cancer [J]. Cancer Res, 2004, 64(16): 5535-5538.
[19] Muller A, Homey B, Soto H, et al. Involvement of chemokine receptors in breast cancer metastasis [J]. Nature, 2001, 410(6824):50-56.
[20] Hall JM, Korach KS. Stromal cell-derived factor 1, a novel target of estrogen receptor action, mediates the mitogenic effects of estradiol in ovarian and breast cancer cells [J]. Mol Endocrinol, 2003,17(5): 792-803.
[21]Ceradini DJ, Kulkami AR, Callaghan MJ, et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1 [J]. Nat Med, 2004,10(8): 858-864.
[22]Fedyk ER, Jones D, Critchley HO, et al. Expression of stromal-derived factor-1 is decreased by IL-1 and TNF and in dermal wound healing [J]. J Immunol, 2001,166(9): 5749-5754.
[23]Helbig G, Christopherson KW 2nd, Bhat-Nakshatri P, et al. NF- κ B promotes breast cancer cell migration and metastasis by inducing the expression of the chemokine receptor CXCR4 [J]. J Biol Chem, 2003, 278(24): 21631-21638.
[24]Hartmann TN, Burger JA, Glodek A, et al. CXCR4 chemokine receptor and integrin signaling co-operate in mediating adhesion and chemoresistance in small cell lung cancer (SCLC) cells [J]. Oncogene, 2005, 24(27): 4462-4471.
[25]Santiaqo B, Baleux F, Palao G, et al.CXCL12 is displayed by rheumatoid endothelial cells through its basic amino.-terminal motif on heparan sulfate proteoglycans [J]. Arthritis Res Ther, 2006,8(2):R43.
[26]Kukreja P, Abdel-Mageed AB, Mondal D, et al. Up-regulation of CXCR4 expression in PC-3 cells by stromal-derived factor-la (CXCL12) increases endothelial adhesion and transendothelial migration: role of MEK/ERK signaling pathway-dependent NF-κB activation [J]. Cancer Res, 2005, 65(21): 9891-9898.
[27] Sato Y, Fujiwara H, Higuchi T, et al. Involvement of dipeptidyl peptidase IV in extravillous trophoblast invasion and differentiation [J]. J Clin Endocrinol Metab, 2002,87(9): 4287-4296.
[28]Poznansky MC, Olszak IT, Foxall R, et al. Active movement of T cells away from a chemokine [J]. Nat Med, 2000, 6(5):543-548.
[29]Staller P, Sulitkova J, Lisztwan J, et al. Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor Pvhl [J]. Nature, 2003,425(6955): 307-311.
[30]Moseman EA, Liang X, Dawson AJ, et al. Human plasmacytoid dendritic cells activated by CpG oligodeoxynucleotides induce the generation of CD4+CD25+ regulatory T cells[J].J Immunol,2004,173(7):4433-4442.
[31]Gilliet M,Liu YJ.Generation of human CD8 T regulatory cells by CD40ligand-activated plasmacytoid dendritic cells[J].J Exp Med,2002,195(6):695-704.
[32]Zeelenberg IS,Ruuls-Van Stalle L,Roos E.The chemokine receptor CXCR4 is required for outgrowth of colon carcinoma micrometastases[J].Cancer Res,2003,63(13):3833-3839.
[33]Uchimura K,Morimoto-Tomita M,Bistrup A,et al.HSulf-2,an extracellular endoglucosamine-6-sulfatase,selectively mobilizes heparin-bound growth factors and chemokines:effects on VEGF,FGF-1,and SDF-1[J].BMC Biochem,2006,Jan 17,7:2.
[2]李湘鸣,刘秀梵.乳腺癌发病率与动物性食物的相关性及死亡队列研究[J].实用肿瘤杂志,2003,18(6):485-488.
[3]Tavassoli FA,Devilee P.WHO classification of tumours.Pathology &genetics,tumours of the breast and female genital organs[M].Lyon:IARC Press,2003:10.
[4]付丽,松山郁生,付笑影,等.乳腺浸润性微乳头状癌的形态学与生物学行为关系的研究[J].中华病理学杂志,2004,33:21-25.
[5]Luna-More S,Gonzalez B,Acedo C,et al.Invasive micropapillary carcinoma of the breast.A new special type of invasive mammary carcinoma[J].Patho Res Pract,1994,190:668-674.
[6]Tsumagari K,Sakamoto G,Akiyama F,et al.The pathological diagnosis and clicical significance of invasive micropapillary carcinoma of the breast[J].Jpn J Breast Cancer,2001,16:441-447.
[7]Pettinato G,Manivel CJ,Panico L,et al.Invasive micropapillary carcinoma of the breast:clinicopathologic study of 62 cases of a poorly recognized variant with highly aggressive behavior[J].Am J Clin Pathol,2004,121:857-866.
[8]De La Cruz C,Moriya T,Endoh M,et al.Invasive micropapillary carcinoma of the breast:Clinicopathological and immunohistochemical study[J].Pathol Int,2004,54:90-96.
[9]付丽.重视乳腺浸润性微乳头状癌的诊断[J].中华病理学杂志,2004,33:305-307.
[10]Salvucci O,Bouchard A,Baccarelli A,et al.The role of CXCR4 receptor expression in breast cancer:a large tissue microarray study[J].Breast Cancer Res Treat.2006,97(3):275-283.
[11]Zou W,Machelon V,Coulomb-L'Hermin A,et al.Stromal derived factor-1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells [J]. Nat Med,2001,7(12): 1339 - 1346.
[12]Bachelder RE, Wendt MA, Mercurio AM. Vascular endothelial growth factor promotes breast carcinoma invasion in an autocrine manner by regulating the chemokine receptor CXCR4 [J]. Cancer Res, 2002, 62:7203-7206.
[13]Kang H, Watkins G, Parr C, et al. Stromal cell derived factor-1: its influence on invasiveness and migration of breast cancer cells in vitro, and its association with prognosis and survival in human breast cancer [J]. Breast Cancer Res, 2005,7:R402-R410.
[14]Barbero S, Bonavia R, Bajetto A, et al. Stromal cell-derived factor 1 alpha stimulates human glioblastoma cell growth through the activation of both extracellular signal-regulated kinases 1/2 and Akt [J]. Cancer Res, 2003, 63:1969-1974.
[15]Koshiba T, Hosotani R, Miyamoto Y, et al. Expression of stromal cell-derived factor 1 and CXCR4 ligand receptor system in pancreatic cancer: A possible role for tumor progression [J]. Clin Cancer Res, 2000, 6:3530-3535.
[16] Singh S, Singh UP, Grizzle WE, et al. CXCL12-CXCR4 interactions modulate prostate cancer cell migration, metalloproteinase expression and invasion [J]. Laboratory Investigation, 2004, 84:1666-1676.
[17] Hall JM, Korach KS. Stromal cell-derived factor 1, a novel target of estrogen receptor action, mediates the mitogenic effects of estradiol in ovarian and breast cancer cells [J]. Mol Endocrinol,2003,17(5): 792-803.
[18]Hartmann TN, Burger JA, Glodek A, et al. CXCR4 chemokine receptor and integrin signaling co-operate in mediating adhesion and chemoresistance in small cell lung cancer (SCLC) cells [J]. Oncogene, 2005, 24(27): 4462-4471.
[19]Santiaqo B, Baleux F, Palao G, et al.CXCL12 is displayed by rheumatoid endothelial cells through its basic amino-terminal motif on heparan sulfate proteoglycans [J]. Arthritis Res Ther, 2006, 8(2):R43.
[20] Muller A, Homey B, Soto H, et al. Involvement of chemokine receptors in breast cancer metastasis [J]. Nature,2001,410(6824):50-56.
[21]Schmid BC, Rudas M, Rezniczek GA, et al. CXCR4 is expressed in ductal carcinoma in situ of the breast and in atypical ductal hyperplasia [J]. Breast Cancer Res Treat, 2004, 84(3): 247-250.
[22]Kato M, Kitayama J, Kazama S, et al. Expression pattern of CXC chemokine receptor-4 is correlated with lymph node metastasis in human invasive ductal carcinoma [J]. Breast Cancer Res, 2003,5(5): R144-R50.
[23]Salvucci O, Bouchard L, Baccarelli A, et al. The role of CXCR4 receptor expression in breast cancer: a large tissue microarray study [J]. Breast Cancer Res Treat, 2006,97(3): 275-283.
[24] Walsh MM, Bleiweiss IJ. Invasive micropapillary carcinoma of the breast: Eighty cases of an underrecognized entity [J]. Hum Pathol, 2001, 32(6): 583-589.
[25]Guo XJ, Chen L, Lang RG, et al. Invasive micropapillary carcinoma of the breast - Association of pathologic features with lymph node metastasis [J]. Am J Clin Pathol, 2006,126(5): 740-746.
[26]Paterakos M, Watkin WG, Edgerton SM, et al. Invasive micropapillary carcinoma of the breast: A prognostic study [J]. Hum Pathol, 1999, 30(12): 1459-1463.
[27]Nassar H, Wallis T, Andea A, et al. Clinicopathologic analysis of invasive micropapillary differentiation in breast carcinoma [J]. Mod Pathol, 2001, 14(9): 836-841.
[28]Zekioglu O, Erhan Y, Ciris M, et al. Invasive micropapillary carcinoma of the breast: high incidence of lymph node metastasis with extranodal extension and its immunohistochemical profile compared with invasive ductal carcinoma [J]. Histopathology, 2004,44(1): 18-23.
[29] Li YS, Kaneko M, Amatya VJ, et al. Expression of vascular endothelial growth factor-C and its receptor in invasive micropapillary carcinoma of the breast [J]. Pathol Int, 2006,56(5): 256-261.
[30] Li Y-s, Kaneko M, Sakamoto DG, et al. The reversed apical pattern of MUC1 expression is characteristics of invasive micropapillary carcinoma of the breast [J]. Breast Cancer, 2006,13(1): 58-63.
[31]Tarasova NI, Stauber RH, Michejda CJ. Spontaneous and ligand-induced trafficking of CXC-chemokine receptor 4 [J]. J Bio Chem, 1998, 273:15883-15886.
[32]Amara A, Lorthioir 0, Valenzuela A, et al. Stromal cell-derived factor-1 alpha associates with heparan sulfates through the first beta-strand of the chemokine [J]. J Bio Chem, 1999,274:23916-23925.
[33] De La Luz Sierra M, Yang F, Narazaki M, et al. Differential processing of stromal-derived factor-lalpha and stromal-derived factor-1beta explains functional diversity [J]. Blood, 2004,103:2452-2459.
[34] Campbell JJ, Hedrick J, Zlotnik A, et al. Chemokines and the arrest of lymphocytes rolling under flow conditions [J]. Science, 1998,279:381-384.
[35]Shamri R, Grabovsky V, Gauguet JM, et al, Lymphocyte arrest requires instantaneous induction of an extended LFA-1 conformation mediated by endothelium-bound chemokines [J]. Nature Immunol, 2005, 6:497-506.
[36]Tsuta K, Ishii G, Kim E, et al. Primary lung adenocarcinoma with massive lymphocyte infiltration [J]. Am J Clin Pathol, 2005,123(4): 547-552.
[37]Canna K, McArdle PA, McMillan DC, et al. The relationship between tumour T-lymphocyte infiltration, the systemic inflammatory response and survival in patients undergoing curative resection for colorectal cancer [J]. Brit J Cancer, 2005, 92(4): 651-654.
[38]Hansen MH, Nielsen HV, Ditzel HJ. Translocation of an intracellular antigen to the surface of medullary breast cancer cells early in apoptosis allows for an antigen-driven antibody response elicited by tumor-infiltrating B cells [J]. J Immunol, 2002,169(5): 2701-2711.
[39]Zou LH, Barnett B, Safah H, et al. Bone marrow is a reservoir for CD4(+)CD25(+) regulatory T cells that traffic through CXCL12/CXCR4 signals [J]. Cancer Res, 2004, 64:8451-8455.
[40] Vermi W, Bonecchi R, Facchetti F, Bianchi D, Sozzani S, Festa S, Berenzi A, Cella M, Colonna M: Recruitment of immature plasmacytoid dendritic cells (plasmacytoid monocytes) and myeloid dendritic cells in primary cutaneous melanomas [J]. J Pathol, 2003,200:255-268.
[41]Orimo A, Gupta PB, Sgroi DC, et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion [J]. Cell, 2005,121(3): 335-348.
[42]Orimo A, Weinberg RA. Stromal fibroblasts in cancer - A novel tumor-promoting cell type [J]. Cell Cycle, 2006,5(15): 1597-601.
[43] Shim H, Lau SK, Devi S et al.Lower expression of CXCR4 in lymph node metastases than in primary breast cancers: potential regulation by ligand-dependent degradation and HIF-lalpha [J]. Biochem Biophys Res Commun, 2006,346(1):252-258.
[1]Rapin V,Contesso G,Mouriesse H,et al.Medullary breast carcinoma.A reevaluation of 95 cases of breast cancer with inflammatory stroma[J].Cancer,1998,61:2503-2510.
[2]Nzula S,Going JJ,Stott DI.Antigen driven clonal proliferation,somatic hypermutation,and selection of B lymphocytes infiltrating human ductal breast carcinomas[J].Cancer Res,2003,63:3275-3280.
[3]郭晓静,陈凌,郎荣刚,等.乳腺浸润性微乳头状癌的病理学特征与淋巴结转移的关系[J].中华病理学杂志,2006,35:8-12.
[4]Tavassoli FA,Devilee P.WHO classification of tumours.Pathology & genetics,tumours of the breast and female genital organs[M].Lyon:IARC Press,2003:10.
[5]Guo XJ,Chen L,Lang RG,et al.Invasive micropapillary carcinoma of the breast -Association of pathologic features with lymph node metastasis[J].Am J Clin Pathol,2006,126:740-746.
[6]Salvucci O,Bouchard L,Baccarelli A,et al.The role of CXCR4 receptor expression in breast cancer:a large tissue microarray study[J].Breast Cancer Res Treat,2006,97:275-283.
[7]Tashiro K,Tada H,Heilker R,et al.SIGNAL SEQUENCE TRAP-A CLONING STRATEGY FOR SECRETED PROTEINS AND TYPE-I MEMBRANE-PROTEINS[J].Science,1993,261:600-603.
[8]Zou WP,Machelon V,Coulomb-L'Hermin A,et al.Stromal-derived factor-1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells[J].Nature Med,2001,7:1339-1346.
[9]Middleton J,Neil S,Wintle J,et al.Transcytosis and surface presentation of IL-8ky venular endothelial cells[J].Cell,1997,91:385-395.
[10]Amara A,Lorthioir O,Valenzuela A,et al.Stromal cell-derived factor-1 alpha associates with heparan sulfates through the first beta-strand of the chemokine[J].J Bio Chem,1999,274:23916-23925.
[11]De La Luz Sierra M,Yang F,Narazaki M,et al.Differential processing of stromal-derived factor-lalpha and stromal-derived factor-lbeta explains functional diversity [J]. Blood, 2004,103:2452-2459.
[12] Campbell JJ, Hedrick J, Zlotnik A, et al. Chemokines and the arrest of lymphocytes rolling under flow conditions [J]. Science, 1998,279:381-384.
[13]Shamri R, Grabovsky V, Gauguet JM, et al. Lymphocyte arrest requires instantaneous induction of an extended LFA-1 conformation mediated by endothelium-bound chemokines [J]. Nature Immunol, 2005, 6:497-506.
[14]Zou LH, Barnett B, Safah H, et al. Bone marrow is a reservoir for CD4(+)CD25(+) regulatory T cells that traffic through CXCL12/CXCR4 signals [J]. Cancer Res, 2004,64:8451-8455.
[15] Vermi W, Bonecchi R, Facchetti F, et al. Recruitment of immature plasmacytoid dendritic cells (plasmacytoid monocytes) and myeloid dendritic cells in primary cutaneous melanomas [J]. J Pathol, 2003,200:255-268.
[16] Muller A, Homey B, Soto H, et al. Involvement of chemokine receptors in breast cancer metastasis [J]. Nature, 2001,410:50-56.
[17] Liang ZX, Wu T, Lou H, et al. Inhibition of breast cancer metastasis by selective synthetic polypeptide against CXCR4 [J]. Cancer Res, 2004,64:4302-4308.
[18] Liang ZX, Yoon YH, Votaw J, et al. Silencing of CXCR4 blocks breast cancer metastasis [J]. Cancer Res, 2005,65:967-971.
[1] Tavassoli FA, Devilee P. WHO classification of tumours. Pathology and genetics, tumours of the breast and female genital organs [M]. Lyon: IARC Press, 2003:10.
[2] Salvucci 0, Bouchard A, Baccarelli A, et al. The role of CXCR4 receptor expression in breast cancer: a large tissue microarray study [J]. Breast Cancer Res Treat, 2006, 97(3):275-283.
[3] Hartmann TN, Burger JA, Glodek A, et al. CXCR4 chemokine receptor and integrin signaling co-operate in mediating adhesion and chemoresistance in small cell lung cancer (SCLC) cells [J]. Oncogene, 2005, 24: 4462 - 4471.
[4] Marchesi F, Monti P, Leone BE, et al. Increased survival, proliferation, and migration in metastatic human pancreatic tumor cells expressing functional CXCR4 [J]. Cancer Res, 2004, 64: 8420 - 8427.
[5] Campbell JJ, Hedrick J, Zlotnik A, et al. Chemokines and the arrest of lymphocytes rolling under flow conditions [J]. Science, 1998,279:381-384.
[6] Shamri R, Grabovsky V, Gauguet JM, et al. Lymphocyte arrest requires instantaneous induction of an extended LFA-1 conformation mediated by endothelium-bound chemokines [J]. Nature Immunology, 2005, 6:497-506.
[7] Zou LH, Barnett B, Safah H, et al. Bone marrow is a reservoir for CD4(+)CD25(+) regulatory T cells that traffic through CXCL12/CXCR4 signals [J]. Cancer Research, 2004,64:8451-8455.
[8] Vermi W, Bonecchi R, Facchetti F, Bianchi D, Sozzani S, Festa S, Berenzi A, Cella M, Colonna M: Recruitment of immature plasmacytoid dendritic cells (plasmacytoid monocytes) and myeloid dendritic cells in primary cutaneous melanomas [J]. Journal of Pathology 2003,200:255-268.
[9] Hall JM, Korach KS. Stromal cell-derived factor 1, a novel target of estrogen receptor action, mediates the mitogenic effects of estradiol in ovarian and breast cancer cells [J]. Mol Endocrinol, 2003,17: 792 - 803.
[10]Li YM, Pan Y, Wei Y, et al. Upregulation of CXCR4 is essential for HER2-mediated tumor metastasis [J]. Cancer Cell, 2004, Nov; 6(5): 459-469.
[11]Cabioglu N, Yazici MS, Arun B, et al. CCR7 and CXCR4 as novel biomarkers predicting axillary lymph node metastasis in T1 breast cancer [J]. Clin Cancer Res, 2005,11(16): 5686-5693.
[1] Tashiro K, Tada H, Heilker R, et al. Signal sequence trap: a cloning strategy for secreted proteins and type I membrane proteins [J]. Science, 1993, 261(5121): 600-603.
[2] Murdoch C. CXCR4: chemokine receptor extraordinaire [J]. Immunol Rev, 2000,177: 175-184.
[3] Bums JM, Summers BC, Wang Y, et al. A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development [J].J Exp Med, 2006,203(9): 2201-2213.
[4] Grunewald M, Avraham I, Dor Y, et al. VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells [J]. Cell, 2006,124(1): 175-189.
[5] Katayama Y, Battista M, Kao WM, et al. Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow [J]. Cell, 2006,124(2): 407-421.
[6] Zou W, Machelon V, Coulomb-L'Hermin A, et al. Stromal derived factor-1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells [J]. Nat Med, 2001,7(12): 1339-1346.
[7] Kang H, Watkins G, Parr C,et al. Stromal cell derived factor-1: its influence on invasiveness and migration of breast cancer cells in vitro, and its association with prognosis and survival in human breast cancer [J]. Breast Cancer Res, 2005,7(4): R402-R410.
[8] Barbero S, Bonavia R, Bajetto A,et al. Stromal cell-derived factor-1α stimulates human glioblastoma cell growth through the activation of both extracellular signal-regulated kinases 1/2 and Akt [J]. Cancer Res, 2003, 63(8): 1969-1974.
[9] Marchesi F, Monti P, Leone BE,et al. Increased survival, proliferation, and migration in metastatic human pancreatic tumor cells expressing functional CXCR4 [J]. Cancer Res, 2004,64(22): 8420-8427.
[10]Darash-Yahana M, Pikarsky E, Abramovitch R, et al. Role of high expression levels of CXCR4 in tumor growth, vascularization, and metastasis [J]. FASEB J,2004,18(11):1240-1242.
[11] Singh S, Singh UP, Grizzle WE, et al. CXCL12-CXCR4 interactions modulate prostate cancer cell migration, metalloproteinase expression and invasion [J]. Lab Invest, 2004,84(12):1666-1676.
[12]Orimo A, Weinberg RA.Stromal fibroblasts in cancer: a novel tumor-promoting cell type [J]. Cell Cycle, 2006,5(15): 1597-1601.
[13]Orimo A, Gupta PB, Sgroi DC,et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion [J]. Cell, 2005,121(3): 335-348.
[14]Allinen M, Beroukhim R, Cai L, et al. Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell,2004,6(1): 17-32.
[15]Zou L, Barnett B, Safah H, et al. Bone marrow is a reservoir for CD4+ CD25+regulatory T cells that traffic through CXCL12/CXCR4 signals [J]. Cancer Res, 2004,64(22): 8451-8455.
[16]Kryczek I, Lange A, Mottram P,et al. CXCL12 and vascular endothelial growth factor synergistically induce neoangiogenesis in human ovarian cancers [J]. Cancer Res, 2005,65(2): 465-472.
[17] Aghi M,Cohen KS,Klein RJ,et al. Tumor Stromal-Derived Factor-1 Recruits Vascular Progenitors to Mitotic Neovasculature, where Microenvironment Influences Their Differentiated Phenotypes [J]. Cancer Res, 2006, 66(18):9054-9064.
[18]Curiel TJ, Cheng P, Mottram P,et al. Dendritic cell subsets differentially regulate angiogenesis in human ovarian cancer [J]. Cancer Res, 2004, 64(16): 5535-5538.
[19] Muller A, Homey B, Soto H, et al. Involvement of chemokine receptors in breast cancer metastasis [J]. Nature, 2001, 410(6824):50-56.
[20] Hall JM, Korach KS. Stromal cell-derived factor 1, a novel target of estrogen receptor action, mediates the mitogenic effects of estradiol in ovarian and breast cancer cells [J]. Mol Endocrinol, 2003,17(5): 792-803.
[21]Ceradini DJ, Kulkami AR, Callaghan MJ, et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1 [J]. Nat Med, 2004,10(8): 858-864.
[22]Fedyk ER, Jones D, Critchley HO, et al. Expression of stromal-derived factor-1 is decreased by IL-1 and TNF and in dermal wound healing [J]. J Immunol, 2001,166(9): 5749-5754.
[23]Helbig G, Christopherson KW 2nd, Bhat-Nakshatri P, et al. NF- κ B promotes breast cancer cell migration and metastasis by inducing the expression of the chemokine receptor CXCR4 [J]. J Biol Chem, 2003, 278(24): 21631-21638.
[24]Hartmann TN, Burger JA, Glodek A, et al. CXCR4 chemokine receptor and integrin signaling co-operate in mediating adhesion and chemoresistance in small cell lung cancer (SCLC) cells [J]. Oncogene, 2005, 24(27): 4462-4471.
[25]Santiaqo B, Baleux F, Palao G, et al.CXCL12 is displayed by rheumatoid endothelial cells through its basic amino.-terminal motif on heparan sulfate proteoglycans [J]. Arthritis Res Ther, 2006,8(2):R43.
[26]Kukreja P, Abdel-Mageed AB, Mondal D, et al. Up-regulation of CXCR4 expression in PC-3 cells by stromal-derived factor-la (CXCL12) increases endothelial adhesion and transendothelial migration: role of MEK/ERK signaling pathway-dependent NF-κB activation [J]. Cancer Res, 2005, 65(21): 9891-9898.
[27] Sato Y, Fujiwara H, Higuchi T, et al. Involvement of dipeptidyl peptidase IV in extravillous trophoblast invasion and differentiation [J]. J Clin Endocrinol Metab, 2002,87(9): 4287-4296.
[28]Poznansky MC, Olszak IT, Foxall R, et al. Active movement of T cells away from a chemokine [J]. Nat Med, 2000, 6(5):543-548.
[29]Staller P, Sulitkova J, Lisztwan J, et al. Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor Pvhl [J]. Nature, 2003,425(6955): 307-311.
[30]Moseman EA, Liang X, Dawson AJ, et al. Human plasmacytoid dendritic cells activated by CpG oligodeoxynucleotides induce the generation of CD4+CD25+ regulatory T cells[J].J Immunol,2004,173(7):4433-4442.
[31]Gilliet M,Liu YJ.Generation of human CD8 T regulatory cells by CD40ligand-activated plasmacytoid dendritic cells[J].J Exp Med,2002,195(6):695-704.
[32]Zeelenberg IS,Ruuls-Van Stalle L,Roos E.The chemokine receptor CXCR4 is required for outgrowth of colon carcinoma micrometastases[J].Cancer Res,2003,63(13):3833-3839.
[33]Uchimura K,Morimoto-Tomita M,Bistrup A,et al.HSulf-2,an extracellular endoglucosamine-6-sulfatase,selectively mobilizes heparin-bound growth factors and chemokines:effects on VEGF,FGF-1,and SDF-1[J].BMC Biochem,2006,Jan 17,7:2.