乳腺癌干细胞与乳腺癌预后、及NOTCH通路的相关性研究
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摘要
第一部分
乳腺癌干细胞与乳腺癌预后的相关性研究
目的：分析CD44+／CD24乳腺癌干细胞、ALDH1+乳腺癌干细胞与临床预后的相关性。
方法：选取121例在我院治疗的原发性乳腺癌患者,收集其石蜡包埋的原发灶121例。免疫组织化学荧光双染法测定乳腺癌干细胞CD44、CD24的表达,免疫组织化学酶标法测定乳腺癌干细胞ALDH1的表达。应用镜下观察及图像处理软件分析其结果。
结果：原发病灶中CD44+／CD24-肿瘤干细胞含量范围0%--70%,中位5.8%。CD44+／CD24-肿瘤细胞干细胞含量与其他病理特征,包括(肿瘤体积、病理分期、LN、ER、PR、HER-2)无明显相关性。CD44+／CD24-肿瘤干细胞含量与乳腺癌的复发、转移无明显相关性。CD44+／CD24-肿瘤干细胞阳性率与三阴性乳腺癌无明显相关性。CD44+／CD24-肿瘤干细胞＝0%组与CD44+／CD24-肿瘤干细胞>0%组间DFS无统计学意义。原发病灶中,ALDH1阳性率54.6%。ALDH1与与其他病理特征,包括(肿瘤体积、病理分期、LN、ER、PR、HER-2)无明显相关性。ALDH1阳性率在SR(-)HER-2(-)组55.7%,较非SR(-)HER-2(-)组阳性率45.0%高,但P>0.05,无统计学差异。故ALDH1与三阴性乳腺癌无明显相关性。CD44+／CD24-肿瘤干细胞中位含量在ALDH1(+)组9.9%,高于ALDH1(-)组6.3%,但P>0.05,尚不能说明两组间CD44+／CD24-肿瘤干细胞含量有显著性差异。ALDH1(+)组与ALDH1(-)组间DFS无显著性差异。因此,ALDH1与乳腺癌预后无明显相关性。
结论：未发现CD44+／CD24-肿瘤干细胞、ALDH1肿瘤干细胞与乳腺癌的复发、转移有相关性。未发现CD44+／CD24-肿瘤干细胞、ALDH1乳腺癌干细胞与三阴性乳腺癌有相关性。未发现CD44+／CD24-肿瘤干细胞、ALDH1乳腺癌干细胞与乳腺癌患者的临床预后有相关性。乳腺癌患者中,以ALDH1为特征的肿瘤干细胞与以CD44+／CD24-为特征的肿瘤干细胞无相关性。
第二部分
乳腺癌干细胞与复发、转移的相关性研究
目的：检测CD44+/CD24-乳腺癌干细胞在原发灶与复发灶中的区别。
检测ALDH1乳腺癌干细胞在原发灶与复发灶中的区别。
方法：121例在我院手术的原发性乳腺癌患者中,选取其中复发、转移患者27例,收集其石蜡包埋的原发灶和复发病灶。免疫组织化学荧光双染法测定乳腺癌干细胞CD44、CD24的表达,免疫组织化学酶标法测定乳腺癌干细胞ALDH1的表达。应用镜下观察及图像处理软件分析其结果。
结果：复发患者中,CD44+/CD24-肿瘤细胞在复发灶中的含量(中位26.9%)高于原发灶的含量(中位7.0%),但P>0.05,不能说明两组间乳腺癌干细胞含量有显著性差异。在复发患者中,ALDH1阳性率在复发灶中60%(9／15),略高于原发灶57.1%(12／21),但P>0.05,尚不能说明两组间ALDH1阳性率有显著性差异。原发病灶的ALDH1阳性表达强度,在有复发、转移患者组中高于无复发、转移的患者组,P<0.005,说明ALDH1与患者的复发、转移有相关性。虽然在第一部分中,ALDH1与患者的DFS无关系,但此结果提示ALDH1 (+)的乳腺癌患者更易出现复发、转移。
结论：ALDH1(+)的乳腺癌患者更易出现复发、转移。
第三部分：
NOTC H信号通路与乳腺癌干细胞的相关性研究
目的：分析NOTCH通路与以ALDH1为代表的乳腺癌干细胞的关系。分析NOTCH通路与以CD44+/CD24为代表的乳腺癌干细胞的关系
方法：收集43例原发性乳腺癌患者,收集其新鲜组织标本及石蜡包埋的原发灶,免疫组织化学荧光双染法测定乳腺癌干细胞CD44、CD24的表达,免疫组织化学酶标法测定乳腺癌干细胞ALDH1及NOTCH1的表达。应用镜下观察及图像处理软件分析其结果。应用荧光定量PCR检测NOTCH1的mRNA的表达。
结果：乳腺癌患者中,NOTCH 1 mRNA的表达在ALDH1(+)组高于ALDH1(-)组,但P>0.05,尚不能说明两组间NOTCH1的mRNA的表达有显著性差异。NOTCH 1蛋白表达在在ALDH1 (+)组阳性率88.2%(15／17),略高于ALDH1(·)组85%(17／20),但P>0.05,尚不能说明两组间NOTCH1蛋白表达有显著性差异。虽然NOTCH 1mRNA的转录水平在ALDH1 (+)组中高,NOTCH1蛋白表达的阳性率也在ALDH1 (+)组中高,但P均>0.05,尚不能说明在乳腺癌患者中,NOTCH1通路与以ALDH1为特征的肿瘤干细胞之间有联系。NOTCH 1mRNA的表达在CD44+/CD24-肿瘤干细胞含量＝0%组,高于CD44+/CD24-仲瘤干细胞含量>0%组。NOTCH1蛋白表达在CD44+/CD24-肿瘤干细胞含量=0%组,阳性率91.7%(11／12)高于在CD44+/CD24肿瘤细胞含量>0%组,阳性率85.2%(23／27)。虽然NOTCH 1 mRNA表达量与NOTCH1蛋白表达量均在CD44+/CD24-肿瘤干细胞=0%组高。但P均>0.05,尚不能说明NOTCH与以CD44+/CD24-为特征的肿瘤干细胞之间有相关性。
结论：未发现乳腺癌患者中,NOTCH信号通路与以ALDH1为特征的肿瘤干细胞的有相关性。未发现乳腺癌患者中,NOTCH通路与以CD44+/CD24-为特征的乳腺癌干细胞的有相关性。
Part1
The Association between Breast Cancer Stem cell and Clinical Outcome
Purpose:To investigate the relevance between clinical prognosis and breast cancer stem cell with CD44+/CD24- characteristics. To investigate the relevance between clinical prognosis and breast cancer stem cell with ALDH1-positive characteristics.
Methods:Primary breast cancer patients (n=121) treated in Peking Union Medical College Hospital were included in the study. The study included paraffin embedded tissue of 121 patients with primary lesion. CD44+/CD24-tumor cell proportions were detected by double-staining immunofluorescence and ALDH1 tumor cells were detected by immunohistochemistry.
Results:There was no significant correlation between CD44+/CD24-cell and other clinical characteristics.There was no significant correlation between CD44+/CD24-cell and tumor progression. The association can not be demonstrated between ER(-)HER-2(-) breast cancer and CD44+/CD24- cell. There was no significant correlation between CD44+/CD24" cell and clinical prognosis. There was no significant correlation between ALDH1 and other clinical characteristics. The association can not be demonstrated between ER(-)HER-2(-) breast cancer and ALDH1. There was no significant difference of CD44+/CD24- cell proportions between ALDH1-positive breast cancer and ALDH1-negtive breast cancer. There was no significant correlation between ALDH1 and clinical prognosis.
Conclusion:Prevelence of CD44+/CD24" tumor cell or ALDH1 may not be associatied with clinical outcome and disease-free survival. There was no significant correlation between tumor stem cell identified by CD44+/CD24- and ER(-)HER-2(-) breast cancer. There was no significant correlation between tumor stem cell identified by ALDH1 and ER(-)HER-2(-) breast cancer.
Part 2
The Association between Breast Cancer Stem Cell and Recurrence、Metastasis
Purpose:To detect the CD44+/CD24-tumor cell proportions difference between primary lesion and recurrence lesion. To detect the ALDH1-positive tumor cell difference between primary lesion and recurrence lesion.
Methods:Primary breast cancer patients (n=121) treated in Peking Union Medical College Hospital were included in the study. The study included paraffin embedded tissue of 27 patients with primary lesion and 27 patients with recurrence lesion. CD44+/CD24- tumor cell proportions were detected by double-staining immunofluorescence and ALDH1 tumor cells were detected by immunohistochemistry.
Results:Although CD44+/CD24-cell proportions was higher in recurrence lesion, compared with primary lesion, there was no significant difference between two teams. Although the percentage of ALDH1-positive in recurrence lesion was higher, compared with primary lesion, there was no significant difference between two teams. The extent of ALDH1(+) positive of primary lesion in patients with recurrence or metastasis was higher, compared with patients without recurrence or metastasis. It suggest that breast cancer with ALDH1-positive may be associated with tumor progression.
Conclusion:ALDH1 may be associated with tumor progression.
Part 3
The Association between NOTCH Signaling Pathway and Breast Cancer Stem Cell
Purpose:To analyze the association between NOTCH signaling pathway and breast cancer stem cell with CD44+/CD24-characteristics. To analyze the association between NOTCH signaling pathway and breast cancer stem cell with ALDH1-positive characteristics.
Methods:Primary breast cancer patients (n=43) treated in Peking Union Medical College Hospital were included in the study. The study included paraffin embedded tissue and fresh tissue. CD44+/CD24-tumor cell proportions were detected by double-staining immunofluorescence and ALDH1 tumor cells and NOTCH 1 were detected by immunohistochemistry. Evaluation was obtained by microscopic pathologic inspection and automated image analysis. NOTCH 1 m RNA was detected by real-time fluorogenetic quantitative PCR.
Results:Although NOTCH 1 mRNA was higher in ALDH1-positive breast cancer compared with ALDH1-negative breast cancer and NOTCH 1 protein was higher in ALDH1-positive breast cancer, compared with ALDH1-negative breast cancer, there was no significant association between NOTH signaling pathway and breast cancer stem cell with ALDH1 characteristics. Although NOTCH1 mRNA was higher in patients with D44+/CD24-cell proportion=0%compared with patients with CD44+/CD24-cell proportion>0%, and NOTCH 1 protein was higher in patients with D44+/CD24-cell proportion=0%compared with patients with CD44+/CD24- cell proportion>0%, there was no significant association between NOTH signaling pathway and breast cancer stem cell with CD44+/CD24-
Conclusion:The association can not be demonstrated between NOTCH signaling pathway and tumor stem cells identified by CD44+/CD24- or ALDH1.
乳腺癌干细胞与乳腺癌预后的相关性研究
目的：分析CD44+／CD24乳腺癌干细胞、ALDH1+乳腺癌干细胞与临床预后的相关性。
方法：选取121例在我院治疗的原发性乳腺癌患者,收集其石蜡包埋的原发灶121例。免疫组织化学荧光双染法测定乳腺癌干细胞CD44、CD24的表达,免疫组织化学酶标法测定乳腺癌干细胞ALDH1的表达。应用镜下观察及图像处理软件分析其结果。
结果：原发病灶中CD44+／CD24-肿瘤干细胞含量范围0%--70%,中位5.8%。CD44+／CD24-肿瘤细胞干细胞含量与其他病理特征,包括(肿瘤体积、病理分期、LN、ER、PR、HER-2)无明显相关性。CD44+／CD24-肿瘤干细胞含量与乳腺癌的复发、转移无明显相关性。CD44+／CD24-肿瘤干细胞阳性率与三阴性乳腺癌无明显相关性。CD44+／CD24-肿瘤干细胞＝0%组与CD44+／CD24-肿瘤干细胞>0%组间DFS无统计学意义。原发病灶中,ALDH1阳性率54.6%。ALDH1与与其他病理特征,包括(肿瘤体积、病理分期、LN、ER、PR、HER-2)无明显相关性。ALDH1阳性率在SR(-)HER-2(-)组55.7%,较非SR(-)HER-2(-)组阳性率45.0%高,但P>0.05,无统计学差异。故ALDH1与三阴性乳腺癌无明显相关性。CD44+／CD24-肿瘤干细胞中位含量在ALDH1(+)组9.9%,高于ALDH1(-)组6.3%,但P>0.05,尚不能说明两组间CD44+／CD24-肿瘤干细胞含量有显著性差异。ALDH1(+)组与ALDH1(-)组间DFS无显著性差异。因此,ALDH1与乳腺癌预后无明显相关性。
结论：未发现CD44+／CD24-肿瘤干细胞、ALDH1肿瘤干细胞与乳腺癌的复发、转移有相关性。未发现CD44+／CD24-肿瘤干细胞、ALDH1乳腺癌干细胞与三阴性乳腺癌有相关性。未发现CD44+／CD24-肿瘤干细胞、ALDH1乳腺癌干细胞与乳腺癌患者的临床预后有相关性。乳腺癌患者中,以ALDH1为特征的肿瘤干细胞与以CD44+／CD24-为特征的肿瘤干细胞无相关性。
第二部分
乳腺癌干细胞与复发、转移的相关性研究
目的：检测CD44+/CD24-乳腺癌干细胞在原发灶与复发灶中的区别。
检测ALDH1乳腺癌干细胞在原发灶与复发灶中的区别。
方法：121例在我院手术的原发性乳腺癌患者中,选取其中复发、转移患者27例,收集其石蜡包埋的原发灶和复发病灶。免疫组织化学荧光双染法测定乳腺癌干细胞CD44、CD24的表达,免疫组织化学酶标法测定乳腺癌干细胞ALDH1的表达。应用镜下观察及图像处理软件分析其结果。
结果：复发患者中,CD44+/CD24-肿瘤细胞在复发灶中的含量(中位26.9%)高于原发灶的含量(中位7.0%),但P>0.05,不能说明两组间乳腺癌干细胞含量有显著性差异。在复发患者中,ALDH1阳性率在复发灶中60%(9／15),略高于原发灶57.1%(12／21),但P>0.05,尚不能说明两组间ALDH1阳性率有显著性差异。原发病灶的ALDH1阳性表达强度,在有复发、转移患者组中高于无复发、转移的患者组,P<0.005,说明ALDH1与患者的复发、转移有相关性。虽然在第一部分中,ALDH1与患者的DFS无关系,但此结果提示ALDH1 (+)的乳腺癌患者更易出现复发、转移。
结论：ALDH1(+)的乳腺癌患者更易出现复发、转移。
第三部分：
NOTC H信号通路与乳腺癌干细胞的相关性研究
目的：分析NOTCH通路与以ALDH1为代表的乳腺癌干细胞的关系。分析NOTCH通路与以CD44+/CD24为代表的乳腺癌干细胞的关系
方法：收集43例原发性乳腺癌患者,收集其新鲜组织标本及石蜡包埋的原发灶,免疫组织化学荧光双染法测定乳腺癌干细胞CD44、CD24的表达,免疫组织化学酶标法测定乳腺癌干细胞ALDH1及NOTCH1的表达。应用镜下观察及图像处理软件分析其结果。应用荧光定量PCR检测NOTCH1的mRNA的表达。
结果：乳腺癌患者中,NOTCH 1 mRNA的表达在ALDH1(+)组高于ALDH1(-)组,但P>0.05,尚不能说明两组间NOTCH1的mRNA的表达有显著性差异。NOTCH 1蛋白表达在在ALDH1 (+)组阳性率88.2%(15／17),略高于ALDH1(·)组85%(17／20),但P>0.05,尚不能说明两组间NOTCH1蛋白表达有显著性差异。虽然NOTCH 1mRNA的转录水平在ALDH1 (+)组中高,NOTCH1蛋白表达的阳性率也在ALDH1 (+)组中高,但P均>0.05,尚不能说明在乳腺癌患者中,NOTCH1通路与以ALDH1为特征的肿瘤干细胞之间有联系。NOTCH 1mRNA的表达在CD44+/CD24-肿瘤干细胞含量＝0%组,高于CD44+/CD24-仲瘤干细胞含量>0%组。NOTCH1蛋白表达在CD44+/CD24-肿瘤干细胞含量=0%组,阳性率91.7%(11／12)高于在CD44+/CD24肿瘤细胞含量>0%组,阳性率85.2%(23／27)。虽然NOTCH 1 mRNA表达量与NOTCH1蛋白表达量均在CD44+/CD24-肿瘤干细胞=0%组高。但P均>0.05,尚不能说明NOTCH与以CD44+/CD24-为特征的肿瘤干细胞之间有相关性。
结论：未发现乳腺癌患者中,NOTCH信号通路与以ALDH1为特征的肿瘤干细胞的有相关性。未发现乳腺癌患者中,NOTCH通路与以CD44+/CD24-为特征的乳腺癌干细胞的有相关性。
Part1
The Association between Breast Cancer Stem cell and Clinical Outcome
Purpose:To investigate the relevance between clinical prognosis and breast cancer stem cell with CD44+/CD24- characteristics. To investigate the relevance between clinical prognosis and breast cancer stem cell with ALDH1-positive characteristics.
Methods:Primary breast cancer patients (n=121) treated in Peking Union Medical College Hospital were included in the study. The study included paraffin embedded tissue of 121 patients with primary lesion. CD44+/CD24-tumor cell proportions were detected by double-staining immunofluorescence and ALDH1 tumor cells were detected by immunohistochemistry.
Results:There was no significant correlation between CD44+/CD24-cell and other clinical characteristics.There was no significant correlation between CD44+/CD24-cell and tumor progression. The association can not be demonstrated between ER(-)HER-2(-) breast cancer and CD44+/CD24- cell. There was no significant correlation between CD44+/CD24" cell and clinical prognosis. There was no significant correlation between ALDH1 and other clinical characteristics. The association can not be demonstrated between ER(-)HER-2(-) breast cancer and ALDH1. There was no significant difference of CD44+/CD24- cell proportions between ALDH1-positive breast cancer and ALDH1-negtive breast cancer. There was no significant correlation between ALDH1 and clinical prognosis.
Conclusion:Prevelence of CD44+/CD24" tumor cell or ALDH1 may not be associatied with clinical outcome and disease-free survival. There was no significant correlation between tumor stem cell identified by CD44+/CD24- and ER(-)HER-2(-) breast cancer. There was no significant correlation between tumor stem cell identified by ALDH1 and ER(-)HER-2(-) breast cancer.
Part 2
The Association between Breast Cancer Stem Cell and Recurrence、Metastasis
Purpose:To detect the CD44+/CD24-tumor cell proportions difference between primary lesion and recurrence lesion. To detect the ALDH1-positive tumor cell difference between primary lesion and recurrence lesion.
Methods:Primary breast cancer patients (n=121) treated in Peking Union Medical College Hospital were included in the study. The study included paraffin embedded tissue of 27 patients with primary lesion and 27 patients with recurrence lesion. CD44+/CD24- tumor cell proportions were detected by double-staining immunofluorescence and ALDH1 tumor cells were detected by immunohistochemistry.
Results:Although CD44+/CD24-cell proportions was higher in recurrence lesion, compared with primary lesion, there was no significant difference between two teams. Although the percentage of ALDH1-positive in recurrence lesion was higher, compared with primary lesion, there was no significant difference between two teams. The extent of ALDH1(+) positive of primary lesion in patients with recurrence or metastasis was higher, compared with patients without recurrence or metastasis. It suggest that breast cancer with ALDH1-positive may be associated with tumor progression.
Conclusion:ALDH1 may be associated with tumor progression.
Part 3
The Association between NOTCH Signaling Pathway and Breast Cancer Stem Cell
Purpose:To analyze the association between NOTCH signaling pathway and breast cancer stem cell with CD44+/CD24-characteristics. To analyze the association between NOTCH signaling pathway and breast cancer stem cell with ALDH1-positive characteristics.
Methods:Primary breast cancer patients (n=43) treated in Peking Union Medical College Hospital were included in the study. The study included paraffin embedded tissue and fresh tissue. CD44+/CD24-tumor cell proportions were detected by double-staining immunofluorescence and ALDH1 tumor cells and NOTCH 1 were detected by immunohistochemistry. Evaluation was obtained by microscopic pathologic inspection and automated image analysis. NOTCH 1 m RNA was detected by real-time fluorogenetic quantitative PCR.
Results:Although NOTCH 1 mRNA was higher in ALDH1-positive breast cancer compared with ALDH1-negative breast cancer and NOTCH 1 protein was higher in ALDH1-positive breast cancer, compared with ALDH1-negative breast cancer, there was no significant association between NOTH signaling pathway and breast cancer stem cell with ALDH1 characteristics. Although NOTCH1 mRNA was higher in patients with D44+/CD24-cell proportion=0%compared with patients with CD44+/CD24-cell proportion>0%, and NOTCH 1 protein was higher in patients with D44+/CD24-cell proportion=0%compared with patients with CD44+/CD24- cell proportion>0%, there was no significant association between NOTH signaling pathway and breast cancer stem cell with CD44+/CD24-
Conclusion:The association can not be demonstrated between NOTCH signaling pathway and tumor stem cells identified by CD44+/CD24- or ALDH1.
引文
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10. Honeth G, Bendahl PO, Ringner M, Saal LH, Gruvberger-Saal SK, Lovgren K, et al. The CD44+/CD24-phenotype is enriched in basal-like breast tumors. Breast Cancer Res.2008;10(3):R53.
11. Abraham BK, Fritz P, McClellan M, Hauptvogel P, Athelogou M, Brauch H. Prevalence of CD44+/CD24-/low cells in breast cancer may not be associated with clinical outcome but may favor distant metastasis. Clin Cancer Res.2005 Feb 1;11(3):1154-9.
12. Ginestier C, Charafe-Jauffret E, Bertucci F, Eisinger F, Geneix J, Bechlian D, et al. Distinct and complementary information provided by use of tissue and DNA microarrays in the study of breast
tumor markers. Am J Pathol.2002 Oct;161(4):1223-33.
13. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med.1997 Jul;3(7):730-7.
14. Lodie TA, Blickarz CE, Devarakonda TJ, He C, Dash AB, Clarke J, et al. Systematic analysis of reportedly distinct populations of multipotent bone marrow-derived stem cells reveals a lack of distinction. Tissue Eng.2002 Oct;8(5):739-51.
15. Sheridan C, Kishimoto H, Fuchs RK, Mehrotra S, Bhat-Nakshatri P, Turner CH, et al. CD44+/CD24-breast cancer cells exhibit enhanced invasive properties:an early step necessary for metastasis. Breast Cancer Res.2006;8(5):R59.
16. Balic M, Lin H, Young L, Hawes D, Giuliano A, McNamara G, et al. Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype. Clin Cancer Res.2006 Oct 1;12(19):5615-21.
17. Chute JP, Muramoto GG, Whitesides J, Colvin M, Safi R, Chao NJ, et al. Inhibition of aldehyde dehydrogenase and retinoid signaling induces the expansion of human hematopoietic stem cells. Proc Natl Acad Sci USA.2006 Aug 1;103(31):11707-12.
18. Tanei T, Morimoto K, Shimazu K, Kim SJ, Tanji Y, Taguchi T, et al. Association of breast cancer stem cells identified by aldehyde dehydrogenase 1 expression with resistance to sequential Paclitaxel and epirubicin-based chemotherapy for breast cancers. Clin Cancer Res.2009 Jun 15;15(12):4234-41.
19. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature.2000 Aug 17;406(6797):747-52.
20. Kreike B, van Kouwenhove M, Horlings H, Weigelt B, Peterse H, Bartelink H, et al. Gene expression profiling and histopathological characterization of triple-negative/basal-like breast carcinomas. Breast Cancer Res.2007;9(5):R65.
21. Pritchard KI, Shepherd LE, O'Malley FP, Andrulis IL, Tu D, Bramwell VH, et al. HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med.2006 May 18;354(20):2103-11.
22. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med.2005 Oct 20;353(16):1659-72.
23. Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res.2004 Aug15;10(16):5367-74.
24. Nakshatri H, Srour EF, Badve S. Breast cancer stem cells and intrinsic subtypes:controversies rage on. Curr Stem Cell Res Ther.2009 Jan;4(1):50-60.
25. Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA. 2001 Sep 11;98(19):10869-74.
26. Smid M, Wang Y, Zhang Y, Sieuwerts AM, Yu J, Klijn JG, et al. Subtypes of breast cancer show preferential site of relapse. Cancer Res.2008 May 1;68(9):3108-14.
27. Ponti D, Costa A, Zaffaroni N, Pratesi G, Petrangolini G, Coradini D, et al. Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res.2005 Jul 1;65(13):5506-11.
28. Neve RM, Chin K, Fridlyand J, Yeh J, Baehner FL, Fevr T, et al. A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell.2006 Dec; 10(6):515-27.
29. Korkaya H, Paulson A, Iovino F, Wicha MS. HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion. Oncogene.2008 Oct 16;27(47):6120-30.
30. Engelmann K, Shen H, Finn OJ. MCF7 side population cells with characteristics of cancer stem/progenitor cells express the tumor antigen MUC1. Cancer Res.2008 Apr 1;68(7):2419-26.
31. Zhang M, Behbod F, Atkinson RL, Landis MD, Kittrell F, Edwards D, et al. Identification of tumor-initiating cells in a p53-null mouse model of breast cancer. Cancer Res.2008 Jun 15;68(12):4674-82.
32. Molyneux G, Regan J, Smalley MJ. Mammary stem cells and breast cancer. Cell Mol Life Sci. 2007 Dec;64(24):3248-60.
33. Dontu G, El-Ashry D, Wicha MS. Breast cancer, stem/progenitor cells and the estrogen receptor. Trends Endocrinol Metab.2004 Jul; 15(5):193-7.
34. Liu R, Wang X, Chen GY, Dalerba P, Gurney A, Hoey T, et al. The prognostic role of a gene signature from tumorigenic breast-cancer cells. N Engl J Med.2007 Jan 18;356(3):217-26.
35. Phillips TM, McBride WH, Pajonk F. The response of CD24(-/low)/CD44+breast cancer-initiating cells to radiation. J Natl Cancer Inst.2006 Dec 20;98(24):1777-85.
36. Woodward WA, Chen MS, Behbod F, Alfaro MP, Buchholz TA, Rosen JM. WNT/beta-catenin mediates radiation resistance of mouse mammary progenitor cells. Proc Natl Acad Sci USA.2007 Jan 9;104(2):618-23.
37. Chen MS, Woodward WA, Behbod F, Peddibhotla S, Alfaro MP, Buchholz TA, et al. Wnt/beta-catenin mediates radiation resistance of Scal+progenitors in an immortalized mammary gland cell line. J Cell Sci.2007 Feb 1;120(Pt 3):468-77.
38. Leong KG, Karsan A. Recent insights into the role of Notch signaling in tumorigenesis. Blood. 2006 Mar 15;107(6):2223-33.
39. Chiba S. Notch signaling in stem cell systems. Stem Cells.2006 Nov;24(11):2437-47.
40. Carlson ME, Conboy IM. Regulating the Notch pathway in embryonic, adult and old stem cells. Curr Opin Pharmacol.2007 Jun;7(3):303-9.
41. Weinmaster G. The ins and outs of notch signaling. Mol Cell Neurosci.1997;9(2):91-102.
42. Grego-Bessa J, Diez J, Timmerman L, de la Pompa JL. Notch and epithelial-mesenchyme transition in development and tumor progression:another turn of the screw. Cell Cycle.2004 Jun;3(6):718-21.
43. Gaiano N, Fishell G. The role of notch in promoting glial and neural stem cell fates. Annu Rev Neurosci.2002;25:471-90.
44. Harrison H, Farnie G, Howell SJ, Rock RE, Stylianou S, Brennan KR, et al. Regulation of breast cancer stem cell activity by signaling through the Notch4 receptor. Cancer Res. Jan 15;70(2):709-18.
45. Lefort K, Dotto GP. Notch signaling in the integrated control of keratinocyte growth/differentiation and tumor suppression. Semin Cancer Biol.2004 Oct;14(5):374-86.
46. Radtke F, Clevers H. Self-renewal and cancer of the gut:two sides of a coin. Science.2005 Mar 25;307(5717):1904-9.
47. Ehebauer M, Hayward P, Martinez-Arias A. Notch signaling pathway. Sci STKE.2006 Dec 5;2006(364):cm7.
48. Carlson ME, O'Connor MS, Hsu M, Conboy IM. Notch signaling pathway and tissue engineering. Front Biosci.2007;12:5143-56.
49. Lai EC. Protein degradation:four E3s for the notch pathway. Curr Biol.2002 Jan 22;12(2):R74-8.
50. Martinez Arias A, Zecchini V, Brennan K. CSL-independent Notch signalling:a checkpoint in cell fate decisions during development? Curr Opin Genet Dev.2002 Oct;12(5):524-33.
51. Purow BW, Haque RM, Noel MW, Su Q, Burdick MJ, Lee J, et al. Expression of Notch-1 and its ligands, Delta-like-1 and Jagged-1, is critical for glioma cell survival and proliferation. Cancer Res. 2005 Mar 15;65(6):2353-63.
52. Nickoloff BJ, Osborne BA, Miele L. Notch signaling as a therapeutic target in cancer:a new approach to the development of cell fate modifying agents. Oncogene.2003 Sep 29;22(42):6598-608.
53. Fan X, Mikolaenko I, Elhassan I, Ni X, Wang Y, Ball D, et al. Notchl and notch2 have opposite effects on embryonal brain tumor growth. Cancer Res.2004 Nov 1;64(21):7787-93.
54. MacKenzie F, Duriez P, Wong F, Noseda M, Karsan A. Notch4 inhibits endothelial apoptosis via RBP-Jkappa-dependent and-independent pathways. J Biol Chem.2004 Mar 19;279(12):11657-63.
55. Nair P, Somasundaram K, Krishna S. Activated Notchl inhibits p53-induced apoptosis and sustains transformation by human papillomavirus type 16 E6 and E7 oncogenes through a PI3K-PKB/Akt-dependent pathway. J Virol.2003 Jun;77(12):7106-12.
56. Nickoloff BJ, Qin JZ, Chaturvedi V, Denning MF, Bonish B, Miele L. Jagged-1 mediated activation of notch signaling induces complete maturation of human keratinocytes through NF-kappaB and PPARgamma. Cell Death Differ.2002 Aug;9(8):842-55.
57. Murata K, Hattori M, Hirai N, Shinozuka Y, Hirata H, Kageyama R, et al. Hesl directly controls cell proliferation through the transcriptional repression of p27Kip1. Mol Cell Biol.2005 May;25(10):4262-71.
58. Sarmento LM, Huang H, Limon A, Gordon W, Fernandes J, Tavares MJ, et al. Notchl modulates timing of G1-S progression by inducing SKP2 transcription and p27 Kipl degradation. J Exp Med. 2005Jul4;202(1):157-68.
59. Masuda S, Kumano K, Shimizu K, Imai Y, Kurokawa M, Ogawa S, et al. Notchl oncoprotein antagonizes TGF-beta/Smad-mediated cell growth suppression via sequestration of coactivator p300. Cancer Sci.2005 May;96(5):274-82.
60. Zavadil J, Cermak L, Soto-Nieves N, Bottinger EP. Integration of TGF-beta/Smad and Jaggedl/Notch signalling in epithelial-to-mesenchymal transition. EMBO J.2004 Mar 10;23(5):1155-65.
61. Timmerman LA, Grego-Bessa J, Raya A, Bertran E, Perez-Pomares JM, Diez J, et al. Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. Genes Dev.2004 Jan 1;18(1):99-115.
62. Hayward SD. Viral interactions with the Notch pathway. Semin Cancer Biol.2004 Oct;14(5):387-96.
63. Nicolas M, Wolfer A, Raj K, Kummer JA, Mill P, van Noort M, et al. Notchl functions as a tumor suppressor in mouse skin. Nat Genet.2003 Mar;33(3):416-21.
64. Sriuranpong V, Borges MW, Ravi RK, Arnold DR, Nelkin BD, Baylin SB, et al. Notch signaling induces cell cycle arrest in small cell lung cancer cells. Cancer Res.2001 Apr 1;61(7):3200-5.
65. Curry CL, Reed LL, Golde TE, Miele L, Nickoloff BJ, Foreman KE. Gamma secretase inhibitor blocks Notch activation and induces apoptosis in Kaposi's sarcoma tumor cells. Oncogene.2005 Sep 22;24(42):6333-44.
66. Noseda M, Chang L, McLean G, Grim JE, Clurman BE, Smith LL, et al. Notch activation induces endothelial cell cycle arrest and participates in contact inhibition:role of p21Cip1 repression. Mol Cell Biol.2004 Oct;24(20):8813-22.
67. Qi R, An H, Yu Y, Zhang M, Liu S, Xu H, et al. Notchl signaling inhibits growth of human hepatocellular carcinoma through induction of cell cycle arrest and apoptosis. Cancer Res.2003 Dec 1;63(23):8323-9.
68. Kadesch T. Notch signaling:a dance of proteins changing partners. Exp Cell Res.2000 Oct 10;260(1):1-8.
2. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001 Nov1;414(6859):105-11.
3. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA.2003 Apr 1;100(7):3983-8.
4. Shipitsin M, Campbell LL, Argani P, Weremowicz S, Bloushtain-Qimron N, Yao J, et al. Molecular definition of breast tumor heterogeneity. Cancer Cell.2007 Mar;11(3):259-73.
5. Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell.2007 Nov;1(5):555-67.
6. Dontu G, Jackson KW, McNicholas E, Kawamura MJ, Abdallah WM, Wicha MS. Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells. Breast Cancer Res. 2004;6(6):R605-15.
7. Callahan R, Egan SE. Notch signaling in mammary development and oncogenesis. J Mammary Gland Biol Neoplasia.2004 Apr;9(2):145-63.
8. Patrawala L, Calhoun T, Schneider-Broussard R, Zhou J, Claypool K, Tang DG. Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+and ABCG2-cancer cells are similarly tumorigenic. Cancer Res.2005 Jul 15;65(14):6207-19.
9. Weijzen S, Rizzo P, Braid M, Vaishnav R, Jonkheer SM, Zlobin A, et al. Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells. Nat Med.2002 Sep;8(9):979-86.
10. Honeth G, Bendahl PO, Ringner M, Saal LH, Gruvberger-Saal SK, Lovgren K, et al. The CD44+/CD24-phenotype is enriched in basal-like breast tumors. Breast Cancer Res.2008;10(3):R53.
11. Abraham BK, Fritz P, McClellan M, Hauptvogel P, Athelogou M, Brauch H. Prevalence of CD44+/CD24-/low cells in breast cancer may not be associated with clinical outcome but may favor distant metastasis. Clin Cancer Res.2005 Feb 1;11(3):1154-9.
12. Ginestier C, Charafe-Jauffret E, Bertucci F, Eisinger F, Geneix J, Bechlian D, et al. Distinct and complementary information provided by use of tissue and DNA microarrays in the study of breast
tumor markers. Am J Pathol.2002 Oct;161(4):1223-33.
13. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med.1997 Jul;3(7):730-7.
14. Lodie TA, Blickarz CE, Devarakonda TJ, He C, Dash AB, Clarke J, et al. Systematic analysis of reportedly distinct populations of multipotent bone marrow-derived stem cells reveals a lack of distinction. Tissue Eng.2002 Oct;8(5):739-51.
15. Sheridan C, Kishimoto H, Fuchs RK, Mehrotra S, Bhat-Nakshatri P, Turner CH, et al. CD44+/CD24-breast cancer cells exhibit enhanced invasive properties:an early step necessary for metastasis. Breast Cancer Res.2006;8(5):R59.
16. Balic M, Lin H, Young L, Hawes D, Giuliano A, McNamara G, et al. Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype. Clin Cancer Res.2006 Oct 1;12(19):5615-21.
17. Chute JP, Muramoto GG, Whitesides J, Colvin M, Safi R, Chao NJ, et al. Inhibition of aldehyde dehydrogenase and retinoid signaling induces the expansion of human hematopoietic stem cells. Proc Natl Acad Sci USA.2006 Aug 1;103(31):11707-12.
18. Tanei T, Morimoto K, Shimazu K, Kim SJ, Tanji Y, Taguchi T, et al. Association of breast cancer stem cells identified by aldehyde dehydrogenase 1 expression with resistance to sequential Paclitaxel and epirubicin-based chemotherapy for breast cancers. Clin Cancer Res.2009 Jun 15;15(12):4234-41.
19. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature.2000 Aug 17;406(6797):747-52.
20. Kreike B, van Kouwenhove M, Horlings H, Weigelt B, Peterse H, Bartelink H, et al. Gene expression profiling and histopathological characterization of triple-negative/basal-like breast carcinomas. Breast Cancer Res.2007;9(5):R65.
21. Pritchard KI, Shepherd LE, O'Malley FP, Andrulis IL, Tu D, Bramwell VH, et al. HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med.2006 May 18;354(20):2103-11.
22. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med.2005 Oct 20;353(16):1659-72.
23. Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res.2004 Aug15;10(16):5367-74.
24. Nakshatri H, Srour EF, Badve S. Breast cancer stem cells and intrinsic subtypes:controversies rage on. Curr Stem Cell Res Ther.2009 Jan;4(1):50-60.
25. Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA. 2001 Sep 11;98(19):10869-74.
26. Smid M, Wang Y, Zhang Y, Sieuwerts AM, Yu J, Klijn JG, et al. Subtypes of breast cancer show preferential site of relapse. Cancer Res.2008 May 1;68(9):3108-14.
27. Ponti D, Costa A, Zaffaroni N, Pratesi G, Petrangolini G, Coradini D, et al. Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res.2005 Jul 1;65(13):5506-11.
28. Neve RM, Chin K, Fridlyand J, Yeh J, Baehner FL, Fevr T, et al. A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell.2006 Dec; 10(6):515-27.
29. Korkaya H, Paulson A, Iovino F, Wicha MS. HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion. Oncogene.2008 Oct 16;27(47):6120-30.
30. Engelmann K, Shen H, Finn OJ. MCF7 side population cells with characteristics of cancer stem/progenitor cells express the tumor antigen MUC1. Cancer Res.2008 Apr 1;68(7):2419-26.
31. Zhang M, Behbod F, Atkinson RL, Landis MD, Kittrell F, Edwards D, et al. Identification of tumor-initiating cells in a p53-null mouse model of breast cancer. Cancer Res.2008 Jun 15;68(12):4674-82.
32. Molyneux G, Regan J, Smalley MJ. Mammary stem cells and breast cancer. Cell Mol Life Sci. 2007 Dec;64(24):3248-60.
33. Dontu G, El-Ashry D, Wicha MS. Breast cancer, stem/progenitor cells and the estrogen receptor. Trends Endocrinol Metab.2004 Jul; 15(5):193-7.
34. Liu R, Wang X, Chen GY, Dalerba P, Gurney A, Hoey T, et al. The prognostic role of a gene signature from tumorigenic breast-cancer cells. N Engl J Med.2007 Jan 18;356(3):217-26.
35. Phillips TM, McBride WH, Pajonk F. The response of CD24(-/low)/CD44+breast cancer-initiating cells to radiation. J Natl Cancer Inst.2006 Dec 20;98(24):1777-85.
36. Woodward WA, Chen MS, Behbod F, Alfaro MP, Buchholz TA, Rosen JM. WNT/beta-catenin mediates radiation resistance of mouse mammary progenitor cells. Proc Natl Acad Sci USA.2007 Jan 9;104(2):618-23.
37. Chen MS, Woodward WA, Behbod F, Peddibhotla S, Alfaro MP, Buchholz TA, et al. Wnt/beta-catenin mediates radiation resistance of Scal+progenitors in an immortalized mammary gland cell line. J Cell Sci.2007 Feb 1;120(Pt 3):468-77.
38. Leong KG, Karsan A. Recent insights into the role of Notch signaling in tumorigenesis. Blood. 2006 Mar 15;107(6):2223-33.
39. Chiba S. Notch signaling in stem cell systems. Stem Cells.2006 Nov;24(11):2437-47.
40. Carlson ME, Conboy IM. Regulating the Notch pathway in embryonic, adult and old stem cells. Curr Opin Pharmacol.2007 Jun;7(3):303-9.
41. Weinmaster G. The ins and outs of notch signaling. Mol Cell Neurosci.1997;9(2):91-102.
42. Grego-Bessa J, Diez J, Timmerman L, de la Pompa JL. Notch and epithelial-mesenchyme transition in development and tumor progression:another turn of the screw. Cell Cycle.2004 Jun;3(6):718-21.
43. Gaiano N, Fishell G. The role of notch in promoting glial and neural stem cell fates. Annu Rev Neurosci.2002;25:471-90.
44. Harrison H, Farnie G, Howell SJ, Rock RE, Stylianou S, Brennan KR, et al. Regulation of breast cancer stem cell activity by signaling through the Notch4 receptor. Cancer Res. Jan 15;70(2):709-18.
45. Lefort K, Dotto GP. Notch signaling in the integrated control of keratinocyte growth/differentiation and tumor suppression. Semin Cancer Biol.2004 Oct;14(5):374-86.
46. Radtke F, Clevers H. Self-renewal and cancer of the gut:two sides of a coin. Science.2005 Mar 25;307(5717):1904-9.
47. Ehebauer M, Hayward P, Martinez-Arias A. Notch signaling pathway. Sci STKE.2006 Dec 5;2006(364):cm7.
48. Carlson ME, O'Connor MS, Hsu M, Conboy IM. Notch signaling pathway and tissue engineering. Front Biosci.2007;12:5143-56.
49. Lai EC. Protein degradation:four E3s for the notch pathway. Curr Biol.2002 Jan 22;12(2):R74-8.
50. Martinez Arias A, Zecchini V, Brennan K. CSL-independent Notch signalling:a checkpoint in cell fate decisions during development? Curr Opin Genet Dev.2002 Oct;12(5):524-33.
51. Purow BW, Haque RM, Noel MW, Su Q, Burdick MJ, Lee J, et al. Expression of Notch-1 and its ligands, Delta-like-1 and Jagged-1, is critical for glioma cell survival and proliferation. Cancer Res. 2005 Mar 15;65(6):2353-63.
52. Nickoloff BJ, Osborne BA, Miele L. Notch signaling as a therapeutic target in cancer:a new approach to the development of cell fate modifying agents. Oncogene.2003 Sep 29;22(42):6598-608.
53. Fan X, Mikolaenko I, Elhassan I, Ni X, Wang Y, Ball D, et al. Notchl and notch2 have opposite effects on embryonal brain tumor growth. Cancer Res.2004 Nov 1;64(21):7787-93.
54. MacKenzie F, Duriez P, Wong F, Noseda M, Karsan A. Notch4 inhibits endothelial apoptosis via RBP-Jkappa-dependent and-independent pathways. J Biol Chem.2004 Mar 19;279(12):11657-63.
55. Nair P, Somasundaram K, Krishna S. Activated Notchl inhibits p53-induced apoptosis and sustains transformation by human papillomavirus type 16 E6 and E7 oncogenes through a PI3K-PKB/Akt-dependent pathway. J Virol.2003 Jun;77(12):7106-12.
56. Nickoloff BJ, Qin JZ, Chaturvedi V, Denning MF, Bonish B, Miele L. Jagged-1 mediated activation of notch signaling induces complete maturation of human keratinocytes through NF-kappaB and PPARgamma. Cell Death Differ.2002 Aug;9(8):842-55.
57. Murata K, Hattori M, Hirai N, Shinozuka Y, Hirata H, Kageyama R, et al. Hesl directly controls cell proliferation through the transcriptional repression of p27Kip1. Mol Cell Biol.2005 May;25(10):4262-71.
58. Sarmento LM, Huang H, Limon A, Gordon W, Fernandes J, Tavares MJ, et al. Notchl modulates timing of G1-S progression by inducing SKP2 transcription and p27 Kipl degradation. J Exp Med. 2005Jul4;202(1):157-68.
59. Masuda S, Kumano K, Shimizu K, Imai Y, Kurokawa M, Ogawa S, et al. Notchl oncoprotein antagonizes TGF-beta/Smad-mediated cell growth suppression via sequestration of coactivator p300. Cancer Sci.2005 May;96(5):274-82.
60. Zavadil J, Cermak L, Soto-Nieves N, Bottinger EP. Integration of TGF-beta/Smad and Jaggedl/Notch signalling in epithelial-to-mesenchymal transition. EMBO J.2004 Mar 10;23(5):1155-65.
61. Timmerman LA, Grego-Bessa J, Raya A, Bertran E, Perez-Pomares JM, Diez J, et al. Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. Genes Dev.2004 Jan 1;18(1):99-115.
62. Hayward SD. Viral interactions with the Notch pathway. Semin Cancer Biol.2004 Oct;14(5):387-96.
63. Nicolas M, Wolfer A, Raj K, Kummer JA, Mill P, van Noort M, et al. Notchl functions as a tumor suppressor in mouse skin. Nat Genet.2003 Mar;33(3):416-21.
64. Sriuranpong V, Borges MW, Ravi RK, Arnold DR, Nelkin BD, Baylin SB, et al. Notch signaling induces cell cycle arrest in small cell lung cancer cells. Cancer Res.2001 Apr 1;61(7):3200-5.
65. Curry CL, Reed LL, Golde TE, Miele L, Nickoloff BJ, Foreman KE. Gamma secretase inhibitor blocks Notch activation and induces apoptosis in Kaposi's sarcoma tumor cells. Oncogene.2005 Sep 22;24(42):6333-44.
66. Noseda M, Chang L, McLean G, Grim JE, Clurman BE, Smith LL, et al. Notch activation induces endothelial cell cycle arrest and participates in contact inhibition:role of p21Cip1 repression. Mol Cell Biol.2004 Oct;24(20):8813-22.
67. Qi R, An H, Yu Y, Zhang M, Liu S, Xu H, et al. Notchl signaling inhibits growth of human hepatocellular carcinoma through induction of cell cycle arrest and apoptosis. Cancer Res.2003 Dec 1;63(23):8323-9.
68. Kadesch T. Notch signaling:a dance of proteins changing partners. Exp Cell Res.2000 Oct 10;260(1):1-8.