乳腺浸润性微乳头状癌中CD44~+/CD24~(-/low)和CD24~+的表达和意义
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摘要
目的:
乳腺浸润性微乳头状癌(Invasive micropapillary carcinoma,IMPC)是乳腺癌中的一种少见类型,具有特殊的形态学特征及高度的淋巴结转移和远处转移等预后不良生物学行为。乳腺癌中表型为CD44~+/CD24~(-/low)。W的肿瘤细胞具有干细胞的特性。研究乳腺浸润性微乳头状癌细胞干性表型,从干细胞和上皮间质转化(epithelial-mesenchymal transition,EMT)角度探讨IMPC高侵袭、高转移恶性生物学行为的原因。
方法:
选取术前未经放化疗治疗患者的乳腺IMPC 82例和非特殊型浸润性导管癌(invasive ductal carcinoma,not otherwise specified,IDC-NOS)80例石蜡包埋组织标本切片,通过免疫组织化学双染技术检测两组肿瘤组织中CD44~+/CD24~(-/low)和CD24~+的定位和分布情况,并结合临床病理学特征分析其表达和意义。
结果:
(1)与对照组IDC-NOS相比,IMPC组的肿瘤最大直径(t=3.000,P=0.003)、病理学分期(Z=-4.467,P=0.000)、淋巴结转移率(Z=-5.379,P=0.000)及淋巴结转移个数(IMPC平均10.85个;IDC-NOS平均5.11个;t=3.750,P=0.000)均明显高于IDC-NOS组,且IMPC还具有更高的淋巴管侵犯(Z=-7.310,P=0.000)及淋巴结外软组织浸润(Z=-2.526,P=0.012),差异均具有统计学意义
(2)IMPC组肿瘤细胞的CD44~+/CD24~(-/low)阳性率为(48.8%,40/82例),明显高于IDC-NOS组(31.3%,25/80例)(P=0.023);
(3)53.7%(44/82例)的IMPC间质组织内见单个散在的CD44~+/CD24~(-/low)肿瘤细胞,且该细胞免疫组化染色Vimentin及α-SMA阳性,E-Cadherin阴性。而IDC-NOS间质内罕见CD44~+/CD24~(-/low)肿瘤细胞;
(4)IMPC组中肿瘤细胞的CD44~+/CD24~(-/low)表达(48.8%)与间质内的CD44~+/CD24~(-/low)表达(53.7%)呈明显正相关(P=0.002),二者分别都与肿瘤细胞的淋巴管侵犯和淋巴结外软组织浸润呈明显正相关(P<0.05);
(5)IMPC组中CD24~+细胞阳性率为79.3%(65/82例),明显高于IDC-NOS组(60.0%,48/80例)(P=0.008),且IMPC中CD24~+的表达与淋巴结转移呈明显正相关(P=0.000)。
结论:
(1)IMPC具有比IDC-NOS更强的淋巴结转移能力,预后较差。
(2)IMPC的生物学行为并不取决于肿瘤中IMPC成分的多少。
(3)肿瘤大小、病理组织学分级与IMPC的淋巴结受累范围密切相关
(4)IMPC肿瘤细胞和其间质中存在一定数量的CD44~+/CD24~(-/low)表型细胞。提示IMPC肿瘤细胞中不乏干细胞的存在,同时在上皮-间质转化过程中少数肿瘤细胞可获得干性表型。这可能是IMPC高淋巴管侵犯、高淋巴结转移及耐药等恶性生物学行为的重要原因之一。
Objective:
Breast cancer cells with a CD44~+/CD24~(-/low)phenotype have been suggested to have tumor-initiating properties with stem cell-like invasive features.It is unclear whether their prevalence associates with clinicopathologic features of Invasive Micropapillary Carcinoma(IMPC) of the Breast,an unusal subtype of breast cancer with a high incidence of lymph node metastasis and poor prognosis.
Methods:
This study included 82 cases of IMPC and 80 cases of invasive ductal carcinoma, not otherwise specified(IDC-NOS),both without chemotherapy and radiotherapy before surgery.CD44 and CD24 expression was determined by double-staining immunohistochemistry in paraffin embedded tissue from each case.
Results:
(1) Compared with the control group of IDC-NOS,IMPC were larger in size (t＝3.000,p＝0.003,table 1),higher staged(Z=-4.467,P=0.000),had a higher lymph node metastasis rate(Z=-5.379,P=0.000,table 1) with more nodes involved per case(10.85 in IMPC versus 5.11 in IDC,t=3.750,P?0.000),and exhibited increased lymphovascular invasion(Z＝-7.310,P＝0.000 ) and extranodal extension(Z=-2.526,P≠0.012).
(2) The prevalence of CD44~+/CD24~(-/ low) tumor cells was higher in IMPC than in IDC- NOS(48.8%versus 31.3%,P=0.023).
(3) The CD44~+/CD24 ~(/low) tumor cells was also detected in adjacent stroma surrounding the micropapillary structure in 53.7%of IMPC,but scarcely in the stroma of IDC.These tumor cells in stroma of IMPC showed positive Vimentin and a-SMA,and negative E-Cadherin staining by immunohistochemistry.
(4) The CD44~+/CD24~(-/low) tumor cells in micropapillary structure of IMPC was associated with that in stroma(P=0.002),moreover,they were both associated with lymphovascular invasion and extranodal extension respectively(P＜0.05).
(5) The proportion of CD24~+ tumor cells was also higher in IMPC than IDC-NOS (79.3%versus 60.0%,P=0.008),and the CD24~+ tumor cells was associated with lymph node metastasis in IMPC(P=0.000).
(1) IMPC had a higher lymph node metastasis rate with more nodes involved per case and poor prognosis.
(2) The percentage of IMPC components in the whole tumor was not significantly associated with lymph node metastasis rate or the number of positive lymph nodes.
(3) In IMPC,tumor size and histological grade are closely related to the extent of lymph nodes involved,
(4) The increased proportion of CD44~+/CD24~(-/low) and CD24~+ tumor cells and the EMT(epithelial-mesenchymal transition) may play an important role in aggressiveness and higher metastatic risk of IMPC of the Breast.
乳腺浸润性微乳头状癌(Invasive micropapillary carcinoma,IMPC)是乳腺癌中的一种少见类型,具有特殊的形态学特征及高度的淋巴结转移和远处转移等预后不良生物学行为。乳腺癌中表型为CD44~+/CD24~(-/low)。W的肿瘤细胞具有干细胞的特性。研究乳腺浸润性微乳头状癌细胞干性表型,从干细胞和上皮间质转化(epithelial-mesenchymal transition,EMT)角度探讨IMPC高侵袭、高转移恶性生物学行为的原因。
方法:
选取术前未经放化疗治疗患者的乳腺IMPC 82例和非特殊型浸润性导管癌(invasive ductal carcinoma,not otherwise specified,IDC-NOS)80例石蜡包埋组织标本切片,通过免疫组织化学双染技术检测两组肿瘤组织中CD44~+/CD24~(-/low)和CD24~+的定位和分布情况,并结合临床病理学特征分析其表达和意义。
结果:
(1)与对照组IDC-NOS相比,IMPC组的肿瘤最大直径(t=3.000,P=0.003)、病理学分期(Z=-4.467,P=0.000)、淋巴结转移率(Z=-5.379,P=0.000)及淋巴结转移个数(IMPC平均10.85个;IDC-NOS平均5.11个;t=3.750,P=0.000)均明显高于IDC-NOS组,且IMPC还具有更高的淋巴管侵犯(Z=-7.310,P=0.000)及淋巴结外软组织浸润(Z=-2.526,P=0.012),差异均具有统计学意义
(2)IMPC组肿瘤细胞的CD44~+/CD24~(-/low)阳性率为(48.8%,40/82例),明显高于IDC-NOS组(31.3%,25/80例)(P=0.023);
(3)53.7%(44/82例)的IMPC间质组织内见单个散在的CD44~+/CD24~(-/low)肿瘤细胞,且该细胞免疫组化染色Vimentin及α-SMA阳性,E-Cadherin阴性。而IDC-NOS间质内罕见CD44~+/CD24~(-/low)肿瘤细胞;
(4)IMPC组中肿瘤细胞的CD44~+/CD24~(-/low)表达(48.8%)与间质内的CD44~+/CD24~(-/low)表达(53.7%)呈明显正相关(P=0.002),二者分别都与肿瘤细胞的淋巴管侵犯和淋巴结外软组织浸润呈明显正相关(P<0.05);
(5)IMPC组中CD24~+细胞阳性率为79.3%(65/82例),明显高于IDC-NOS组(60.0%,48/80例)(P=0.008),且IMPC中CD24~+的表达与淋巴结转移呈明显正相关(P=0.000)。
结论:
(1)IMPC具有比IDC-NOS更强的淋巴结转移能力,预后较差。
(2)IMPC的生物学行为并不取决于肿瘤中IMPC成分的多少。
(3)肿瘤大小、病理组织学分级与IMPC的淋巴结受累范围密切相关
(4)IMPC肿瘤细胞和其间质中存在一定数量的CD44~+/CD24~(-/low)表型细胞。提示IMPC肿瘤细胞中不乏干细胞的存在,同时在上皮-间质转化过程中少数肿瘤细胞可获得干性表型。这可能是IMPC高淋巴管侵犯、高淋巴结转移及耐药等恶性生物学行为的重要原因之一。
Objective:
Breast cancer cells with a CD44~+/CD24~(-/low)phenotype have been suggested to have tumor-initiating properties with stem cell-like invasive features.It is unclear whether their prevalence associates with clinicopathologic features of Invasive Micropapillary Carcinoma(IMPC) of the Breast,an unusal subtype of breast cancer with a high incidence of lymph node metastasis and poor prognosis.
Methods:
This study included 82 cases of IMPC and 80 cases of invasive ductal carcinoma, not otherwise specified(IDC-NOS),both without chemotherapy and radiotherapy before surgery.CD44 and CD24 expression was determined by double-staining immunohistochemistry in paraffin embedded tissue from each case.
Results:
(1) Compared with the control group of IDC-NOS,IMPC were larger in size (t＝3.000,p＝0.003,table 1),higher staged(Z=-4.467,P=0.000),had a higher lymph node metastasis rate(Z=-5.379,P=0.000,table 1) with more nodes involved per case(10.85 in IMPC versus 5.11 in IDC,t=3.750,P?0.000),and exhibited increased lymphovascular invasion(Z＝-7.310,P＝0.000 ) and extranodal extension(Z=-2.526,P≠0.012).
(2) The prevalence of CD44~+/CD24~(-/ low) tumor cells was higher in IMPC than in IDC- NOS(48.8%versus 31.3%,P=0.023).
(3) The CD44~+/CD24 ~(/low) tumor cells was also detected in adjacent stroma surrounding the micropapillary structure in 53.7%of IMPC,but scarcely in the stroma of IDC.These tumor cells in stroma of IMPC showed positive Vimentin and a-SMA,and negative E-Cadherin staining by immunohistochemistry.
(4) The CD44~+/CD24~(-/low) tumor cells in micropapillary structure of IMPC was associated with that in stroma(P=0.002),moreover,they were both associated with lymphovascular invasion and extranodal extension respectively(P＜0.05).
(5) The proportion of CD24~+ tumor cells was also higher in IMPC than IDC-NOS (79.3%versus 60.0%,P=0.008),and the CD24~+ tumor cells was associated with lymph node metastasis in IMPC(P=0.000).
(1) IMPC had a higher lymph node metastasis rate with more nodes involved per case and poor prognosis.
(2) The percentage of IMPC components in the whole tumor was not significantly associated with lymph node metastasis rate or the number of positive lymph nodes.
(3) In IMPC,tumor size and histological grade are closely related to the extent of lymph nodes involved,
(4) The increased proportion of CD44~+/CD24~(-/low) and CD24~+ tumor cells and the EMT(epithelial-mesenchymal transition) may play an important role in aggressiveness and higher metastatic risk of IMPC of the Breast.
引文
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[20]Kalirai H,Clarke R B.Human breast epithelial stem cells and their regulation[J].J Pathol,2006;208:7-16
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[22]Al Hajj M,Wicha MS,Renito H A.et al.Prospective identification of tumorigenic breast cancer cells[J].Proc Natl Acad Sci USA,2003,100(7):3983-3988.
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[24]Kondo T,Setoguchi T,Taga T.Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line[J].Proc Nail Acad Sci USA,2004,101(3):781-786.
[25]Grimshaw MJ,Cooper L,Papazisis K,et al.Mammosphere culture of metastatic breast cancer cells enriches for tumorigenic breast cancer cells[J].Breast Cancer Res,2008,10(3):R(52)
[26]Gabriella Honeth,Par-Ola Bendahl,Markus Ringner,et al.The CD44~+/CD24~- phenotype is enriched in basal-like breast tumors[J].Breast Cancer Res,2008,10(3):R(53)
[27]Hanahan D,Weinberg RA The hallmark of cancer[J]Cell.2000,100(1):57-70
[28]Bao S,wu Q,McLendon RE,et al.Glioma stem cells promote Radio resistance by preferential activation of the DNA damage response[J].Nature,2006,444(7120):756-760.
[29]Ponti D,Zaffaroni N,Capelli C,et al.Breast cancer stem cells:an overview[J].Euro J Cancer,2006,42:1219-1224.
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[1]Reya T,Morrison SJ,Clarke MF,et al.Stem cells,cancer,and cancer stem cells[J].Nature,2001,414(6859):105-111.
[2]Woodward WA,Chen MS,Behbod F,et al.On mammary stem cells[J].J Cell Sci,2005,118(16):3585-3594.
[3]Ponti D,Costa A,Zaffaroni N,et al.Isolation and In vitro Propagation of Tumorigenic Breast Cancer Cells with Stem/Progenitor Cell Properties[J].Cancer Res,2005,65(13):5505-5511.
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[9]Chepko G,Smith GH.Ultra-structure of the putative stem cell niche in rat mammary epithelium[J].Tissue Cell,2003,35(2):83-93.
[10]Ginestier C,Hur MH,Charafe-Jauffret E,et al.ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome[J].Cell stem cell,2007,1(5):555-567.
[11]Stingl J,Eirew P,Ricketson I et al.Purification and unique properties of mammary epithelial stem cells[J].Nature,2006,439(7079):993-997
[12]Shackleton M,Vaillant F,Simpson KJ et al.Generation of a functional mammary gland from a single stem cell[J].Nature,2006,439(5):84-88.
[13]Wang RH.The new portrait of mammary gland stem cells[J].Nature,2006,2(4):186-187.
[14]Krause DS.Regulation of hematopoietic stem cell fate[J].Oncogene,2002,21:3262-3269.
[15]Soriano JV,Uyttendaele H,Kitajewski J,et al.Expression of an activated Notch4(int-3) oncoprotein disrupts morphogenesis and induces an invasive phenotype in mammary epithelial cells in vitro[J].Int J Cancer,2000,86:652-659.
[16]Li Y,Welm B,Podsypanina K,et al.Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells[J].Proc Natl Acad Sci USA,2003,100(26):15853-15858.
[17]Liu S,Dontu G,Mantle ID,et al.Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells[J].Cancer Res,2006,66(12):6963-6071
[18]Kubo M,Nakamura M,Tasaki A,et al.Hedgehog signaling pathway is a new therapeutic target for patients with breast cancer[J].Cancer Res,2004,64:6071-6074.
[19]Cariati M,Purushotham AD.Stem cells and breast cancer[J].Histopathology,2008,52:99-107.
[20]Kalirai H,Clarke R B.Human breast epithelial stem cells and their regulation[J].J Pathol,2006;208:7-16
[21]Smalley M,Ashworth A.Stem cell and breast cancer:a field in transit[J].Nature,2003,3(11):832-844.
[22]Al Hajj M,Wicha MS,Renito H A.et al.Prospective identification of tumorigenic breast cancer cells[J].Proc Natl Acad Sci USA,2003,100(7):3983-3988.
[23]Al Hajj M,Clarke MF.Self-renewal and solid tumor stem cells[J].Oncogene, 2004,23(43):7274-7282.
[24]Kondo T,Setoguchi T,Taga T.Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line[J].Proc Nail Acad Sci USA,2004,101(3):781-786.
[25]Grimshaw MJ,Cooper L,Papazisis K,et al.Mammosphere culture of metastatic breast cancer cells enriches for tumorigenic breast cancer cells[J].Breast Cancer Res,2008,10(3):R(52)
[26]Gabriella Honeth,Par-Ola Bendahl,Markus Ringner,et al.The CD44~+/CD24~- phenotype is enriched in basal-like breast tumors[J].Breast Cancer Res,2008,10(3):R(53)
[27]Hanahan D,Weinberg RA The hallmark of cancer[J]Cell.2000,100(1):57-70
[28]Bao S,wu Q,McLendon RE,et al.Glioma stem cells promote Radio resistance by preferential activation of the DNA damage response[J].Nature,2006,444(7120):756-760.
[29]Ponti D,Zaffaroni N,Capelli C,et al.Breast cancer stem cells:an overview[J].Euro J Cancer,2006,42:1219-1224.
[30]Xiaoxian Li,Michael T.Lewis,Jian Huang,et al.Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy [J].J Natl Cancer Inst 2008,100(9),673-679.
[31]Kakarala M,Wicha MS.Implications of the cancer stem-cell hypothesis for breast cancer prevention and therapy[J].J Clin Oncol,2008,26(17):2813-2820.