骨桥蛋白对内皮祖细胞增殖作用和机制及二者在乳腺癌中相关性的研究
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摘要
[背景]
传统观点认为,成体中血管再生和改建仅由邻近血管内皮细胞增殖和爬行这种“血管新生(angiogenisis)"方式来实现。1997年,Asahara等首次在Science上提出内皮祖细胞(endothelial progenitor cell, EPC)并证实EPC具有在体内外增殖、迁徙、分化为成熟内皮细胞形成血管的能力。随后大量研究证实,成体新生血管除了血管新生方式外,还可以由干细胞分化成能定向分化为内皮细胞的前体细胞EPC,再分化为成熟血管内皮细胞,形成血管的“血管生成(vasculogenesis)"方式来实现。肿瘤生长、侵袭、转移均为血管生成依赖性的。研究表明,EPC的增生与分化是肿瘤血管形成的关键步骤,EPC是内皮细胞的前体细胞,在肿瘤新生血管形成中占有重要地位。当前,EPC的分离、培养、鉴定,体内分布、来源、分化、迁徙、归巢、功能及应用等方面正被广泛而深入的研究。本研究第一部分,对从人骨髓分离、培养、扩增出的EPC及细胞鉴定进行探讨。
某些类型肿瘤中,肿瘤负荷,组织学分级,病理分期,预后与外周血循环EPC数量明显相关。肿瘤分泌VEGF, SDF-1, G-CSF, GM-CSF等多种细胞因子和趋化因子调控EPC的动员、增生、迁移、分化及归巢功能。骨桥蛋白(osteopontin, OPN)称为“恶性转化相关因子”。肿瘤组织和血浆血清中高表达OPN的乳腺癌患者容易发生转移,预后不良。研究发现OPN作为成血管因子,与肿瘤血管形成相关。OPN在肿瘤中的高表达与肿瘤血管密度(MVD)相关,Takahashi F等研究发现OPN在体外可以促进人脐静脉内皮细胞增殖,提示了OPN有可能通过血管形成的参与者内皮细胞来提高肿瘤血管形成,从而有利于肿瘤生长与转移。但是OPN对于EPC的增殖作用及其机制未见报道。OPN是否能够促进肿瘤血管形成的重要参与者内皮细胞的前体细胞EPC增殖,从而在祖细胞水平,也即有很强的集落形成能力的细胞阶段使其数量大为扩增,而形成用以满足肿瘤生长与转移所必需的大量营养物质的新生血管的作用及机制需要深入研究。
[研究目的]
探讨从人骨髓中分离、培养EPC的方法。观察OPN对EPC的增殖作用并初步探索其作用机制,以及检测乳癌OPN表达与循环EPC数量的相关性。
[研究方法]
1、人骨髓来源EPC的分离、培养和鉴定：采用密度梯度离心法,从人骨髓中分离单个核细胞；采用差速贴壁培养法,从人骨髓分离出的单个核细胞中,培养、扩增EPC。主要从细胞形态学、对比应用多种内皮细胞的特征标记及功能检测等方面证实所获细胞为EPC,完成细胞鉴定,为下一步研究提供基础。
2、OPN促进EPC的增殖作用及机制初探：对培养出的EPC用免疫组化及RT-PCR方法检测OPN蛋白及mRNA水平的表达,并用不同浓度(0.5,1,2,4ug/ml) OPN进行干预,CCK-8法检测细胞增殖水平。将PI3K抑制剂——LY294002和AKT抑制剂- AKT inhibitor预处理过的EPC加入OPN检测其增殖水平来初步探讨OPN对EPC增殖作用的信号传导机制。
3、检测乳癌患者OPN表达与循环EPC数量的相关性：流式细胞仪计数循环EPC,ELISA法检测血浆中OPN浓度,免疫组化法检测癌组织OPN的表达,评估乳腺癌中循环EPC数量与不同乳癌病理特点、血浆OPN浓度、癌组织OPN表达之间的相关性。
[结果]
1、从人骨髓细胞中可分离培养出EPC。从人骨髓中分离出的细胞悬液经密度梯度离心后,可分离出骨髓来源的单个核细胞(bone marrow-derived mononuclear cell, BMNC);经差速贴壁法培养后,可获得EPC。细胞呈梭状,可形成集落,符合祖细胞特性；培养15天左右,可形成典型“铺路石”样内皮细胞。细胞表达CD34, KDR,CD133等分子标记,培养的细胞可吞噬Dil-acLDL,可结合UEA-1。
2、OPN促进EPC增殖,且呈浓度依赖性。EPC本身可以表达OPN,加入培养基的VEGF,bFGF均可以增加EPC中OPN mRNA水平。加入外源性OPN不能增加EPC内源性OPN mRNA水平。将不同浓度(0.5,1,2,4ug/ml)的人重组OPN加入基础培养液中进行干预,EPC增殖功能增强,且随EPC浓度的增加而增加,预先加入的LY294002和AKT inhibitor都抑制了OPN诱导的EPC增殖。显示：OPN通过PI3K/Akt信号通路促进EPC的增殖。
3、乳腺肿瘤患者外周血中EPC数量和血浆OPN浓度及二者相关性检测。转移性乳腺癌(11例)外周血中成血-血管干细胞源性内皮祖细胞即CD45neg-dim/CD34+/KDR+内皮祖细胞(中位数为65/ml,四分位数间距：32.0-92.0/ml)高于早期乳腺癌(29例)(中位数为35/ml,四分位数间距：7.0-56.5/ml),差异有统计学意义。早期乳腺癌外周血中CD45neg-dim/CD34+/KDR+内皮祖细胞数量与良性乳腺病变(9例)(中位数为13/ml,四分位间距：1.5-45.5/ml)相比,无统计学差别。乳腺癌外周血中髓系祖细胞源性内皮祖细胞CD45+/KDR+单核细胞数量高于乳腺良性病变(473.45±201.63 cells/ml比319.78±183.52 cells/ml; P<0.05);但不随乳腺癌分期越高而增加。CD45neg-dim／CD34+／KDR+EPC在>3cm乳腺癌中为56.5／ml(四分位数间距：37.5-77.0/ml),高于<3cm乳腺癌：27.5/ml(四分位数间距：7.5-61.0/ml),P<0.05。而CD45+／KDR+单核细胞数量在两组无统计学差别(P=0.055)。组织分级G3乳腺癌患者CD45neg-dim／CD34+／KDR+EPC数量为68.0／ml(IQR:38.50-96.50／ml)与G2乳腺癌(29.5／ml,IQR:8.50-50.25／ml)比较有统计学差别(P=0.008),而G1和G2比较,G1和G3比较均无统计学差别(P=0.788；P=0.138)。乳腺癌病人血浆中OPN与VEGF的浓度分别为7.9615±1.7026 pg/ml和401.49±86.71 pg/ml,二者均高于乳腺良性病变患者血浆中的OPN与VEGF的浓度(6.2922±2.0795 pg／ml；170.73±29.04 pg／ml)P<0.05.在早期与转移性乳腺癌中未见二者浓度有统计学上的不同。在乳腺癌病人血浆中,我们没有发现这两个细胞因子浓度有相关性,也没有发现他们与外周血中两个EPC细胞群之间有相关性。癌组织OPN的表达也未发现与外周血循环中的EPC数量相关。
[结论]
用密度梯度离心法从人骨髓中分离出BMNC,采用差速贴壁法可培养、扩增出EPC。人重组OPN通过P13K／Akt信号通路促进EPC的增殖。转移性乳腺癌患者外周血中CD45neg-dim／CD34+／KDR+EPC数量高于早期乳腺癌和乳腺良性病变患者,乳腺癌患者血浆中OPN与VEGF浓度均高于乳腺良性病变。但未发现乳腺癌患者外周血中EPC数量与血浆中OPN浓度及癌组织中OPN的表达相关。
[Background]
According to the traditional view, adult vascular regeneration and reconstruction depended only on the adjacent vascular endothelial cell proliferation and reptiles,which was "angiogenesis". In 1997, Asahara et al raised the definition of endothelial progenitor cell (EPC) for the first time in Science,and confirmed that EPC could proliferate, migrate, differentiate into mature endothelial cell(EC) to form blood vessels in vivo and in invitro. Lately, a large number of studies indicated that apart from angiogenesis, stem cells could differentiate into EPC, and then differentiate into mature EC to form blood vessels, which was called "vasculogenesis", and it was another neovascularization way in adult. Tumor growth, invasion and metastasis are vascular-dependent. Studies showed that EPC proliferation and differentiation was a key step in tumor angiogenesis. EPC as precursor cell, played an important role in tumor neovascularization. Emerging researches on derivation, distribution, differentiation, migration, homing, function and potential usage of EPC were launched in the recent years. In the first part of present study, we cultured EPC from bone marrow-derived mononuclear cell (BMNC), and identified them.
Tumor burden, histological grade, pathological stage and prognosis were significantly correlated with circulating EPC number in certain types of tumor. The cytokines and chemokines secreted by tumor cells such as VEGF, SDF-1, G-CSF, GM-CSF have been proved to regulate EPC mobilization, proliferation, migration, differentiation and homing capabilities. Osteopontin (OPN) was called as "malignant transformation-related factor." Breast cancer patients with high expression of OPN in tumor tissue and plasma were prone to metastasis and had poor prognosis. Studies found that OPN was also associated with tumor neovascularization as angiogenesis factor. Higher OPN expression in cancer tissue was related with tumor blood vessel density (MVD). Takahashi F et al found that OPN in vitro could promote the proliferation of human umbilical vein endothelial cells, which suggested that OPN might increase blood vessels formation through regulating endothelial cells-the participants in the formation of tumor new blood vessels, thus contribute to tumor growth and metastasis. However, there was no report showing whether OPN had the same favorable effects on EPC. Whether and how OPN can promote another important participant in tumor neovascularization-EPC proliferation, then to form new blood vessels will be needed to be studied in depth.
[Objective]
To investigate the methods of isolation and culture of human bone marrow-derived endothelial progenitor cell(BM-EPC). To demonstrate the proliferative effects of OPN on EPC, and then preliminarily explore the mechanism. To explore the relevance between OPN expression and the number of circulating EPC in breast cancer.
[Methods]
1、Isolation, culture and identification of human bone marrow-derived EPC:Bone marrow-derived mononuclear cells (BMNCs) was collected from human by density gradient centrifugation, and EPCs were obtained and expanded by means of attachment technique from the BMNCs.EPCs were identified Mainly from the cell morphology, a variety of endothelial cell characteristics markers and functional testing, etc. the completion of EPC culture and identification provided the basis for further research.
2、The proliferative effects of OPN on EPC:OPN mRNA and protein expression were detected with the immunohistochemistry and RT-PCR in the EPC.EPCs pretreated with different concentration of OPN (0.5,1,2,4 ug/ml) were detected the level of cell proliferation with CCK-8 method. EPCs, pretreated with the PI3K inhibitor (LY294002) and AKT inhibitor, then treated with OPN for 24 hours, were detected the level of cell proliferation with CCK-8 method to explore the signal transduction mechanisms about the proliferative effects OPN on EPC.
3、Exploration of the relevance between OPN expression and the number of circulating EPCs in breast cancer:EPCs in peripheral blood were counted with flow cytometry. Plasma OPN concentration was measured with ELISA assay. OPN expression in cancer tissues was detected by immunohistochemical. Then we assessed the correlation between the amount of circulating EPC and different pathological characteristics, plasma OPN concentration and OPN expression in cancer tissue in breast cancer patients.
[Results]
1、EPCs could be cultured and expanded from bone marrow-derived cells of human. Bone marrow-derived mononuclear cells were isolated from human bone marrow-derived cells by density gradient centrifugation, and EPCs could be expanded by means of differential attachment technique. The cells exhibited spindle-shape morphology, and formed endothelial colonies, which was one of characteristics of stem/progenitor cells. They showed the shape of "slabstone"after culture for 15 days or so in vitro, which was a typical characterization of endothelial cells. EPC was characterized by their phonotypical expression of CD34, KDR, CD 133 and other molecular markers, EPC could uptake Dil-acLDL and bind UEA-1.
2、OPN could promote EPC proliferation in a dose-dependent manner. EPC itself could express OPN. VEGF, bFGF in medium might increase the expression level of OPN mRNA in EPC. Exogenous OPN could not increase the expression level of endogenous OPN mRNA in EPC. After different concentrations (0.5,1,2,4 ug/ml) of human recombinant OPN were added to basic culture medium, the proliferative ability of EPC enhanced with the increase of OPN concentration. EPC pretreated with LY294002 and AKT inhibitor inhibited the proliferative effect of OPN on EPC. Accordingly, our study indicated that OPN promoted EPC proliferation through the PI3K/Akt signaling pathway.
3、In patients with metastatic breast cancer(n=11) the median value of CD45neg-dim CD34+KDR+EPCs was 65/ml(IQR:32.0-92.0/ml) in comparison to 35/ml(IQR:7.0-56.5/ml) in those with early breast cancer(n=29), and P<0.05. There was no statistical difference in the number of CD45neg-dim CD34+KDR+EPCs between breast cancer patients with stageⅠ&Ⅱand benign lesion patients. In addition, we analyzed the amount of another EPC population-CD45+KDR+monocyte, which was higher in breast cancer patients than benign breast lesion patients.(473.45±201.63 cells/ml vs 319.78±183.52 cells/ml;P<0.05). However there wasn't increasing trend in the number of the EPC population with stage elevation. Considering breast cancer pathological characteristics such as tumor size, nodal status, molecular subgroups, histological grading and OPN expression as possible influencing factors for EPCs, we evaluated, respectively, these correlations with CD45neg-dim/CD34+/KDR+EPCs and CD45+/KDR+ monocytes. The number of CD45neg-dim/CD34+/KDR+ EPCs in tumors<3 cm in diameter was 27.5 cells/ml (IQR:7.5-61.0cells/ml) compared with 56.5 cells/ml (IQR:37.5-77.0cells/ml) in tumors >3 cm in diameter (P＜0.05). The number of CD45neg-dim/CD34+/KDR+EPCs in cases of breast cancer histologically graded G3 was 68.0 cells/ml (IQR:38.50-96.50 cells/ml) compared with 29.5 cells/mL (IQR:8.50-50.25 cells/ml) in cases graded G2 (P=0.008). There was no statistical difference in EPC number between gradings G1 and G2 (P=0.788), nor G1 and G3 (P=0.138). There was no statistical difference in the number of CD45nes-dim/CD34+/KDR+EPCs among different nodal statuses(p=0.645), molecular subgroups (0.143), and OPN expression (p=0.079). In addition, none of these pathological characteristics were related to the number of CD45+/KDR+monocytes. There was a statistical increase of the value of soluble OPN and VEGF-A in plasma in the breast cancer patients than in benign breast lesion patients. Unexpectedly, we could not find the obvious correlation between the plasma level or expression in cancer tissue of OPN and the enumeration of peripheral blood EPCs in breast cancer patients.
[Conclusion]
BMNCs of human can be collected by density gradient centrifugation. By means of differential attachment technique, EPCs can be obtained from BMNCs, then amplified Human recombinant OPN may promote EPC proliferation through the PI3K/Akt signaling pathway. The number of CD45neg-dimCD34+KDR+EPCs in peripheral blood of patients with metastatic breast cancer(n=11) was higher than those with early breast cancer(n=29) and breast benigh lesion(n=9). There was a statistical increase of the value of soluble OPN and VEGF-A in plasma in the breast cancer patients than benign breast lesion patients. But we could not find the obvious correlation between the plasma level or expression in cancer tissue of OPN and the enumeration of peripheral blood EPCs in breast cancer patients.
传统观点认为,成体中血管再生和改建仅由邻近血管内皮细胞增殖和爬行这种“血管新生(angiogenisis)"方式来实现。1997年,Asahara等首次在Science上提出内皮祖细胞(endothelial progenitor cell, EPC)并证实EPC具有在体内外增殖、迁徙、分化为成熟内皮细胞形成血管的能力。随后大量研究证实,成体新生血管除了血管新生方式外,还可以由干细胞分化成能定向分化为内皮细胞的前体细胞EPC,再分化为成熟血管内皮细胞,形成血管的“血管生成(vasculogenesis)"方式来实现。肿瘤生长、侵袭、转移均为血管生成依赖性的。研究表明,EPC的增生与分化是肿瘤血管形成的关键步骤,EPC是内皮细胞的前体细胞,在肿瘤新生血管形成中占有重要地位。当前,EPC的分离、培养、鉴定,体内分布、来源、分化、迁徙、归巢、功能及应用等方面正被广泛而深入的研究。本研究第一部分,对从人骨髓分离、培养、扩增出的EPC及细胞鉴定进行探讨。
某些类型肿瘤中,肿瘤负荷,组织学分级,病理分期,预后与外周血循环EPC数量明显相关。肿瘤分泌VEGF, SDF-1, G-CSF, GM-CSF等多种细胞因子和趋化因子调控EPC的动员、增生、迁移、分化及归巢功能。骨桥蛋白(osteopontin, OPN)称为“恶性转化相关因子”。肿瘤组织和血浆血清中高表达OPN的乳腺癌患者容易发生转移,预后不良。研究发现OPN作为成血管因子,与肿瘤血管形成相关。OPN在肿瘤中的高表达与肿瘤血管密度(MVD)相关,Takahashi F等研究发现OPN在体外可以促进人脐静脉内皮细胞增殖,提示了OPN有可能通过血管形成的参与者内皮细胞来提高肿瘤血管形成,从而有利于肿瘤生长与转移。但是OPN对于EPC的增殖作用及其机制未见报道。OPN是否能够促进肿瘤血管形成的重要参与者内皮细胞的前体细胞EPC增殖,从而在祖细胞水平,也即有很强的集落形成能力的细胞阶段使其数量大为扩增,而形成用以满足肿瘤生长与转移所必需的大量营养物质的新生血管的作用及机制需要深入研究。
[研究目的]
探讨从人骨髓中分离、培养EPC的方法。观察OPN对EPC的增殖作用并初步探索其作用机制,以及检测乳癌OPN表达与循环EPC数量的相关性。
[研究方法]
1、人骨髓来源EPC的分离、培养和鉴定：采用密度梯度离心法,从人骨髓中分离单个核细胞；采用差速贴壁培养法,从人骨髓分离出的单个核细胞中,培养、扩增EPC。主要从细胞形态学、对比应用多种内皮细胞的特征标记及功能检测等方面证实所获细胞为EPC,完成细胞鉴定,为下一步研究提供基础。
2、OPN促进EPC的增殖作用及机制初探：对培养出的EPC用免疫组化及RT-PCR方法检测OPN蛋白及mRNA水平的表达,并用不同浓度(0.5,1,2,4ug/ml) OPN进行干预,CCK-8法检测细胞增殖水平。将PI3K抑制剂——LY294002和AKT抑制剂- AKT inhibitor预处理过的EPC加入OPN检测其增殖水平来初步探讨OPN对EPC增殖作用的信号传导机制。
3、检测乳癌患者OPN表达与循环EPC数量的相关性：流式细胞仪计数循环EPC,ELISA法检测血浆中OPN浓度,免疫组化法检测癌组织OPN的表达,评估乳腺癌中循环EPC数量与不同乳癌病理特点、血浆OPN浓度、癌组织OPN表达之间的相关性。
[结果]
1、从人骨髓细胞中可分离培养出EPC。从人骨髓中分离出的细胞悬液经密度梯度离心后,可分离出骨髓来源的单个核细胞(bone marrow-derived mononuclear cell, BMNC);经差速贴壁法培养后,可获得EPC。细胞呈梭状,可形成集落,符合祖细胞特性；培养15天左右,可形成典型“铺路石”样内皮细胞。细胞表达CD34, KDR,CD133等分子标记,培养的细胞可吞噬Dil-acLDL,可结合UEA-1。
2、OPN促进EPC增殖,且呈浓度依赖性。EPC本身可以表达OPN,加入培养基的VEGF,bFGF均可以增加EPC中OPN mRNA水平。加入外源性OPN不能增加EPC内源性OPN mRNA水平。将不同浓度(0.5,1,2,4ug/ml)的人重组OPN加入基础培养液中进行干预,EPC增殖功能增强,且随EPC浓度的增加而增加,预先加入的LY294002和AKT inhibitor都抑制了OPN诱导的EPC增殖。显示：OPN通过PI3K/Akt信号通路促进EPC的增殖。
3、乳腺肿瘤患者外周血中EPC数量和血浆OPN浓度及二者相关性检测。转移性乳腺癌(11例)外周血中成血-血管干细胞源性内皮祖细胞即CD45neg-dim/CD34+/KDR+内皮祖细胞(中位数为65/ml,四分位数间距：32.0-92.0/ml)高于早期乳腺癌(29例)(中位数为35/ml,四分位数间距：7.0-56.5/ml),差异有统计学意义。早期乳腺癌外周血中CD45neg-dim/CD34+/KDR+内皮祖细胞数量与良性乳腺病变(9例)(中位数为13/ml,四分位间距：1.5-45.5/ml)相比,无统计学差别。乳腺癌外周血中髓系祖细胞源性内皮祖细胞CD45+/KDR+单核细胞数量高于乳腺良性病变(473.45±201.63 cells/ml比319.78±183.52 cells/ml; P<0.05);但不随乳腺癌分期越高而增加。CD45neg-dim／CD34+／KDR+EPC在>3cm乳腺癌中为56.5／ml(四分位数间距：37.5-77.0/ml),高于<3cm乳腺癌：27.5/ml(四分位数间距：7.5-61.0/ml),P<0.05。而CD45+／KDR+单核细胞数量在两组无统计学差别(P=0.055)。组织分级G3乳腺癌患者CD45neg-dim／CD34+／KDR+EPC数量为68.0／ml(IQR:38.50-96.50／ml)与G2乳腺癌(29.5／ml,IQR:8.50-50.25／ml)比较有统计学差别(P=0.008),而G1和G2比较,G1和G3比较均无统计学差别(P=0.788；P=0.138)。乳腺癌病人血浆中OPN与VEGF的浓度分别为7.9615±1.7026 pg/ml和401.49±86.71 pg/ml,二者均高于乳腺良性病变患者血浆中的OPN与VEGF的浓度(6.2922±2.0795 pg／ml；170.73±29.04 pg／ml)P<0.05.在早期与转移性乳腺癌中未见二者浓度有统计学上的不同。在乳腺癌病人血浆中,我们没有发现这两个细胞因子浓度有相关性,也没有发现他们与外周血中两个EPC细胞群之间有相关性。癌组织OPN的表达也未发现与外周血循环中的EPC数量相关。
[结论]
用密度梯度离心法从人骨髓中分离出BMNC,采用差速贴壁法可培养、扩增出EPC。人重组OPN通过P13K／Akt信号通路促进EPC的增殖。转移性乳腺癌患者外周血中CD45neg-dim／CD34+／KDR+EPC数量高于早期乳腺癌和乳腺良性病变患者,乳腺癌患者血浆中OPN与VEGF浓度均高于乳腺良性病变。但未发现乳腺癌患者外周血中EPC数量与血浆中OPN浓度及癌组织中OPN的表达相关。
[Background]
According to the traditional view, adult vascular regeneration and reconstruction depended only on the adjacent vascular endothelial cell proliferation and reptiles,which was "angiogenesis". In 1997, Asahara et al raised the definition of endothelial progenitor cell (EPC) for the first time in Science,and confirmed that EPC could proliferate, migrate, differentiate into mature endothelial cell(EC) to form blood vessels in vivo and in invitro. Lately, a large number of studies indicated that apart from angiogenesis, stem cells could differentiate into EPC, and then differentiate into mature EC to form blood vessels, which was called "vasculogenesis", and it was another neovascularization way in adult. Tumor growth, invasion and metastasis are vascular-dependent. Studies showed that EPC proliferation and differentiation was a key step in tumor angiogenesis. EPC as precursor cell, played an important role in tumor neovascularization. Emerging researches on derivation, distribution, differentiation, migration, homing, function and potential usage of EPC were launched in the recent years. In the first part of present study, we cultured EPC from bone marrow-derived mononuclear cell (BMNC), and identified them.
Tumor burden, histological grade, pathological stage and prognosis were significantly correlated with circulating EPC number in certain types of tumor. The cytokines and chemokines secreted by tumor cells such as VEGF, SDF-1, G-CSF, GM-CSF have been proved to regulate EPC mobilization, proliferation, migration, differentiation and homing capabilities. Osteopontin (OPN) was called as "malignant transformation-related factor." Breast cancer patients with high expression of OPN in tumor tissue and plasma were prone to metastasis and had poor prognosis. Studies found that OPN was also associated with tumor neovascularization as angiogenesis factor. Higher OPN expression in cancer tissue was related with tumor blood vessel density (MVD). Takahashi F et al found that OPN in vitro could promote the proliferation of human umbilical vein endothelial cells, which suggested that OPN might increase blood vessels formation through regulating endothelial cells-the participants in the formation of tumor new blood vessels, thus contribute to tumor growth and metastasis. However, there was no report showing whether OPN had the same favorable effects on EPC. Whether and how OPN can promote another important participant in tumor neovascularization-EPC proliferation, then to form new blood vessels will be needed to be studied in depth.
[Objective]
To investigate the methods of isolation and culture of human bone marrow-derived endothelial progenitor cell(BM-EPC). To demonstrate the proliferative effects of OPN on EPC, and then preliminarily explore the mechanism. To explore the relevance between OPN expression and the number of circulating EPC in breast cancer.
[Methods]
1、Isolation, culture and identification of human bone marrow-derived EPC:Bone marrow-derived mononuclear cells (BMNCs) was collected from human by density gradient centrifugation, and EPCs were obtained and expanded by means of attachment technique from the BMNCs.EPCs were identified Mainly from the cell morphology, a variety of endothelial cell characteristics markers and functional testing, etc. the completion of EPC culture and identification provided the basis for further research.
2、The proliferative effects of OPN on EPC:OPN mRNA and protein expression were detected with the immunohistochemistry and RT-PCR in the EPC.EPCs pretreated with different concentration of OPN (0.5,1,2,4 ug/ml) were detected the level of cell proliferation with CCK-8 method. EPCs, pretreated with the PI3K inhibitor (LY294002) and AKT inhibitor, then treated with OPN for 24 hours, were detected the level of cell proliferation with CCK-8 method to explore the signal transduction mechanisms about the proliferative effects OPN on EPC.
3、Exploration of the relevance between OPN expression and the number of circulating EPCs in breast cancer:EPCs in peripheral blood were counted with flow cytometry. Plasma OPN concentration was measured with ELISA assay. OPN expression in cancer tissues was detected by immunohistochemical. Then we assessed the correlation between the amount of circulating EPC and different pathological characteristics, plasma OPN concentration and OPN expression in cancer tissue in breast cancer patients.
[Results]
1、EPCs could be cultured and expanded from bone marrow-derived cells of human. Bone marrow-derived mononuclear cells were isolated from human bone marrow-derived cells by density gradient centrifugation, and EPCs could be expanded by means of differential attachment technique. The cells exhibited spindle-shape morphology, and formed endothelial colonies, which was one of characteristics of stem/progenitor cells. They showed the shape of "slabstone"after culture for 15 days or so in vitro, which was a typical characterization of endothelial cells. EPC was characterized by their phonotypical expression of CD34, KDR, CD 133 and other molecular markers, EPC could uptake Dil-acLDL and bind UEA-1.
2、OPN could promote EPC proliferation in a dose-dependent manner. EPC itself could express OPN. VEGF, bFGF in medium might increase the expression level of OPN mRNA in EPC. Exogenous OPN could not increase the expression level of endogenous OPN mRNA in EPC. After different concentrations (0.5,1,2,4 ug/ml) of human recombinant OPN were added to basic culture medium, the proliferative ability of EPC enhanced with the increase of OPN concentration. EPC pretreated with LY294002 and AKT inhibitor inhibited the proliferative effect of OPN on EPC. Accordingly, our study indicated that OPN promoted EPC proliferation through the PI3K/Akt signaling pathway.
3、In patients with metastatic breast cancer(n=11) the median value of CD45neg-dim CD34+KDR+EPCs was 65/ml(IQR:32.0-92.0/ml) in comparison to 35/ml(IQR:7.0-56.5/ml) in those with early breast cancer(n=29), and P<0.05. There was no statistical difference in the number of CD45neg-dim CD34+KDR+EPCs between breast cancer patients with stageⅠ&Ⅱand benign lesion patients. In addition, we analyzed the amount of another EPC population-CD45+KDR+monocyte, which was higher in breast cancer patients than benign breast lesion patients.(473.45±201.63 cells/ml vs 319.78±183.52 cells/ml;P<0.05). However there wasn't increasing trend in the number of the EPC population with stage elevation. Considering breast cancer pathological characteristics such as tumor size, nodal status, molecular subgroups, histological grading and OPN expression as possible influencing factors for EPCs, we evaluated, respectively, these correlations with CD45neg-dim/CD34+/KDR+EPCs and CD45+/KDR+ monocytes. The number of CD45neg-dim/CD34+/KDR+ EPCs in tumors<3 cm in diameter was 27.5 cells/ml (IQR:7.5-61.0cells/ml) compared with 56.5 cells/ml (IQR:37.5-77.0cells/ml) in tumors >3 cm in diameter (P＜0.05). The number of CD45neg-dim/CD34+/KDR+EPCs in cases of breast cancer histologically graded G3 was 68.0 cells/ml (IQR:38.50-96.50 cells/ml) compared with 29.5 cells/mL (IQR:8.50-50.25 cells/ml) in cases graded G2 (P=0.008). There was no statistical difference in EPC number between gradings G1 and G2 (P=0.788), nor G1 and G3 (P=0.138). There was no statistical difference in the number of CD45nes-dim/CD34+/KDR+EPCs among different nodal statuses(p=0.645), molecular subgroups (0.143), and OPN expression (p=0.079). In addition, none of these pathological characteristics were related to the number of CD45+/KDR+monocytes. There was a statistical increase of the value of soluble OPN and VEGF-A in plasma in the breast cancer patients than in benign breast lesion patients. Unexpectedly, we could not find the obvious correlation between the plasma level or expression in cancer tissue of OPN and the enumeration of peripheral blood EPCs in breast cancer patients.
[Conclusion]
BMNCs of human can be collected by density gradient centrifugation. By means of differential attachment technique, EPCs can be obtained from BMNCs, then amplified Human recombinant OPN may promote EPC proliferation through the PI3K/Akt signaling pathway. The number of CD45neg-dimCD34+KDR+EPCs in peripheral blood of patients with metastatic breast cancer(n=11) was higher than those with early breast cancer(n=29) and breast benigh lesion(n=9). There was a statistical increase of the value of soluble OPN and VEGF-A in plasma in the breast cancer patients than benign breast lesion patients. But we could not find the obvious correlation between the plasma level or expression in cancer tissue of OPN and the enumeration of peripheral blood EPCs in breast cancer patients.
引文
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国家自然科学研究基金课题
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国家自然科学研究基金课题
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