1. 兔骨髓间充质干细胞对VX2膀胱肿瘤生长及间质重构的影响 2. 钬激光治疗非肌层浸润性膀胱肿瘤的疗效与安全性评价
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摘要
研究背景
骨髓间充质干细胞(mesenchymal stem cells,MSCs)是骨髓非造血组织中的一类多潜能成体干细胞,其具有高度的可塑性和多向分化潜能,在体外具有高度的扩增能力,并可被诱导分化为骨、软骨、肌肉、脂肪和神经等组织细胞,由于避免了胚胎干细胞在伦理、道德、法律等方面的限制,目前MSCs成为组织工程和再生医学中理想的供体细胞。而且,MSCs易于外源基因的转染和表达、极好的迁移能力(migratory ability)和肿瘤趋向性(tropism)、低免疫原性的特点,使其成为肿瘤基因治疗和靶向治疗的理想载体细胞。然而随着近年来对MSCs生理特性和肿瘤研究的不断深入,有研究发现MSCs本身可能与肿瘤发生、发展之间存在着密切的关系,提示MSCs应用的生物安全性问题值得关注。我们在前期的工作中,已经初步观察到将培养的自体MSCs回输到已经发生的VX2膀胱肿瘤组织后,能够促进肿瘤的生长,并发现MSCs在体外、体内肿瘤局部微环境可以分化为肌纤维母细胞。因此,MSCs来源的肌纤维母细胞或其他间质细胞可能参与了肿瘤间质重构,而肿瘤间质重构(remodeling)是肿瘤生长发展与侵袭的关键步骤。本部分研究我们拟通过体外扩增新西兰兔MSCs后,膀胱粘膜下接种不同比例的自体MSCs和VX2肿瘤细胞混合液,观察不同数量的MSCs对膀胱VX2肿瘤发生、发展的影响,进一步研究MSCs与VX2膀胱肿瘤发生发展的关系;同时,监测MSCs对肿瘤组织某些生长因子和间质重构蛋白的表达的影响,藉此研究MSCs来源的间质细胞与肿瘤细胞间相互作用的具体信号机制。
目的
探讨MSCs对VX2膀胱肿瘤发生、发展的影响;研究MSCs对肿瘤组织某些生长因子和间质重构蛋白的表达的影响,证实MSCs是否参与了实体肿瘤的间质重构。
方法
1.兔骨髓间充质干细胞的分离、培养和鉴定:雄性新西兰大白兔30只,每只动物均行胫骨近端骨髓穿刺抽取骨髓MSCs,体外密度梯度离心法联合细胞贴壁法分离培养扩增新西兰兔MSCs,形态学、流式细胞技术检测表面抗原等方法鉴定扩增的MSCs。
2.兔VX2膀胱肿瘤模型的建立及监测:MSCs培养成功后,制备VX2肿瘤细胞悬液,将DAPI标记的自体骨髓MSCs细胞悬液和VX2肿瘤细胞细胞悬液混合,制备一总体积为介质为300μl PBS的混合细胞悬液,行膀胱粘膜下接种,按照两种细胞比例的不同,30只新西兰大白兔按照随机原则分为3组,每组10只,具体如下:A组(10~6VX2),B组[(VX2/MSCs=1:1):10~6VX2+10~6 MSCs],C组[(VX2/MSC=1:10):10~6VX2+10~7 MSCs]。细胞膀胱粘膜下接种建立膀胱肿瘤模型,于第3、4、5、6、7、14、21、28d分别行膀胱超声多切面扫查一次,记录肿瘤最长最短直径,建立生长曲线,比较各组生长速率差异。第4周处死所有动物,取出膀胱肿瘤标本,同时记录各组远处转移情况。
3.免疫组织化学(IHC)测定各组肿瘤组织中的间质重构因子和蛋白:IHC测定各组肿瘤组织生长因子(TGFβ1、bFGF、HGF)和基质重构蛋白酶(MMP2、MMP9)的表达差异,应用Image Pro Plus 5.0数字图像分析软件计算平均积分光密度(intergrated optical density,IOD),对免疫组化(IHC)强度进行半定量分析,以IOD值代表蛋白的表达水平。从而探讨MSCs对肿瘤组织生长因子和MMPs表达的影响。
4.实时荧光定量PCR监测上述生长因子和基质重构蛋白酶mRNA:应用SYBRGreenⅠ法Real-time PCR测定各组肿瘤组织上述生长因子和基质蛋白酶,数据分析采用2~(-ΔCtΔCt)法。
结果
1.体外培养的MSCs形态均匀,生长曲线显示增长能力强,经鉴定为兔MSCs,而非造血系细胞。
2.MSCs对VX2膀胱肿瘤发生发展的影响:细胞接种后第5天,A、B、C组分别有2(2/10)、2(2/10)、6(6/10)只动物超声检查能够监测到接种部位肿瘤生长。接种第6天三组分别有6(6/10)、7(7/10)、8(8/10)只能够监测到肿瘤生长。在第一、二、三周时间点时三组动物肿瘤体积A组＜B组＜C组,差异有统计学意义(P均＜0.001),生长曲线提示,MSCs能够促进VX2膀胱肿瘤的发展。第四周时A、B、C三组生成膀胱肿瘤的质量分别为4.0±1.2g、11.3±3.5g、12.8±3.9g,B、C组大于A组,差异均有统计学意义(P＜0.05)。A组实验动物前三周均未出现腹股沟淋巴结转移,第四周时有3只(3/10)新西兰兔出现腹股沟淋巴结转移的情况;B组实验动物前两周未出现腹股沟淋巴结转移,第三周时3只(3/10)动物出现沟淋巴结转移,而第四周时共7只(7/10)出现淋巴结转移;C组实验动物第三周5只(5/10)动物出现腹股沟淋巴结,第四周时共8(8/10)只出现淋巴结转移。三组动物第四周处死解剖后均能发现膀胱肿瘤存在,生成的肿瘤大致呈圆形,形态较规则,无明显子灶形成。病理HE染色显示符合移植性VX2肿瘤的一般特点。
3.肿瘤组织中生长因子和间质重构蛋白酶IHC测定结果:生长因子:间质细胞(成纤维细胞、内皮细胞、炎性细胞等)和肿瘤细胞(胞核、胞浆)均有阳性表达。B组TGFβ1、bFGF、HGF免疫组化IOD值水平(依次为15396.10±3230.57、9280.66±3754.99、13203.17±3990.86)显著高于A组(依次为8948.70±2462.91、5632.70±1943.18、7824.43±4077.94),P均＜0.05;C组TGFβ1、bFGF、HGF免疫组化IOD值水平依次为20875.40±6737.11、13811.14±4311.62、14523.69±3865.41,分别高于A组,P均＜0.05,且其中TGFβ1、bFGF的IOD值高于B组,差异有统计学意义(P＜0.05);基质金属蛋白酶:阳性表达主要分布于间质细胞(成纤维细胞、内皮细胞、炎性细胞等)和肿瘤细胞胞膜、胞浆,尤其以肿瘤浸润活跃处为著。MMP2免疫组化IOD值在A、B、C三组依次为25337.20±8151.51、51507.50±17679.55、61535.66±19449.11,B、C组高于A组,差异有统计学意义(P＜0.05),B、C组差异无统计学意义(P=0.231):MMP9免疫组化IOD值在A、B、C三组依次为34172.91±5243.75、60582.28±22975.45、90287.45±31362.21,B、C组高于A组,差异有统计学意义(P＜0.05),C组高于B组,差异有统计学意义(P=0.024)。
4.肿瘤组织中生长因子和间质重构蛋白酶mRNA水平:生长因子:B组TGFβ1、bFGF、HGF mRNA表达水平(依次为3.250±0.587、2.970±0.490、2.101±0.527)显著高于A组(依次为为1.087±0.194、1.134±0.165、1.185±0.247),P均＜0.05;C组TGFβ1、bFGF、HGF mRNA表达水平依次为3.620±0.670、3.651±0.744、3.052±0.438,分别高于A组,P均＜0.05,其中C组bFGF、HGF mRNA表达高于B组,且差异有统计学意义(P＜0.05)。基质金属蛋白酶:MMP2 mRNA表达水平在A、B、C三组依次为1.134±0.243、3.67±0.945、3.845±1.159,B、C高于A组,差异有统计学意义(P＜0.05):MMP9mRNA表达水平在A、B、C三组依次为0.955±0.166、3.360±0.628、4.045±1.084,依次升高,各组间差异均有统计学意义,P均＜0.05。
结论
1.VX2肿瘤细胞悬液膀胱粘膜下接种建立膀胱肿瘤模型具有量化、均一、稳定的特点,并且能够反映膀胱肿瘤的发生发展过程。
2.骨髓MSCs在体内膀胱微环境下能够促进VX2实体肿瘤的发生发展。
3.骨髓MSCs能够诱导肿瘤微环境高表达某些生长因子,并且可能是MSCs在肿瘤局部促进肿瘤生长的基础机制。
4.骨髓MSCs胞能够促进肿瘤间质某些基质蛋白酶(MMPs)表达,可能是其促进肿瘤间质重构和侵袭转移的机制之一。
目的以标准的经尿道膀胱肿瘤电切(Transurethral Electroresection of BladderTumor,TURBT)作为对照,对钬激光治疗非肌层浸润性膀胱肿瘤(Holmium LaserResection of Bladder Tumor,HOLRBT)的临床治疗效果与安全性进行评价。
方法收集212例原发性非肌层浸润性膀胱肿瘤的患者资料,按照所接受的手术方式不同将其分为两组(HOLRBT组和TURBT组)。同时,将每组患者按照复发风险(EAU 2002)的不同,分为低、中、高危非浸润性膀胱肿瘤三个亚组。总结两组患者临床及病理资料,对两组手术时间、闭孔神经反射及膀胱穿孔发生率、术后需要膀胱冲洗的患者比例、留置导尿管时间、术后住院时间等指标进行比较,从而对其手术安全性进行评价;通过Kaplan-Meier分析和Log-rank检验比较两组患者整体上及各个亚组间的无复发生存情况(Recurrence-Free Survival,RFS),基于与TURBT的比较,评价HOLRBT的临床治疗效果。
结果两组患者的一般资料与病理特点差异无统计学意义(P＞0.05),HOLRBT组与TURBT组的手术时间分别为30.69 min±16.10 min、24.90 min±14.44 min。HOLRBT组无闭孔神经反射发生,而TURBT组7(7/111)例发生闭孔神经反射,术后需要膀胱冲洗的患者比例(P=0.038)、留置尿管时间和术后住院时间均小于TURBT组(P＜0.01)。平均随访时间34 mon,Kaplan-Meier统计分析揭示HOLRBT组与TURBT整体相比,RFS差异无统计学意义(P=0.283)。经过复发危险度分层校正后,低危、中危、高危亚组内,两种手术方式的RFS相比,差异均无统计学意义,三个亚组内相关的P值依次为0.816、0.352、0.592(P＞0.05)。
结论钬激光切除治疗非肌层浸润性膀胱肿瘤的近期复发率(100%-RFS)与经尿道膀胱肿瘤电切相近,但在控制术中出血及闭孔神经反射,缩短术后留置尿管时间和膀胱冲洗时间方面更有优势。
BACKGROUD
Bone marrow-derived mesenchymal stem cells(MSCs) come from bone marrow non-hematopoietic tissue,which are a kind of pluripotent adult stem cells,have high degree of plasticity,and are capable of developing into diverse functional cell lineages, including bone,cartilage,myoblasts,fat and neural cells cells.Instead of embryonic stem cells,MSCs avoid the ethical,moral and legal constraints,and have been considered to represent ideal cell sources of regenerative medicine and tissue engineering currently.As a consequence,MSCs has aroused widespread interest. Moreover,MSCs can be readily transfected,allowing for easy ex vivo modification., have excellent migratory ability,the tumor tropism and low immunogenicity of the characteristics,which make them ideal vector cells in tumor gene therapy and targeted therapy.However,with the increasing apprehension of physiological characteristics regarding MSCs and the deepening of tumor research in recent years.Some scholars have found that MSCs themselves might be associated with tumorigenesis closely, suggesting that long-term biosafety of MSCs for clinical applications deserves further assessment.In previous work,We have initially observed that cultured autologous MSCs transfusion into VX2 bladder tumor tissue could promote tumor growth,and found that MSCs could be differentiated into myofibroblast in vitro and in vivo tumor micro-environment,which is regarded as an important cancer-associated fibroblast in tumor stroma.Therefore,MSCs derived myofibroblast or other stroma cells may be involved in tumor stroma remodeling.And activated tumor micro-environment or stroma remodeling plays a key role in tumor growth and infiltration.In this section, we intend to amplify of MSCs in vitro first,then establish tumor model through bladder submucosal innoculation of different proportions of autologous MSCs and VX2 tumor cells,observing the effect of different numbers of MSCs on VX2 bladder tumor occurrence and development in New Zealand rabbit.In this way,we try to study the relationship accurately between MSCs and VX2 bladder tumor occurrence and development;Meanwhile,by monitoring the tumor tissue growth factors and some stromal remodeling enzyme,we try to disclose the concrete signaling mechanism of MSCs induced stroma remodeling and the interaction between tumor cells and stroma cells.
OBJECTIVE
To investigate the effect of MSCs on the VX2 bladder tumor occurrence and development,to explore tumor tissue growth factor and stromal remodeling enzyme expression change induced by MSCs and whether MSCs are involved in the tumor stroma remodeling.
METHODS
1.Isolation,culture and identification of rabbit MSCs in vitro:A total of 30 male New Zealand rabbits were used.Marrow aspirates were obtained from the proximal tibia of each animal,and density gradient centrifugation followed by repeated adherence in plastic bottle were applied in MSCs isolation and amplification.Morphology and flow cytometry detection of surface antigen were used to identify and confirmation cultured MSCs.
2.Rabbit VX2 bladder tumor model establishment and monitoring:After successful MSCs cultivation,VX2 tumor cell suspension was prepared and mixed with DAPI labeled autologous MSCs in a total volume for 300μl PBS.The mixed cell suspension was transplanted by bladder submucosal innoculation.Based on the ratio of two different cells,30 New Zealand rabbits were randomly divided into 3 groups with 10 in each group,as follows:Group A(10~6 VX2),Group B [(VX2/MSCs=1:1):10~6 VX2 + 10~6 MSCs]and Group C[(VX2/MSC=1:10): 10~6 VX2 + 10~7 MSCs].Multisection ultrasound scanning was conducted 3,4,5,6, 7,14,21,28d respectively after cell innoculation to monitor tumor occurrence and growth.The tumor growth curve was set up and inguinal lymph nodes metastasis was observed to compare tumor progression in 3 groups.All animals were sacrificed at 4 weeks point.Bladder tumor specimens were obtained to make frozen and paraffin section,and distant organ metastasis was recorded.
3.Immunohistochemistry(IHC) assay of tumor growth factors and remodeling enzymes:growth factors(TGFβ1,bFGF,HGF) and matrix remodeling proteases (MMP2,MMP9) expression was detected in developed tumor,and Image Pro Plus 5.0 Software was used to analyze IHC intensity semi-quantitatively.Integral optical density(IOD) value represents the level of protein expression and was applied to compare the difference in 3 groups.
4.Real-time quantitative PCR assay of the above-mentioned growth factors and matrix remodeling protease mRNA:SYBR Green I method was used technically, and data analysis using 2~(ΔCtΔCt) method was conducted.
RESULTS
1.Cultured MSCs in vitro present uniform morphology and its growth curve showed strong amplification ability,and were identified as rabbit MSCs,rather than hematopoietic cells.
2.The effect of MSCs on tumor development:on 5~(th) day after cell inoculation,2 (2/10),2(2/10),6(6/10) animals in Group A,B,C respectively could be found by ultrasound in the bladder injection site,and 6(6/10)、7(7/10)、8(8/10) animals could be monitored in Group A,B,C respectively on 6~(th) day.At the 1~(st),2~(nd) and 3~(rd) week time point,tumor volume in group A＜group B＜group C,and the difference has statistical significance(P all＜0.001).Tumor growth curve showed that MSCs could promote VX2 bladder tumor growth.The weight of bladder tumor at 4~(th) week was 4.0±1.2 g,11.3±3.5 g,12.8±3.9g in Group A,B,C respectively.Animals in Group A did not present inguinal lymph node metastasis(ILNM) in first 3 weeks,ILNM appeared in 3(3/10) rabbits at the 4~(th) week point.Animals in Group B did not present ILNM in first 2 weeks,and 3(3/10) rabbits showed ILNM at 3~(rd) week point,and a total of 7(7/10) at 4~(th) week point.5(5/10) rabbits in Group C appeared ILNM at 3~(rd) week point and a total of 8(8/10) at 4~(th) week point.Bladder tumor could be found in all animals when they were sacrificed at 4~(th) week point,and generated tumor approximately were regular and most are round in shape.No obvious satellite focus was found.HE staining showed that tumor pathology was in line with the general characteristics of transplanted VX2 tumor.
3.Tumor tissue growth factors and stromal remodeling protease IHC results:growth factors:Stroma cells(fibroblasts,endothelial cells and inflammatory cells,etc.) and tumor cells(nucleus,cytoplasm) have positive expression.TGFβ1,bFGF and HGF IOD value in Group B(15396.10±3230.57,9280.66±3754.99 and 13203.17±3990.86,respectvely) were significantly higher than Group A (8948.70±2462.91,5632.70±1943.18 and 7824.43±4077.94,respectvely),P all＜0.05;TGFβ1,bFGF and HGF IOD value in Group C were 20875.40±6737.11,13811.14±4311.62 and 14523.69±3865.41,respectively,which was higher than in Group A,P all＜0.05,and TGFβ1,bFGF IOD value is higher than Group B,the difference has statistical significance(P＜0.05);Matrix metalloproteinases:The positive expression was mainly located in stromal cells (fibroblasts,endothelial cells,inflammatory cells,etc.) and tumor cell membrane, cytoplasm,particularly in active tumor infiltrating area.MMP2 IOD values in Group A,B,C were 25337.20±8151.51,51507.50±17679.55 and 61535.66±19449.11,respectvely.Levels in Group B,C was higher than in Group A,and the difference has statistical significance(P＜0.05);MMP9 IOD values in group A,B, C were 34172.91±5243.75,60582.28±22975.45 and 90287.45±31362.21, respectvely.Group B,C was higher than Group A(P＜0.05),Group C was higher than Group B(P = 0.024).
4.Tissue tumor growth factor and stromal remodeling protease mRNA levels: growth factors:TGFβ1,bFGF and HGF mRNA levels in Group B(3.250±0.587, 2.970±0.490 and 2.101±0.527,respectvely.) was significantly higher than Group A(1.087±0.194,1.134±0.165 and1.185±0.247,respectvely)(both P＜0.05);TGFβ1,bFGF and HGF mRNA levels in Group C were 3.620±0.670, 3.651±0.744 and 3.052±0.438,respectively,higher than the Group A(all P＜0.05),and bFGF,HGF mRNA levels were higher than Group B(P＜0.05).Matrix MetaUoproteinases:MMP2 mRNA levels in Group A,B,C were 1.134±0.243, 3.67±0.945 and 3.845±1.159,and levels in Group B,C is higher than group A, (both P＜0.05);MMP9 mRNA levels in Group A,B,C were 0.955±0.166,3.360±0.628 and 4.045±1.084,respectively,and differences among all groups were statistically significant(all P＜0.05).
CONCLUSIONS
1.VX2 tumor cell suspension submucosal injection is a homogeneous and stable method to establish bladder tumor model,and can better reflect the pathogenesis of bladder tumor.
2.Bone marrow derived MSCs can promote the bladder VX2 tumor growth and development in vivo.
3.MSCs can induce high expression of certain growth factors in tumor micro-environment,which presumebly is the basic mechanism to promote tumor growth.
4.MSCs can stimulate matrix protease(MMPs) expression,which is probably one of the pathway to promote stromal remodeling and tumor invasion and metastasis.
OBJECTIVES
To assess the safety and efficacy of holmium laser resection for primary clinically non-muscle invasive bladder cancer(HOLRBT) compared with standard transurethral resection(TURBT).
METHODS
Data of a total of 212 patients with primary non-muscle invasive bladder cancer (NMIBC) was collected in this study.These patients treated by holmium laser resection(HOLRBT group) or transurethral electroresection(TURBT group) were divided into 2 groups.Patients in each group were stratified into 3 risk subgroups (low,intermediate and high risk) according to prognostic factors for recurrence,based on EAU guideline.Patient demographics and tumor characteristics regarding each group were summarized and compared.Then,HOLRBT and TURBT groups were compared,concerning intraoperative complications and postoperative characteristics, including obturator nerve reflex and bladder perforation incidence,the proportion needing postoperative bladder irrigation,as well as postoperative catheter drainage period and hospital stay.Efficacy indicated by recurrence-free survival in overall group and stratified subgroup was meanwhile analyzed and compared by Kaplan-Meier technique,as well as log-rank test.
RESULTS
Patient demographics and tumor characteristics in the 2 groups were comparable, and no statistical significance was found between the 2 groups.HOLRBT is superior to TURBT in terms of intraoperative complications such as obturator nerve reflex and postoperative catheterization time and hospital stay(P＜0.001).The mean follow-up after surgey was 34 months.Recurrence-free survival after HOLRBT treatment is similar with that of TURBT(P = 0.283).P values in low,intermediate and high risk subgroups were 0.816,0.352,and 0.592,respectively.
CONCLUSIONS
Our results have indicated that HOLRBT is a feasible,safe and effective alternative for the management of primary clinically NMIBC when compared to TURBT,with similar recurrence-free survival and less perioperative complications, meanwhile providing sufficient material for pathology evaluation.
骨髓间充质干细胞(mesenchymal stem cells,MSCs)是骨髓非造血组织中的一类多潜能成体干细胞,其具有高度的可塑性和多向分化潜能,在体外具有高度的扩增能力,并可被诱导分化为骨、软骨、肌肉、脂肪和神经等组织细胞,由于避免了胚胎干细胞在伦理、道德、法律等方面的限制,目前MSCs成为组织工程和再生医学中理想的供体细胞。而且,MSCs易于外源基因的转染和表达、极好的迁移能力(migratory ability)和肿瘤趋向性(tropism)、低免疫原性的特点,使其成为肿瘤基因治疗和靶向治疗的理想载体细胞。然而随着近年来对MSCs生理特性和肿瘤研究的不断深入,有研究发现MSCs本身可能与肿瘤发生、发展之间存在着密切的关系,提示MSCs应用的生物安全性问题值得关注。我们在前期的工作中,已经初步观察到将培养的自体MSCs回输到已经发生的VX2膀胱肿瘤组织后,能够促进肿瘤的生长,并发现MSCs在体外、体内肿瘤局部微环境可以分化为肌纤维母细胞。因此,MSCs来源的肌纤维母细胞或其他间质细胞可能参与了肿瘤间质重构,而肿瘤间质重构(remodeling)是肿瘤生长发展与侵袭的关键步骤。本部分研究我们拟通过体外扩增新西兰兔MSCs后,膀胱粘膜下接种不同比例的自体MSCs和VX2肿瘤细胞混合液,观察不同数量的MSCs对膀胱VX2肿瘤发生、发展的影响,进一步研究MSCs与VX2膀胱肿瘤发生发展的关系;同时,监测MSCs对肿瘤组织某些生长因子和间质重构蛋白的表达的影响,藉此研究MSCs来源的间质细胞与肿瘤细胞间相互作用的具体信号机制。
目的
探讨MSCs对VX2膀胱肿瘤发生、发展的影响;研究MSCs对肿瘤组织某些生长因子和间质重构蛋白的表达的影响,证实MSCs是否参与了实体肿瘤的间质重构。
方法
1.兔骨髓间充质干细胞的分离、培养和鉴定:雄性新西兰大白兔30只,每只动物均行胫骨近端骨髓穿刺抽取骨髓MSCs,体外密度梯度离心法联合细胞贴壁法分离培养扩增新西兰兔MSCs,形态学、流式细胞技术检测表面抗原等方法鉴定扩增的MSCs。
2.兔VX2膀胱肿瘤模型的建立及监测:MSCs培养成功后,制备VX2肿瘤细胞悬液,将DAPI标记的自体骨髓MSCs细胞悬液和VX2肿瘤细胞细胞悬液混合,制备一总体积为介质为300μl PBS的混合细胞悬液,行膀胱粘膜下接种,按照两种细胞比例的不同,30只新西兰大白兔按照随机原则分为3组,每组10只,具体如下:A组(10~6VX2),B组[(VX2/MSCs=1:1):10~6VX2+10~6 MSCs],C组[(VX2/MSC=1:10):10~6VX2+10~7 MSCs]。细胞膀胱粘膜下接种建立膀胱肿瘤模型,于第3、4、5、6、7、14、21、28d分别行膀胱超声多切面扫查一次,记录肿瘤最长最短直径,建立生长曲线,比较各组生长速率差异。第4周处死所有动物,取出膀胱肿瘤标本,同时记录各组远处转移情况。
3.免疫组织化学(IHC)测定各组肿瘤组织中的间质重构因子和蛋白:IHC测定各组肿瘤组织生长因子(TGFβ1、bFGF、HGF)和基质重构蛋白酶(MMP2、MMP9)的表达差异,应用Image Pro Plus 5.0数字图像分析软件计算平均积分光密度(intergrated optical density,IOD),对免疫组化(IHC)强度进行半定量分析,以IOD值代表蛋白的表达水平。从而探讨MSCs对肿瘤组织生长因子和MMPs表达的影响。
4.实时荧光定量PCR监测上述生长因子和基质重构蛋白酶mRNA:应用SYBRGreenⅠ法Real-time PCR测定各组肿瘤组织上述生长因子和基质蛋白酶,数据分析采用2~(-ΔCtΔCt)法。
结果
1.体外培养的MSCs形态均匀,生长曲线显示增长能力强,经鉴定为兔MSCs,而非造血系细胞。
2.MSCs对VX2膀胱肿瘤发生发展的影响:细胞接种后第5天,A、B、C组分别有2(2/10)、2(2/10)、6(6/10)只动物超声检查能够监测到接种部位肿瘤生长。接种第6天三组分别有6(6/10)、7(7/10)、8(8/10)只能够监测到肿瘤生长。在第一、二、三周时间点时三组动物肿瘤体积A组＜B组＜C组,差异有统计学意义(P均＜0.001),生长曲线提示,MSCs能够促进VX2膀胱肿瘤的发展。第四周时A、B、C三组生成膀胱肿瘤的质量分别为4.0±1.2g、11.3±3.5g、12.8±3.9g,B、C组大于A组,差异均有统计学意义(P＜0.05)。A组实验动物前三周均未出现腹股沟淋巴结转移,第四周时有3只(3/10)新西兰兔出现腹股沟淋巴结转移的情况;B组实验动物前两周未出现腹股沟淋巴结转移,第三周时3只(3/10)动物出现沟淋巴结转移,而第四周时共7只(7/10)出现淋巴结转移;C组实验动物第三周5只(5/10)动物出现腹股沟淋巴结,第四周时共8(8/10)只出现淋巴结转移。三组动物第四周处死解剖后均能发现膀胱肿瘤存在,生成的肿瘤大致呈圆形,形态较规则,无明显子灶形成。病理HE染色显示符合移植性VX2肿瘤的一般特点。
3.肿瘤组织中生长因子和间质重构蛋白酶IHC测定结果:生长因子:间质细胞(成纤维细胞、内皮细胞、炎性细胞等)和肿瘤细胞(胞核、胞浆)均有阳性表达。B组TGFβ1、bFGF、HGF免疫组化IOD值水平(依次为15396.10±3230.57、9280.66±3754.99、13203.17±3990.86)显著高于A组(依次为8948.70±2462.91、5632.70±1943.18、7824.43±4077.94),P均＜0.05;C组TGFβ1、bFGF、HGF免疫组化IOD值水平依次为20875.40±6737.11、13811.14±4311.62、14523.69±3865.41,分别高于A组,P均＜0.05,且其中TGFβ1、bFGF的IOD值高于B组,差异有统计学意义(P＜0.05);基质金属蛋白酶:阳性表达主要分布于间质细胞(成纤维细胞、内皮细胞、炎性细胞等)和肿瘤细胞胞膜、胞浆,尤其以肿瘤浸润活跃处为著。MMP2免疫组化IOD值在A、B、C三组依次为25337.20±8151.51、51507.50±17679.55、61535.66±19449.11,B、C组高于A组,差异有统计学意义(P＜0.05),B、C组差异无统计学意义(P=0.231):MMP9免疫组化IOD值在A、B、C三组依次为34172.91±5243.75、60582.28±22975.45、90287.45±31362.21,B、C组高于A组,差异有统计学意义(P＜0.05),C组高于B组,差异有统计学意义(P=0.024)。
4.肿瘤组织中生长因子和间质重构蛋白酶mRNA水平:生长因子:B组TGFβ1、bFGF、HGF mRNA表达水平(依次为3.250±0.587、2.970±0.490、2.101±0.527)显著高于A组(依次为为1.087±0.194、1.134±0.165、1.185±0.247),P均＜0.05;C组TGFβ1、bFGF、HGF mRNA表达水平依次为3.620±0.670、3.651±0.744、3.052±0.438,分别高于A组,P均＜0.05,其中C组bFGF、HGF mRNA表达高于B组,且差异有统计学意义(P＜0.05)。基质金属蛋白酶:MMP2 mRNA表达水平在A、B、C三组依次为1.134±0.243、3.67±0.945、3.845±1.159,B、C高于A组,差异有统计学意义(P＜0.05):MMP9mRNA表达水平在A、B、C三组依次为0.955±0.166、3.360±0.628、4.045±1.084,依次升高,各组间差异均有统计学意义,P均＜0.05。
结论
1.VX2肿瘤细胞悬液膀胱粘膜下接种建立膀胱肿瘤模型具有量化、均一、稳定的特点,并且能够反映膀胱肿瘤的发生发展过程。
2.骨髓MSCs在体内膀胱微环境下能够促进VX2实体肿瘤的发生发展。
3.骨髓MSCs能够诱导肿瘤微环境高表达某些生长因子,并且可能是MSCs在肿瘤局部促进肿瘤生长的基础机制。
4.骨髓MSCs胞能够促进肿瘤间质某些基质蛋白酶(MMPs)表达,可能是其促进肿瘤间质重构和侵袭转移的机制之一。
目的以标准的经尿道膀胱肿瘤电切(Transurethral Electroresection of BladderTumor,TURBT)作为对照,对钬激光治疗非肌层浸润性膀胱肿瘤(Holmium LaserResection of Bladder Tumor,HOLRBT)的临床治疗效果与安全性进行评价。
方法收集212例原发性非肌层浸润性膀胱肿瘤的患者资料,按照所接受的手术方式不同将其分为两组(HOLRBT组和TURBT组)。同时,将每组患者按照复发风险(EAU 2002)的不同,分为低、中、高危非浸润性膀胱肿瘤三个亚组。总结两组患者临床及病理资料,对两组手术时间、闭孔神经反射及膀胱穿孔发生率、术后需要膀胱冲洗的患者比例、留置导尿管时间、术后住院时间等指标进行比较,从而对其手术安全性进行评价;通过Kaplan-Meier分析和Log-rank检验比较两组患者整体上及各个亚组间的无复发生存情况(Recurrence-Free Survival,RFS),基于与TURBT的比较,评价HOLRBT的临床治疗效果。
结果两组患者的一般资料与病理特点差异无统计学意义(P＞0.05),HOLRBT组与TURBT组的手术时间分别为30.69 min±16.10 min、24.90 min±14.44 min。HOLRBT组无闭孔神经反射发生,而TURBT组7(7/111)例发生闭孔神经反射,术后需要膀胱冲洗的患者比例(P=0.038)、留置尿管时间和术后住院时间均小于TURBT组(P＜0.01)。平均随访时间34 mon,Kaplan-Meier统计分析揭示HOLRBT组与TURBT整体相比,RFS差异无统计学意义(P=0.283)。经过复发危险度分层校正后,低危、中危、高危亚组内,两种手术方式的RFS相比,差异均无统计学意义,三个亚组内相关的P值依次为0.816、0.352、0.592(P＞0.05)。
结论钬激光切除治疗非肌层浸润性膀胱肿瘤的近期复发率(100%-RFS)与经尿道膀胱肿瘤电切相近,但在控制术中出血及闭孔神经反射,缩短术后留置尿管时间和膀胱冲洗时间方面更有优势。
BACKGROUD
Bone marrow-derived mesenchymal stem cells(MSCs) come from bone marrow non-hematopoietic tissue,which are a kind of pluripotent adult stem cells,have high degree of plasticity,and are capable of developing into diverse functional cell lineages, including bone,cartilage,myoblasts,fat and neural cells cells.Instead of embryonic stem cells,MSCs avoid the ethical,moral and legal constraints,and have been considered to represent ideal cell sources of regenerative medicine and tissue engineering currently.As a consequence,MSCs has aroused widespread interest. Moreover,MSCs can be readily transfected,allowing for easy ex vivo modification., have excellent migratory ability,the tumor tropism and low immunogenicity of the characteristics,which make them ideal vector cells in tumor gene therapy and targeted therapy.However,with the increasing apprehension of physiological characteristics regarding MSCs and the deepening of tumor research in recent years.Some scholars have found that MSCs themselves might be associated with tumorigenesis closely, suggesting that long-term biosafety of MSCs for clinical applications deserves further assessment.In previous work,We have initially observed that cultured autologous MSCs transfusion into VX2 bladder tumor tissue could promote tumor growth,and found that MSCs could be differentiated into myofibroblast in vitro and in vivo tumor micro-environment,which is regarded as an important cancer-associated fibroblast in tumor stroma.Therefore,MSCs derived myofibroblast or other stroma cells may be involved in tumor stroma remodeling.And activated tumor micro-environment or stroma remodeling plays a key role in tumor growth and infiltration.In this section, we intend to amplify of MSCs in vitro first,then establish tumor model through bladder submucosal innoculation of different proportions of autologous MSCs and VX2 tumor cells,observing the effect of different numbers of MSCs on VX2 bladder tumor occurrence and development in New Zealand rabbit.In this way,we try to study the relationship accurately between MSCs and VX2 bladder tumor occurrence and development;Meanwhile,by monitoring the tumor tissue growth factors and some stromal remodeling enzyme,we try to disclose the concrete signaling mechanism of MSCs induced stroma remodeling and the interaction between tumor cells and stroma cells.
OBJECTIVE
To investigate the effect of MSCs on the VX2 bladder tumor occurrence and development,to explore tumor tissue growth factor and stromal remodeling enzyme expression change induced by MSCs and whether MSCs are involved in the tumor stroma remodeling.
METHODS
1.Isolation,culture and identification of rabbit MSCs in vitro:A total of 30 male New Zealand rabbits were used.Marrow aspirates were obtained from the proximal tibia of each animal,and density gradient centrifugation followed by repeated adherence in plastic bottle were applied in MSCs isolation and amplification.Morphology and flow cytometry detection of surface antigen were used to identify and confirmation cultured MSCs.
2.Rabbit VX2 bladder tumor model establishment and monitoring:After successful MSCs cultivation,VX2 tumor cell suspension was prepared and mixed with DAPI labeled autologous MSCs in a total volume for 300μl PBS.The mixed cell suspension was transplanted by bladder submucosal innoculation.Based on the ratio of two different cells,30 New Zealand rabbits were randomly divided into 3 groups with 10 in each group,as follows:Group A(10~6 VX2),Group B [(VX2/MSCs=1:1):10~6 VX2 + 10~6 MSCs]and Group C[(VX2/MSC=1:10): 10~6 VX2 + 10~7 MSCs].Multisection ultrasound scanning was conducted 3,4,5,6, 7,14,21,28d respectively after cell innoculation to monitor tumor occurrence and growth.The tumor growth curve was set up and inguinal lymph nodes metastasis was observed to compare tumor progression in 3 groups.All animals were sacrificed at 4 weeks point.Bladder tumor specimens were obtained to make frozen and paraffin section,and distant organ metastasis was recorded.
3.Immunohistochemistry(IHC) assay of tumor growth factors and remodeling enzymes:growth factors(TGFβ1,bFGF,HGF) and matrix remodeling proteases (MMP2,MMP9) expression was detected in developed tumor,and Image Pro Plus 5.0 Software was used to analyze IHC intensity semi-quantitatively.Integral optical density(IOD) value represents the level of protein expression and was applied to compare the difference in 3 groups.
4.Real-time quantitative PCR assay of the above-mentioned growth factors and matrix remodeling protease mRNA:SYBR Green I method was used technically, and data analysis using 2~(ΔCtΔCt) method was conducted.
RESULTS
1.Cultured MSCs in vitro present uniform morphology and its growth curve showed strong amplification ability,and were identified as rabbit MSCs,rather than hematopoietic cells.
2.The effect of MSCs on tumor development:on 5~(th) day after cell inoculation,2 (2/10),2(2/10),6(6/10) animals in Group A,B,C respectively could be found by ultrasound in the bladder injection site,and 6(6/10)、7(7/10)、8(8/10) animals could be monitored in Group A,B,C respectively on 6~(th) day.At the 1~(st),2~(nd) and 3~(rd) week time point,tumor volume in group A＜group B＜group C,and the difference has statistical significance(P all＜0.001).Tumor growth curve showed that MSCs could promote VX2 bladder tumor growth.The weight of bladder tumor at 4~(th) week was 4.0±1.2 g,11.3±3.5 g,12.8±3.9g in Group A,B,C respectively.Animals in Group A did not present inguinal lymph node metastasis(ILNM) in first 3 weeks,ILNM appeared in 3(3/10) rabbits at the 4~(th) week point.Animals in Group B did not present ILNM in first 2 weeks,and 3(3/10) rabbits showed ILNM at 3~(rd) week point,and a total of 7(7/10) at 4~(th) week point.5(5/10) rabbits in Group C appeared ILNM at 3~(rd) week point and a total of 8(8/10) at 4~(th) week point.Bladder tumor could be found in all animals when they were sacrificed at 4~(th) week point,and generated tumor approximately were regular and most are round in shape.No obvious satellite focus was found.HE staining showed that tumor pathology was in line with the general characteristics of transplanted VX2 tumor.
3.Tumor tissue growth factors and stromal remodeling protease IHC results:growth factors:Stroma cells(fibroblasts,endothelial cells and inflammatory cells,etc.) and tumor cells(nucleus,cytoplasm) have positive expression.TGFβ1,bFGF and HGF IOD value in Group B(15396.10±3230.57,9280.66±3754.99 and 13203.17±3990.86,respectvely) were significantly higher than Group A (8948.70±2462.91,5632.70±1943.18 and 7824.43±4077.94,respectvely),P all＜0.05;TGFβ1,bFGF and HGF IOD value in Group C were 20875.40±6737.11,13811.14±4311.62 and 14523.69±3865.41,respectively,which was higher than in Group A,P all＜0.05,and TGFβ1,bFGF IOD value is higher than Group B,the difference has statistical significance(P＜0.05);Matrix metalloproteinases:The positive expression was mainly located in stromal cells (fibroblasts,endothelial cells,inflammatory cells,etc.) and tumor cell membrane, cytoplasm,particularly in active tumor infiltrating area.MMP2 IOD values in Group A,B,C were 25337.20±8151.51,51507.50±17679.55 and 61535.66±19449.11,respectvely.Levels in Group B,C was higher than in Group A,and the difference has statistical significance(P＜0.05);MMP9 IOD values in group A,B, C were 34172.91±5243.75,60582.28±22975.45 and 90287.45±31362.21, respectvely.Group B,C was higher than Group A(P＜0.05),Group C was higher than Group B(P = 0.024).
4.Tissue tumor growth factor and stromal remodeling protease mRNA levels: growth factors:TGFβ1,bFGF and HGF mRNA levels in Group B(3.250±0.587, 2.970±0.490 and 2.101±0.527,respectvely.) was significantly higher than Group A(1.087±0.194,1.134±0.165 and1.185±0.247,respectvely)(both P＜0.05);TGFβ1,bFGF and HGF mRNA levels in Group C were 3.620±0.670, 3.651±0.744 and 3.052±0.438,respectively,higher than the Group A(all P＜0.05),and bFGF,HGF mRNA levels were higher than Group B(P＜0.05).Matrix MetaUoproteinases:MMP2 mRNA levels in Group A,B,C were 1.134±0.243, 3.67±0.945 and 3.845±1.159,and levels in Group B,C is higher than group A, (both P＜0.05);MMP9 mRNA levels in Group A,B,C were 0.955±0.166,3.360±0.628 and 4.045±1.084,respectively,and differences among all groups were statistically significant(all P＜0.05).
CONCLUSIONS
1.VX2 tumor cell suspension submucosal injection is a homogeneous and stable method to establish bladder tumor model,and can better reflect the pathogenesis of bladder tumor.
2.Bone marrow derived MSCs can promote the bladder VX2 tumor growth and development in vivo.
3.MSCs can induce high expression of certain growth factors in tumor micro-environment,which presumebly is the basic mechanism to promote tumor growth.
4.MSCs can stimulate matrix protease(MMPs) expression,which is probably one of the pathway to promote stromal remodeling and tumor invasion and metastasis.
OBJECTIVES
To assess the safety and efficacy of holmium laser resection for primary clinically non-muscle invasive bladder cancer(HOLRBT) compared with standard transurethral resection(TURBT).
METHODS
Data of a total of 212 patients with primary non-muscle invasive bladder cancer (NMIBC) was collected in this study.These patients treated by holmium laser resection(HOLRBT group) or transurethral electroresection(TURBT group) were divided into 2 groups.Patients in each group were stratified into 3 risk subgroups (low,intermediate and high risk) according to prognostic factors for recurrence,based on EAU guideline.Patient demographics and tumor characteristics regarding each group were summarized and compared.Then,HOLRBT and TURBT groups were compared,concerning intraoperative complications and postoperative characteristics, including obturator nerve reflex and bladder perforation incidence,the proportion needing postoperative bladder irrigation,as well as postoperative catheter drainage period and hospital stay.Efficacy indicated by recurrence-free survival in overall group and stratified subgroup was meanwhile analyzed and compared by Kaplan-Meier technique,as well as log-rank test.
RESULTS
Patient demographics and tumor characteristics in the 2 groups were comparable, and no statistical significance was found between the 2 groups.HOLRBT is superior to TURBT in terms of intraoperative complications such as obturator nerve reflex and postoperative catheterization time and hospital stay(P＜0.001).The mean follow-up after surgey was 34 months.Recurrence-free survival after HOLRBT treatment is similar with that of TURBT(P = 0.283).P values in low,intermediate and high risk subgroups were 0.816,0.352,and 0.592,respectively.
CONCLUSIONS
Our results have indicated that HOLRBT is a feasible,safe and effective alternative for the management of primary clinically NMIBC when compared to TURBT,with similar recurrence-free survival and less perioperative complications, meanwhile providing sufficient material for pathology evaluation.
引文
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