Objective To construct the proteome expression profile of tumor microenvironment in muscleinvasivebladder cancer of different metastatic risk groups and to discuss the decisive role of biological pathwaychange in cancer heterogeneity. Methods Laser capture microdissection was employed to harvest purified muscleinvasivebladder cancer stromal cells from 3 different metastatic risk groups. Isobaric tags for relative and absolutequantitation(iTRAQ) and two-dimensional liquid chromatography tandem mass spectrometry(2D LC-MS / MS) wereused to identify the differentially expressed proteins. Subsequently,the differentially expressed proteins were furtheranalyzed by bioinformatics tools. Results Authors identified 1 049 differentially expressed proteins by match -paired comparison(high risk vs. median,low risk and normal groups; median risk vs. low risk and normal groups,low risk vs. normal group; a total of 6 comparisons). A total of 510,549,548 proteins as significantly altered(ratio fold -change ≥1.5 or ≤0.667 between the metastatic potential risk group and the normal group) werepresented in the low / median / high metastatic risk group,respectively. Pathway analysis revealed that thedifferentially expressed proteins were mainly located in the Kyoto Encyclopedia of Genes and Genomes pathways,including focal adhesion pathway,systemic lupus erythematosus pathway and ECM -receptor interaction pathway.Conclusions Stromal cells,an important part of the cancer tissue,are pivotal for regulating the heterogeneity ofcancer. Common changes in biological pathways determine the malignant phenotype of muscle -invasive bladdercancer.%目的：构建肌层浸润性膀胱癌肿瘤微环境蛋白质表达谱，并探讨生物通路改变在肿瘤异质性中的决定性作用。方法①按照不同的转移风险收集浸润性膀胱癌患者临床标本，激光捕获显微切割获得纯化的间质细胞；②同位素标记相对和绝对定量（iTRAQ）技术和二维液相色谱串联质谱鉴定蛋白质表达谱；③生物信息学方法进一步分析鉴定差异表达蛋白质，并从生物通路层面揭示癌发生机制。结果不同转移风险组中配对癌间质／正常上皮间质标本中鉴定出差异表达蛋白1049个，其中分别有510、549、548个显著差异表达的蛋白质分别在低危、中危、高危转移组中表达（高、低转移风险组与正常组比值设定为≥1．5或≤0．667）。通路分析显示差异表达蛋白主要位于KEGG通路中，包括：聚合黏附、系统性红斑狼疮、细胞外基质受体相互作用途径。结论本研究验证了肿瘤微环境在调节癌异质性中起到了关键性作用。生物通路的改变决定肌层浸润性膀胱癌的恶性表型。
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