Lumican and versican protein expression are associated with colorectal adenoma-to-carcinoma progression

BackgroundOne prominent event associated with colorectal adenoma-to-carcinoma progression is genomic instability. Approximately 85% of colorectal cancer cases exhibit chromosomal instability characterized by accumulation of chromosome copy number aberrations (CNAs). Adenomas with gain of chromosome 8q, 13q, and/or 20q are at high risk of progression to cancer. Tumor progression is also associated with expansion of the extracellular matrix (ECM) and the activation of non-malignant cells within the tumor stroma. The glycoproteins versican and lumican are overexpressed at the mRNA level in colon carcinomas compared to adenomas, and are associated with the formation of tumor stroma.PurposeThe aim of this study was to characterize versican and lumican protein expression in tumor progression and investigate their association with CNAs commonly associated with adenoma-to-carcinoma progression.MethodsTissue microarrays were constructed with colon adenomas and carcinomas that were characterized for MSI-status and DNA copy number gains of chromosomes 8q, 13q and 20q. Sections were immunohistochemically stained for lumican and versican. Protein expression levels were evaluated using digitized slides, and scores were finally dichotomized into a positive or negative score per sample.ResultsLumican and versican expression were both observed in neoplastic cells and in the tumor stroma of colon adenomas and carcinomas. Lumican expression was more frequently present in epithelial cells of carcinomas than adenomas (49% versus 18%; P = 0.0001) and in high-risk adenomas and carcinomas combined compared to low-risk adenomas (43% versus 16%; P = 0.005). Versican staining in the tumor stroma was more often present in high-risk adenomas combined with carcinomas compared to low-risk adenomas (57% versus 36%; P = 0.03) and was associated with the presence of gain of 13q (71% versus 44%; P = 0.04).ConclusionEpithelial lumican and stromal versican protein expression are increased during colorectal adenoma-to-carcinoma progression.

背景 与结直肠腺瘤-癌进展相关的核心事件之一为基因组不稳定（genomic instability）。约85%的结直肠癌病例表现出染色体不稳定（chromosomal instability），其特征为染色体拷贝数畸变（copy number aberrations, CNAs）的累积。携带8q、13q和/或20q染色体拷贝数获得的腺瘤进展为癌症的风险较高。肿瘤进展还与细胞外基质（extracellular matrix, ECM）的重塑以及肿瘤间质内非恶性细胞的活化相关。糖蛋白Versican（versican）与Lumican（lumican）在结直肠癌组织中的mRNA表达水平较腺瘤组织更高，且与肿瘤间质的形成相关。
目的 本研究旨在明确肿瘤进展过程中Versican与Lumican的蛋白表达特征，并探究其与腺瘤-癌进展相关的常见拷贝数畸变的关联。
方法 本研究构建了结直肠腺瘤与癌组织的组织微阵列（tissue microarrays），并对样本的微卫星不稳定性（microsatellite instability, MSI）状态以及8q、13q、20q染色体的DNA拷贝数获得情况进行鉴定。对组织切片进行Lumican与Versican的免疫组化染色。通过数字化玻片评估蛋白表达水平，最终将每个样本的评分二分为阳性与阴性。
结果 在结直肠腺瘤与癌组织的肿瘤细胞及肿瘤间质中，均检测到Lumican与Versican的表达。癌组织上皮细胞中Lumican的表达阳性率高于腺瘤组织（49% vs 18%；P=0.0001）；高危腺瘤与癌组织联合队列的上皮Lumican阳性率也高于低危腺瘤队列（43% vs 16%；P=0.005）。肿瘤间质中Versican的染色阳性率在高危腺瘤联合癌组织队列中高于低危腺瘤队列（57% vs 36%；P=0.03），且与13q染色体拷贝数获得相关（71% vs 44%；P=0.04）。
结论 结直肠腺瘤-癌进展过程中，上皮细胞Lumican与肿瘤间质Versican的蛋白表达水平均显著升高。