Mesker Wilma E, Liefers Gerrit-Jan, Junggeburt Jan M C, van Pelt Gabi W, Alberici Paola, Kuppen Peter J K, Miranda Noel F, van Leeuwen Karin A M, Morreau Hans, Szuhai Karoly, Tollenaar Rob A E M, Tanke Hans J
Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
Cell Oncol. 2009;31(3):169-78. doi: 10.3233/CLO-2009-0478.
For stage I-II colon cancer a significant number (5-25%) of patients has recurrent disease within 5 years. There is need to identify these high-risk patients as they might benefit from additional treatment. Stroma-tissue surrounding the cancer cells plays an important role in the tumor behavior. The proportion of intra-tumor stroma was evaluated for the identification of high-risk patients. In addition, protein expression of markers involved in pathways related to stroma production and epithelial-to-mesenchymal transition (EMT) was analyzed: beta-catenin, TGF-beta-R2 and SMAD4.
In a retrospective study of 135 patients with stage I-II colon cancer, the amount of stroma was estimated on routine haematoxylin-eosin stained histological sections. Sections were also immunohistochemically stained for beta-catenin, TGF-beta-R2 and SMAD4.
Of 135 analyzed patients 34 (25.2%) showed a high proportion of stroma (stroma-high) and 101 (74.8%) a low proportion (stroma-low). Significant differences in overall-survival and disease-free-survival were observed between the two groups, with stroma-high patients showing poor survival (OS p<0.001, HZ 2.73, CI 1.73-4.30; DFS p<0.001, HZ 2.43, CI 1.55-3.82). A high-risk group was identified with stroma-high and SMAD4 loss (OS p=0.008, HZ 7.98, CI 4.12-15.44, DFS p=0.005, HZ 6.57, CI 3.43-12.56); 12 of 14 (85.7%) patients died within 3 years. In a logistic-regression analysis a high proportion of stroma and SMAD4 loss were strongly related (HZ 5.42, CI 2.13-13.82, p<0.001).
Conventional haematoxylin-eosin stained tumor slides contain more prognostic information than previously fathomed. This can be unleashed by assessing the tumor-stroma ratio. The combination of analyzing the tumor-stroma ratio and staining for SMAD4 results in an independent parameter for confident prediction of clinical outcome.
对于I-II期结肠癌患者，相当一部分（5%-25%）在5年内会出现疾病复发。有必要识别出这些高危患者，因为他们可能从额外的治疗中获益。癌细胞周围的基质组织在肿瘤行为中起着重要作用。评估肿瘤内基质的比例以识别高危患者。此外，还分析了与基质产生和上皮-间质转化（EMT）相关途径中标志物的蛋白表达：β-连环蛋白、转化生长因子-β受体2（TGF-β-R2）和SMAD4。
在一项对135例I-II期结肠癌患者的回顾性研究中，在常规苏木精-伊红染色的组织学切片上估计基质的量。切片还进行了β-连环蛋白、TGF-β-R2和SMAD4的免疫组织化学染色。
在135例分析患者中，34例（25.2%）显示基质比例高（基质高），101例（74.8%）显示基质比例低（基质低）。两组患者的总生存期和无病生存期存在显著差异，基质高的患者生存期较差（总生存期p<0.001，风险比2.73，置信区间1.73-4.30；无病生存期p<小0.001，风险比2.43，置信区间1.55-3.82）。确定了一个高危组，其特征为基质高且SMAD4缺失（总生存期p=0.008，风险比7.98，置信区间4.12-15.44；无病生存期p=0.005，风险比6.57，置信区间3.43-12.56）；14例患者中有12例（85.7%）在3年内死亡。在逻辑回归分析中，基质比例高和SMAD4缺失密切相关（风险比5.42，置信区间2.13-13.82，p<0.001）。
传统苏木精-伊红染色的肿瘤切片包含的预后信息比以前认为的更多。通过评估肿瘤-基质比例可以揭示这些信息。分析肿瘤-基质比例和SMAD4染色相结合可产生一个独立参数，用于可靠预测临床结果。
