Mezheyeuski Artur, Strell Carina, Hrynchyk Ina, Guren Tormod Kyrre, Dragomir Anca, Doroshenko Tatyana, Pashkova Oksana, Gorgun Julia, Ruksha Kseniya, Pfeiffer Per, Kure Elin H, Sorbye Halfdan, Edler David, Martling Anna, Glimelius Bengt, Östman Arne, Portyanko Anna
Department of Oncology-Pathology, Karolinska Institutet, Cancer Centre Karolinska, R8:03, Stockholm, Sweden.
Department of Pathology, Belarusian State Medical University, Minsk, Belarus.
Virchows Arch. 2018 Mar;472(3):395-405. doi: 10.1007/s00428-017-2263-3. Epub 2017 Nov 13.
Claudin-2 is a trans-membrane protein-component of tight junctions in epithelial cells. Elevated claudin-2 expression has been reported in colorectal cancer (CRC). The aim of this study was to investigate the expression patterns of claudin-2 in human CRC samples and analyze its association with clinical characteristics and treatment outcome. TMAs of primary tumors from two cohorts of metastatic CRC (mCRC) were used. Claudin-2 IHC staining was evaluated in a semi-quantitative manner in different regions and cell types. Claudin-2 expression was also analyzed by immunofluorescence in primary cultures of human CRC cancer-associated fibroblasts (CAFs). Initial analyses identified previously unrecognized expression patterns of claudin-2 in CAFs of human CRC. Claudin-2 expression in CAFs of the invasive margin was associated with shorter progression-free survival. Subgroup analyses demonstrated that the survival associations occurred among cases that received 5-FU+oxaliplatin combination treatment, but not in patients receiving 5-FU±irinotecan. The finding was validated by analyses of the independent cohort. In summary, previously unreported stromal expression of claudin-2 in CAFs of human CRC was detected together with significant association between high claudin-2 expression in CAFs and shorter survival in 5-FU+oxaliplatin-treated mCRC patients.
Claudin-2是上皮细胞紧密连接的一种跨膜蛋白成分。据报道，结直肠癌（CRC）中Claudin-2表达升高。本研究的目的是调查Claudin-2在人CRC样本中的表达模式，并分析其与临床特征及治疗结果的关联。使用了来自两个转移性CRC（mCRC）队列的原发性肿瘤组织芯片（TMAs）。对Claudin-2免疫组化染色在不同区域和细胞类型中进行半定量评估。还通过免疫荧光在人CRC癌相关成纤维细胞（CAFs）的原代培养物中分析Claudin-2表达。初步分析确定了人CRC的CAFs中Claudin-2以前未被认识的表达模式。侵袭边缘CAFs中Claudin-2表达与无进展生存期较短相关。亚组分析表明，生存关联发生在接受5-氟尿嘧啶+奥沙利铂联合治疗的病例中，而在接受5-氟尿嘧啶±伊立替康治疗的患者中未出现。该发现通过对独立队列的分析得到验证。总之，检测到了人CRC的CAFs中Claudin-2以前未报道的基质表达，并且在接受5-氟尿嘧啶+奥沙利铂治疗的mCRC患者中，CAFs中Claudin-2高表达与较短生存期之间存在显著关联。
