Claudin‐18 is associated with poor prognosis of colorectal cancer

Claudins are a family of tetraspan transmembrane proteins of the tight junctions. Tight junctions establish the paracellular barrier that controls the flow of molecules in the intercellular space between an epithelium’s cells. There are at least 24 Claudin proteins with organ-specific expression. Evidence of altered Claudin expression in various human malignancies has been accumulating.

Claudin 18 is one such protein, playing a key role in constructing tight junctions. There are two isoforms, Claudin 18.1 and Claudin 18.2. Claudin 18.1 is found primarily in the lungs. While in normal human tissues, expression of Claudin 18.2 is exclusively found in gastric epithelial cells and not in other organs, including the esophagus, colon, pancreas, and lung.

However, altered Claudin-18 expression has been documented in various diseases. Expression is increased in both experimental colitis and human inflammatory bowel disease. Frequent ectopic activation of Claudin-18 was reported in pancreatic, esophageal, ovarian, and lung tumors, using quantitative reverse transcription-PCR.

Matsuda, et al. have previously reported that expression of Claudin-18 is retained in about half of gastric cancers, which correlated with a survival rate. Gastric cancers are classified as having a gastric, gastric and intestinal mixed, or intestinal phenotype depending on mucin phenotypic markers’ expression. In the article, “Immunohistochemical analysis of colorectal cancer with gastric phenotype: Claudin-18 is associated with poor prognosis”, Matsuda and researchers investigate the significance of Claudin-18 expression in colorectal cancer and its association with clinicopathological factors. Investigators performed immunohistochemical analysis of surgically resected colorectal cancer samples. In addition, they reviewed the association between Claudin-18 and various markers including gastric/ intestinal phenotype (MUC5AC, MUC6, MUC2, CD10), CDX2, other Claudins (Claudin-3 and Claudin-4), p53 and Ki-67. And finally, they evaluated the relationship between Claudin-18 expression and patients’ prognosis.

Primary tumor samples were collected from 569 patients with colorectal cancer. Immunohistochemical staining was performed. Claudin-18, CDX2, and p53 staining were classified according to the percentage of stained cancer cells. According to Matsuda et al., expression was considered ‘negative’ if <10% of cancer cells were stained. When at least 10% of cancer cells were stained, the result of immunostaining was considered ‘positive.’ Expression of Claudin-3 and Claudin-4 was considered to be ‘reduced’ if less than 50% of cancer cells were stained. When at least 50% of cancer cells were stained, the immunostaining was considered ‘preserved’. Ki-67 expression was classified into two groups according to the percentage of stained cancer cells. Claudin-18 expression was detected in 21 of the 569 colorectal cancer samples (4%) and was seen exclusively on the cell membrane. Expression of Claudin-18 was not correlated with T grade, N grade, tumor staging, or histological type colorectal cancer. Positive expression of Claudin-18 was significantly more frequent in MUC5AC-positive cases than MUC5AC-negative cases; in immunohistochemical staining, coexpression of Claudin-18 and MUC5AC was often detected. On the other hand, CDX2 was detected in 448 of the 569 (79%) cases, and positive expression of Claudin-18 was significantly more frequent in CDX2-negative cases than CDX2-positive cases.

Ectopic expression of Claudin-18 in colorectal cancer was correlated with poor survival, in direct opposite of an earlier study performed by the same group. Claudin family members are crucial components of tight junction and exhibit highly tissue-specific patterns. In gastric cancer, down-regulation of Claudins could increase the diffusion of nutrients and other extracellular growth factors that promote cancer cell growth, survival, and motility. In this study, researchers found colorectal cancer with Claudin-18 expression has a poor prognosis and demonstrates a gastric phenotype that is significantly MUC5AC-positive or CDX2- negative in expression. Claudin-18 may be a useful marker to predict colorectal cancer with poor prognosis.