Table 2.
Expression of the different claudins in various types of cancers and their clinicopathologic correlations.
| CLDN | Malignancy | Expression | Clinicopathologic Correlations |
|---|---|---|---|
| CLDN1 | Laryngeal SCC [59] | Increased | |
| Thyroid [60] | Increased | Higher expressions were noted in PTC > FV-PTC > FTC > FA. | |
| Esophageal SCC [9,61] | Decreased | Decreased expression is correlated with recurrence status, short DFS, and OS. | |
| Colorectal [62,63,64,65,66] | Increased | Associated with cancer stemness and chemoresistance. Decreased expression is significantly associated with the progression of histopathologic grade, larger tumor size, vascular invasion, higher pathological tumor stage, high metastatic lymph node ratio, and worse OS and PFS. |
|
| Lung adenocarcinoma [67] | Increased | Overexpression is associated with chemoresistance (to cisplatin and doxorubicin). | |
| Breast [68,69,70,71] | Increased | High expression is associated with aggressive forms of BC, including inflammatory BC, hereditary BC, some high-grade invasive ductal carcinomas, and the basal-like subtypes. Expression is noted to increase following neoadjuvant chemotherapy. |
|
| BCC of skin [72] | Increased in low-grade BCC | ||
| Prostate [73] | Increased | Expression is associated with lower pT, low Gleason score, and reduced risk of PSA recurrence. | |
| Ovarian cancer [9,74] | Increased | ||
| CLDN2 | Lung adenocarcinoma [75,76] | Increased | |
| Oral SCC [77] | Increased | Increased expression is associated with shorter RFS. | |
| Breast [78] | Increased | ||
| Colorectal [63,66,79] | Increased | Increased expression is associated with replacement-type liver metastasis, which carries a worse prognosis compared to the desmoplastic type. | |
| CLDN3 | Breast [9,70,78,80,81] | Increased in bilateral breast cancer (BC) | Loss of CLDN3 is more prominent in ER-negative subgroup of bilateral BC. Expression is associated with tumor size > 2 cm and with menopause. Expression is noted to decrease following neoadjuvant chemotherapy. |
| Prostate [82,83] | Decreased. However, other study showed increased levels [9] | Decreased expression is associated with CRPC, cases with Gleason score ≥ 8, and locally advanced cases. It is also associated with worse DFS and OS. | |
| Colorectal | Decreased [84], but other study showed increased expression [66] | CRC is characterized by cytoplasmic expression instead of apical and lateral membrane expression of CLDN3. High expression is associated with worse OS in CMS2 and CMS3 molecular subtypes [85]. Expression is negatively associated with CD4+ T cell infiltration. |
|
| Gastric [86] | CLDN3 has high expression in the immunologically cold tumors and negative correlation with CD8+ T cells in GC. | ||
| Ovarian [9,74] | Increased | Overexpression is correlated with worse OS and PFS. | |
| Lung [9] | Increased | ||
| CLDN4 | Breast [9,78,80,87,88,89,90,91,92] | Increased (more in unilateral BC compared to bilateral BC) | Increased expression is associated with poor OS and with a higher level of circulating tumor DNA. Its expression has a negative correlation with ER and PR and a positive correlation with HER2-neu. CLDN-low TNBC phenotypically behaves like mammary stem cells or epithelial precursor cells and has a poor prognosis associated with early onset of cancer, high histology grade, large tumor size, lymphocytic infiltration, and low local recurrence rate. |
| BCC of skin | Decreased in low-grade BCC | ||
| Oral SCC [77] | Decreased | Reduced expression had a negative impact on RFS. | |
| Lung [9] | Increased | ||
| Ovarian [9,74,93] | Increased | CLDN4 can be used to differentiate serous carcinomas (expressed in all cases) from peritoneal mesothelioma (not expressed). Overexpression is correlated with worse OS and PFS. |
|
| Cervical [94] | Increased | Overexpression promotes cervical cancer cell migration and invasion. | |
| Endometrial [95] | Decreased or absent but increased in uterine carcinosarcomas [96] | ||
| Prostate [97] | Increased at both RNA and protein levels | Expression is more pronounced in lower-grade primary tumors and also in metastases. | |
| Pancreatic [9] | Increased | ||
| Gastric [9,98] | Increased | Higher expression is noted in intestinal rather than diffuse type. | |
| Colorectal [66] | Increased | ||
| CLDN5 | Breast [78] | Decreased | Increased expression is associated with better OS. |
| Oral SCC [77] | Decreased | ||
| Ovarian [74] | Decreased | ||
| Cervical [99] | Decreased | ||
| Colorectal [63,66] | Decreased | ||
| CLDN6 | Breast [78,100,101] | Increased in ERβ+ | Decreases the invasion and migration of breast cancer cells. |
| Endometrial [102] | Increased | Aberrant CLDN6 expression promotes tumor growth and invasion in endometrial cancer tissues. | |
| Cervical [103] | Increased | Overexpression is associated with lymph node metastasis and lymphovascular infiltration. It also contributes to chemoresistance. | |
| Colon [104] | Expression is associated with decreased migration and invasion abilities of cells. | ||
| Gastric [105,106,107] | Increased | It enhances an array of proteins important for the EMT. Its expression is linked to worse OS in intestinal-type gastric cancer. |
|
| Ovarian [74] | Increased | Overexpression is correlated with worse OS and PFS. | |
| CLDN7 | Breast [78,81,90,91,92] | Increased in poorly differentiated tumors. | CLDN-low TNBC phenotypically behaves like mammary stem cells or epithelial precursor cells and has a poor prognosis associated with early onset of cancer, high histology grade, large tumor size, lymphocytic infiltration, and low local recurrence rate. |
| Oral SCC [77] | Decreased | Reduced expression is associated with the tumor stage and presence of lymph node metastases. | |
| Ovarian [9,74] | Increased | ||
| Colorectal [66] | Increased | ||
| Esophageal SCC [108,109] | Increased | Reduced expression is associated with the depth of invasion, stage, lymphatics, and lymph node invasion. | |
| Salivary adenoid cystic carcinoma [110] | Increased | ||
| Lung [9,111,112] | Increased | Reduced expression is associated with worse OS. | |
| Thyroid [9] | Increased | ||
| Gastric [9,113] | Increased | ||
| Pancreatic [9] | Increased | ||
| CLDN8 | Breast [78] | Decreased | |
| Colorectal [63,79] | Decreased | It is highly expressed in desmoplastic metastases. | |
| CLDN9 | Breast [78] | Increased | |
| Endometrial [42] | Increased | Higher expression is associated with lower 5-year disease-specific OS. | |
| Ovarian [74] | Increased | ||
| CLDN10 | Breast [78] | Decreased | |
| Ovarian [74] | Increased | Overexpression is correlated with good OS, PFS, and post-progression survival. | |
| CLDN11 | Breast [78] | Decreased | Increased expression is associated with better OS. |
| Ovarian [74] | Decreased | ||
| Gastric [114] | Decreased | Significantly associated with smoking, alcohol, Helicobacter pylori infection, and Borrmann classification. | |
| Colorectal [66] | Decreased | Overexpression is associated with worse OS. There is a positive correlation with macrophage, dendritic cell, and CD4+ T cell infiltration. |
|
| CLDN12 | Cervical [115] | Increased. It is expressed throughout the cytoplasm of both LSIL and HSIL, with variable signal intensity in SCC |
Reduced expression is associated with worse DFS and RFS. |
| Colorectal [66] | Increased | Expression is positively correlated with CD4+ T cell infiltration. | |
| CLDN14 | Breast [78] | Increased | Increased expression is associated with poor OS. |
| Gastric [116] | Increased | ||
| CLDN15 | Breast [78] | Decreased | |
| Ovarian [74] | Decreased | Overexpression is predictive of a good prognosis. | |
| CLDN16 | Ovarian [74] | Increased | Overexpression is correlated with worse OS and PFS. |
| Breast [117] | Increased | ||
| CLDN17 | Hepatocellular carcinoma [118] | Increased | Expression is associated with a poor prognosis. |
| Gastric [116] | Decreased | ||
| Oral cancer [119] | Decreased | Lower CLDN17 expression is associated with higher tumor staging, poorer tumor histological grading, and a worse clinical prognosis. | |
| CLDN18.2 | Gastric [120,121,122,123,124,125] | Decreased | Therapeutic targeting available. Negative CLDN18.2 expression and tumor infiltration with CD4+ T-cells or CD8+ T-cells are associated with a better prognosis. Similarly, higher expression is associated with an advanced cancer stage, poor prognosis, and heightened infiltration of CAFs. On the other hand, other studies showed that overexpression is associated with a younger age, a lower invasion depth limited to the mucosa/submucosa, and less frequent lymphovascular invasion. CLDN18.2 expression is usually more positive in the intestinal type compared to the diffuse type, but, in other reports, it was associated with the diffuse subtype. There is no OS difference between patients with and without CLDN18.2 expression. |
| Esophagogastric [126] | Triple positivity for Annexin A10, CLDN18, and SOX2 is more frequent in esophagogastric tumors than in other gastrointestinal tract tumors. | ||
| Pancreatic [127,128] | Increased | Expression correlates with lymph node metastasis, distant metastasis, neural invasion, and stage. Nevertheless, higher expression correlates with better OS. | |
| CLDN19 | Breast [78] | Decreased | |
| CLDN20 | Breast [78,129] | Decreased | Increased expression is associated with poor OS. |
| CLDN23 | Colorectal [63,66,130] | Decreased | Associated with longer OS in the CMS4/C4 molecular subtypes but shorter OS in the CMS2/C1 subtypes. |
| Pancreatic [131] | Has a role in pancreatic cancer cells’ dissociation and hence metastasis. | ||
| Gastric [114] | Decreased | Significantly associated with vessel cancer embolus. |
BC: breast cancer; BCC: basal cell carcinoma; CMS2: epithelial and canonical subtype of colon cancer; CMS4: mesenchymal subtype of colon cancer; CRC: colorectal cancer; DFS: disease-free survival; EMT: epithelial–mesenchymal transition; ER: estrogen receptor; FA: follicular adenoma; FTC: follicular thyroid cancer; FV-PTC: follicular variant-papillary thyroid cancer; GC: gastric cancer; LXRβ: liver X receptor β; OS: overall survival; PFS: progression-free survival; PR: progesterone receptor; PTC: papillary thyroid cancer; PSA: prostate-specific antigen; RFS: relapse-free survival; SCC: squamous cell carcinoma; SOX2: (sex-determining region Y)-box 2; TNBC: triple-negative breast cancer.