A Complex of EpCAM, Claudin-7, CD44 Variant Isoforms, and Tetraspanins Promotes Colorectal Cancer Progression

Abstract

High expression of EpCAM and the tetraspanin CO-029 has been associated with colorectal cancer progression. However, opposing results have been reported on CD44 variant isoform v6 (CD44v6) expression. We recently noted in rat gastrointestinal tumors that EpCAM, claudin-7, CO-029, and CD44v6 were frequently coexpressed and could form a complex. This finding suggested the possibly that the complex, rather than the individual molecules, could support tumor progression. The expression of EpCAM, claudin-7, CO-029, and CD44v6 expression was evaluated in colorectal cancer (n = 104), liver metastasis (n = 66), and tumor-free colon and liver tissue. Coexpression and complex formation of the molecules was correlated with clinical variables and apoptosis resistance. EpCAM, claudin-7, CO-029, and CD44v6 expression was up-regulated in colon cancer and liver metastasis. Expression of the four molecules did not correlate with tumor staging and grading. However, coexpression inversely correlated with disease-free survival. Coexpression was accompanied by complex formation and recruitment into tetraspanin-enriched membrane microdomains (TEM). Claudin-7 contributes to complex formation inasmuch as in the absence of claudin-7, EpCAM hardly associates with CO-029 and CD44v6 and is not recruited into TEMs. Notably, colorectal cancer lines that expressed the EpCAM/claudin-7/CO-029/CD44v6 complex displayed a higher degree of apoptosis resistance than lines devoid of any one of the four molecules. Expression of EpCAM, claudin-7, CO-029, and CD44v6 by themselves cannot be considered as prognostic markers in colorectal cancer. However, claudin-7 -associated EpCAM is recruited into TEM and forms a complex with CO-029 and CD44v6 that facilitates metastasis formation. (Mol Cancer Res 2007;5(6):553 -67)

Claudin-2 is selectively enriched in and promotes the formation of breast cancer liver metastases through engagement of integrin complexes

“…For example, claudin-11 interacts with OAP-1 to form a complex with integrins, which results in increased oligodendrocyte proliferation and migration (Tiwari-Woodruff et al, 2001). In addition, claudin-7 has been shown to form a complex with tetraspanins, EpCam and CD44 in colorectal cancers, and expression of these molecules was inversely correlated with disease-free survival (Kuhn et al, 2007). Interestingly, we performed immunofluorescence staining for claudin-2 in MDA-MB-231 cells and found that claudin-2 displays a punctate staining pattern when cells are plated on fibronectin (data not shown).…”

Nasal speech and hypothyroidism are common hallmarks of 12q15 microdeletions

“…Tetraspanin 8 affects protein trafficking and is known to influence a wide variety of physiological processes. 19 GWA studies for schizophrenia and bipolar disorder revealed association between TSPAN8 and both psychiatric disorders. 20 Finally,…”

Claudin-7 Regulates EpCAM-Mediated Functions in Tumor Progression

“…Depending on the tumor type, high EpC expression correlates with tumor grading and/or tumor-nodemetastasis staging and/or decreased overall and poor diseasefree survival (4,5,13,14). EpC has also been described as a cancer-initiating cell marker of mammary, colorectal, and pancreatic cancers (15)(16)(17)(18)(19).…”

“…In the metastatic BSp73ASML subline, EpC is associated with claudin-7 (cld-7), CD44v, several integrins, and the tetraspanin D6.1A (33)(34)(35), where only the EpC-cld-7 association is based on a direct protein-protein interaction (14,34). Tetraspanins are located in glycolipid-enriched membrane microdomains (14,34), called tetraspanin-enriched membrane microdomains (TEM), which serve as a signaling platform (36,37). According to its association with tetraspanins, the EpC-cld-7 complex is supposed to be TEM located.…”

“…According to its association with tetraspanins, the EpC-cld-7 complex is supposed to be TEM located. In fact, there is evidence for cooperative activity of the EpC-cld-7-CD44v-tetraspanin complex (14,33,34). Matrix adhesion and cluster formation of tumor cells expressing the complex, but not the individual molecules, is reduced after partial cholesterol depletion, which destroys TEM.…”