title: 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.
authors.affiliation: Department of Tumor Progression and Immune Defense, German Cancer Research Center, Im Neuenheimer Feld, 280 D-69120 Heidelberg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kuhn
authors.forename: Moritz
authors.initials: M
authors.lastname: Koch
authors.forename: Tobias
authors.initials: T
authors.lastname: Nübel
authors.forename: Markus
authors.initials: M
authors.lastname: Ladwein
authors.forename: Dalibor
authors.initials: D
authors.lastname: Antolovic
authors.forename: Pamela
authors.initials: P
authors.lastname: Klingbeil
authors.forename: Dagmar
authors.initials: D
authors.lastname: Hildebrand
authors.forename: Gerhard
authors.initials: G
authors.lastname: Moldenhauer
authors.forename: Lutz
authors.initials: L
authors.lastname: Langbein
authors.forename: Werner W
authors.initials: WW
authors.lastname: Franke
authors.forename: Jürgen
authors.initials: J
authors.lastname: Weitz
authors.forename: Margot
authors.initials: M
authors.lastname: Zöller
mesh_terms: D000951:Antigens, Neoplasm / Q000502:physiology*; D017209:Apoptosis; D015815:Cell Adhesion Molecules / Q000502:physiology*; D045744:Cell Line, Tumor; D057167:Claudins; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000473:pathology*; D018450:Disease Progression; D018572:Disease-Free Survival; D000071858:Epithelial Cell Adhesion Molecule; D006801:Humans; D018960:Hyaluronan Receptors / Q000502:physiology*; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000502:physiology*; D021962:Membrane Microdomains / Q000737:chemistry; D008565:Membrane Proteins / Q000502:physiology*; D009362:Neoplasm Metastasis; D020033:Protein Isoforms; D059470:Tetraspanins
chemical_list: D000951:Antigens, Neoplasm; C473255:CLDN7 protein, human; D015815:Cell Adhesion Molecules; D057167:Claudins; D000071858:Epithelial Cell Adhesion Molecule; D018960:Hyaluronan Receptors; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D020033:Protein Isoforms; C065609:TSPAN8 protein, human; D059470:Tetraspanins