A complex of EpCAM, claudin-7, CD44 variant isoforms, and tetraspanins promotes colorectal cancer progression.
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.
Kuhn
Sebastian
S
Department of Tumor Progression and Immune Defense, German Cancer Research Center, Im Neuenheimer Feld, 280 D-69120 Heidelberg, Germany.
Koch
Moritz
M
Nübel
Tobias
T
Ladwein
Markus
M
Antolovic
Dalibor
D
Klingbeil
Pamela
P
Hildebrand
Dagmar
D
Moldenhauer
Gerhard
G
Langbein
Lutz
L
Franke
Werner W
WW
Weitz
Jürgen
J
Zöller
Margot
M
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
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