Overexpression of the cell adhesion molecules DDR1, Claudin 3, and Ep-CAM in metaplastic ovarian epithelium and ovarian cancer.
OBJECTIVE
A better understanding of the molecular pathways underlying the development of epithelial ovarian cancer (EOC) is critical to identify ovarian tumor markers for use in diagnostic or therapeutic applications. The aims of this study were to integrate the results from 14 transcript profiling studies of EOC to identify novel biomarkers and to examine their expression in early and late stages of the disease.


METHODS
A database incorporating genes identified as being highly up-regulated in each study was constructed. Candidate tumor markers were selected from genes that overlapped between studies and by evidence of surface membrane or secreted expression. The expression patterns of three integral membrane proteins, discoidin domain receptor 1 (DDR1), claudin 3 (CLDN3), and epithelial cell adhesion molecule, all of which are involved in cell adhesion, were evaluated in a cohort of 158 primary EOC using immunohistochemistry.


RESULTS
We confirmed that these genes are highly overexpressed in all histological subtypes of EOC compared with normal ovarian surface epithelium, identifying DDR1 and CLDN3 as new biomarkers of EOC. Furthermore, we determined that these genes are also expressed in ovarian epithelial inclusion cysts, a site of metaplastic changes within the normal ovary, in borderline tumors and in low-grade and stage cancer. A trend toward an association between low CLDN3 expression and poor patient outcome was also observed.


CONCLUSIONS
These results suggest that up-regulation of DDR1, CLDN3, and epithelial cell adhesion molecule are early events in the development of EOC and have potential application in the early detection of disease.
Heinzelmann-Schwarz
Viola A
VA
Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia.
Gardiner-Garden
Margaret
M
Henshall
Susan M
SM
Scurry
James
J
Scolyer
Richard A
RA
Davies
Michael J
MJ
Heinzelmann
Matthias
M
Kalish
Larry H
LH
Bali
Anish
A
Kench
James G
JG
Edwards
Lyndal S
LS
Vanden Bergh
Patricia M
PM
Hacker
Neville F
NF
Sutherland
Robert L
RL
O'Brien
Philippa M
PM
D000951:Antigens, Neoplasm / Q000096:biosynthesis*; D014408:Biomarkers, Tumor; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D062465:Claudin-3; D015331:Cohort Studies; D018076:DNA, Complementary / Q000378:metabolism; D019992:Databases as Topic; D000070819:Discoidin Domain Receptor 1; D018450:Disease Progression; D018572:Disease-Free Survival; D000071858:Epithelial Cell Adhesion Molecule; D004848:Epithelium / Q000378:metabolism; D005260:Female; D005819:Genetic Markers; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000096:biosynthesis*; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000378:metabolism*; D010053:Ovary / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis*; D013997:Time Factors; D016896:Treatment Outcome; D015854:Up-Regulation
D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; C568122:CLDN3 protein, human; D015815:Cell Adhesion Molecules; D062465:Claudin-3; D018076:DNA, Complementary; D000071858:Epithelial Cell Adhesion Molecule; D005819:Genetic Markers; D008565:Membrane Proteins; D012333:RNA, Messenger; C092030:DDR1 protein, human; D000070819:Discoidin Domain Receptor 1; D020794:Receptor Protein-Tyrosine Kinases