title: Activated leukocyte cell adhesion molecule soluble form: a potential biomarker of epithelial ovarian cancer is increased in type II tumors.
abstract: Activated leukocyte cell adhesion molecule (ALCAM) is involved in cell-cell interactions in cancer. Shedding of its ectodomain by the metalloprotease ADAM17/TACE generates a soluble form (sALCAM). Here, we show that serum sALCAM levels were significantly higher in epithelial ovarian cancer (EOC) (p < 0.005) than in controls. The performance of sALCAM as classifier, tested by receiver operating characteristic curve, resulted in an area under the curve (AUC) of 0.8067. Serum sALCAM levels showed direct correlation with Carbohydrate Antigen-125 (CA125/MUC16). Moreover, significantly higher levels were found in type II tumors, even in stage I/II, suggesting that elevated sALCAM is an early feature of aggressive EOC. In addition, sALCAM levels were higher in ascites than in sera, suggesting local processing of ALCAM in the peritoneal cavity. In immunodeficient mice, intraperitoneally implanted with a human EOC cell line, human sALCAM progressively increased in serum and was even higher in the ascites. The biochemical characterization of the sALCAM in EOC sera and ascites, showed two predominant forms of approximately 95 and 65 kDa but no EOC-specific isoform. In addition, full-length transmembrane ALCAM but no soluble form was detected in tumor-derived exosomes found in ascites. Finally, in vitro invasion assays showed that inhibition of ADAM17/TACE activity decreased EOC invasive properties, while opposite effects were mediated by a sALCAM-Fc chimera and by an antibody interfering with ALCAM/ALCAM interactions. Altogether these data suggest that sALCAM is a marker of EOC, which correlates with more aggressive type II tumors, and that ADAM17/TACE activity and sALCAM itself mediate enhanced invasiveness.
authors.affiliation: Department of Integrated Oncological Therapies, IRCCS AOU San Martino-IST, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: Grazia
authors.initials: G
authors.lastname: Carbotti
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Orengo
authors.forename: Delia
authors.initials: D
authors.lastname: Mezzanzanica
authors.forename: Marina
authors.initials: M
authors.lastname: Bagnoli
authors.forename: Antonella
authors.initials: A
authors.lastname: Brizzolara
authors.forename: Laura
authors.initials: L
authors.lastname: Emionite
authors.forename: Andrea
authors.initials: A
authors.lastname: Puppo
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Centurioni
authors.forename: Milena
authors.initials: M
authors.lastname: Bruzzone
authors.forename: Paola
authors.initials: P
authors.lastname: Marroni
authors.forename: Armando
authors.initials: A
authors.lastname: Rossello
authors.forename: Silvana
authors.initials: S
authors.lastname: Canevari
authors.forename: Silvano
authors.initials: S
authors.lastname: Ferrini
authors.forename: Marina
authors.initials: M
authors.lastname: Fabbi
mesh_terms: D002288:Adenocarcinoma, Mucinous / Q000097:blood / Q000175:diagnosis*; D000328:Adult; D000368:Aged; D000818:Animals; D015703:Antigens, CD / Q000097:blood*; D001201:Ascites / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000097:blood*; D015153:Blotting, Western; D000077216:Carcinoma, Ovarian Epithelial; D016022:Case-Control Studies; D015816:Cell Adhesion Molecules, Neuronal / Q000097:blood*; D018284:Cystadenocarcinoma, Serous / Q000097:blood / Q000175:diagnosis*; D016889:Endometrial Neoplasms / Q000097:blood / Q000175:diagnosis*; D055354:Exosomes / Q000378:metabolism; D005260:Female; D005326:Fetal Proteins / Q000097:blood*; D005434:Flow Cytometry; D005500:Follow-Up Studies; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009375:Neoplasms, Glandular and Epithelial / Q000097:blood / Q000175:diagnosis*; D010051:Ovarian Neoplasms / Q000097:blood / Q000175:diagnosis*; D010053:Ovary / Q000378:metabolism; D011379:Prognosis; D011446:Prospective Studies; D014407:Tumor Cells, Cultured; D020410:Activated-Leukocyte Cell Adhesion Molecule
chemical_list: D015703:Antigens, CD; D014408:Biomarkers, Tumor; D015816:Cell Adhesion Molecules, Neuronal; D005326:Fetal Proteins; C105613:ALCAM protein, human; D020410:Activated-Leukocyte Cell Adhesion Molecule