title: Activated leukocyte cell adhesion molecule (ALCAM) is a marker of recurrence and promotes cell migration, invasion, and metastasis in early-stage endometrioid endometrial cancer.
abstract: Endometrial cancer is the most common gynaecological cancer in western countries, being the most common subtype of endometrioid tumours. Most patients are diagnosed at an early stage and present an excellent prognosis. However, a number of those continue to suffer recurrence, without means of identification by risk classification systems. Thus, finding a reliable marker to predict recurrence becomes an important unmet clinical issue. ALCAM is a cell-cell adhesion molecule and member of the immunoglobulin superfamily that has been associated with the genesis of many cancers. Here, we first determined the value of ALCAM as a marker of recurrence in endometrioid endometrial cancer by conducting a retrospective multicentre study of 174 primary tumours. In early-stage patients (N = 134), recurrence-free survival was poorer in patients with ALCAM-positive compared to ALCAM-negative tumours (HR 4.237; 95% CI 1.01-17.76). This difference was more significant in patients with early-stage moderately-poorly differentiated tumours (HR 9.259; 95% CI 2.12-53.47). In multivariate analysis, ALCAM positivity was an independent prognostic factor in early-stage disease (HR 6.027; 95% CI 1.41-25.74). Then we demonstrated in vitro a role for ALCAM in cell migration and invasion by using a loss-of-function model in two endometrial cancer cell lines. ALCAM depletion resulted in a reduced primary tumour size and reduced metastatic local spread in an orthotopic murine model. Gene expression analysis of ALCAM-depleted cell lines pointed to motility, invasiveness, cellular assembly, and organization as the most deregulated functions. Finally, we assessed some of the downstream effector genes that are involved in ALCAM-mediated cell migration; specifically FLNB, TXNRD1, and LAMC2 were validated at the mRNA and protein level. In conclusion, our results highlight the potential of ALCAM as a recurrent biomarker in early-stage endometrioid endometrial cancer and point to ALCAM as an important molecule in endometrial cancer dissemination by regulating cell migration, invasion, and metastasis. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Biomedical Research Group in Gynecology, Vall Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Devis
authors.affiliation: Biomedical Research Group in Gynecology, Vall Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Cristian P
authors.initials: CP
authors.lastname: Moiola
authors.affiliation: Cell Cycle and Ovarian Cancer Group, Biomedical Research Group in Gynecology, Vall Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Masia
authors.affiliation: Biomedical Research Group in Gynecology, Vall Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Martinez-Garcia
authors.affiliation: Pathological Oncology Group and Pathology Department, Hospital Arnau de Vilanova, Lleida, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Santacana
authors.affiliation: Institut Curie, CNRS, UMR168, Paris, France.
authors.forename: Tomita Vasilica
authors.initials: TV
authors.lastname: Stirbat
authors.affiliation: Institut Curie, CNRS, UMR168, Paris, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Brochard-Wyart
authors.affiliation: Pathology Department, Vall Hebron University Hospital, Barcelona, Spain.
authors.forename: Ángel
authors.initials: Á
authors.lastname: García
authors.affiliation: Pathology Department, Hospital del Mar, Barcelona, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Alameda
authors.affiliation: Gynecological Oncology Department, Vall Hebron University Hospital, Barcelona, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Cabrera
authors.affiliation: Department of Pathology, Hospital Universitario Ramón y Cajal, 28031 Madrid, Spain.
authors.forename: Jose
authors.initials: J
authors.lastname: Palacios
authors.affiliation: Hospital MD Anderson Cancer Centre Madrid, 28033 Madrid, Spain.|Departament of Biochemistry, Universidad Autonoma de Madrid (UAM), Instituto de Investigaciones Biomedicas 'Alberto Sols' (CSIC-UAM), IdiPAZ, 28046 Madrid, Spain.
authors.forename: Gema
authors.initials: G
authors.lastname: Moreno-Bueno
authors.affiliation: Translational Medical Oncology, Health Research Institute of Santiago (IDIS), Fundacion Ramon Dominguez, SERGAS, 15706 Santiago de Compostela, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Abal
authors.affiliation: Department of Natural Sciences, Colby-Sawyer College, New London, NH 03257, USA.
authors.forename: William
authors.initials: W
authors.lastname: Thomas
authors.affiliation: Institut Curie, CNRS, UMR144, Paris, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Dufour
authors.affiliation: Pathological Oncology Group and Pathology Department, Hospital Arnau de Vilanova, Lleida, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Matias-Guiu
authors.affiliation: Cell Cycle and Ovarian Cancer Group, Biomedical Research Group in Gynecology, Vall Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Santamaria
authors.affiliation: Biomedical Research Group in Gynecology, Vall Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.|Basic Sciences Department, International University of Catalonia, Barcelona, Spain.
authors.forename: Jaume
authors.initials: J
authors.lastname: Reventos
authors.affiliation: Biomedical Research Group in Gynecology, Vall Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.|Gynecological Oncology Department, Vall Hebron University Hospital, Barcelona, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Gil-Moreno
authors.affiliation: Biomedical Research Group in Gynecology, Vall Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.|Pathological Oncology Group and Pathology Department, Hospital Arnau de Vilanova, Lleida, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Colas
mesh_terms: D000368:Aged; D000818:Animals; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D018269:Carcinoma, Endometrioid / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics* / Q000378:metabolism; D002465:Cell Movement; D016889:Endometrial Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D005260:Female; D005326:Fetal Proteins / Q000235:genetics* / Q000378:metabolism; D064448:Filamins / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007797:Laminin / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011379:Prognosis; D012189:Retrospective Studies; D015398:Signal Transduction; D054481:Thioredoxin Reductase 1 / Q000235:genetics / Q000378:metabolism; D020410:Activated-Leukocyte Cell Adhesion Molecule
chemical_list: D015703:Antigens, CD; D014408:Biomarkers, Tumor; D015816:Cell Adhesion Molecules, Neuronal; D005326:Fetal Proteins; D064448:Filamins; D007797:Laminin; D054481:Thioredoxin Reductase 1; C105613:ALCAM protein, human; D020410:Activated-Leukocyte Cell Adhesion Molecule; C578662:FLNB protein, human; C400567:LAMC2 protein, human; C516124:TXNRD1 protein, human
keywords: ALCAM; CD166; cell migration; early stage; endometrioid endometrial cancer; invasion; metastasis; predictive biomarker; recurrence