Oncotarget

Research Papers:

ALCAM shedding at the invasive front of the tumor is a marker of myometrial infiltration and promotes invasion in endometrioid endometrial cancer

Laura Devis _, Elena Martinez-Garcia, Cristian P. Moiola, Maria Teresa Quiles, Maria Antonia Arbos, Tomita Vasilica Stirbat, Françoise Brochard-Wyart, Ángel García, Lorena Alonso-Alconada, Miguel Abal, Berta Diaz-Feijoo, William Thomas, Sylvie Dufour, Gemma Mancebo, Francesc Alameda, Jaume Reventos, Antonio Gil-Moreno and Eva Colas

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Oncotarget. 2018; 9:16648-16664. https://doi.org/10.18632/oncotarget.24625

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Abstract

Laura Devis1, Elena Martinez-Garcia1, Cristian P. Moiola1, Maria Teresa Quiles2, Maria Antonia Arbos2, Tomita Vasilica Stirbat3, Françoise Brochard-Wyart3, Ángel García4, Lorena Alonso-Alconada5, Miguel Abal5, Berta Diaz-Feijoo6, William Thomas7, Sylvie Dufour8,9, Gemma Mancebo10, Francesc Alameda11, Jaume Reventos1,12,*, Antonio Gil-Moreno1,6,* and Eva Colas1,*

1Biomedical Research Group in Gynecology, Vall Hebron Research Institute, Universitat Autònoma de Barcelona, CIBERONC, Barcelona, Spain

2Grup de Recerca en Cirugia General, Institut de Recerca Vall d’Hebron, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain

3Institut Curie, CNRS, Paris, France

4Pathology Department, Vall Hebron University Hospital, Barcelona, Spain

5Translational Laboratory, Medical Oncology Department, Complexo Hospitalario Universitario de Santiago, SERGAS, CIBERONC, Santiago de Compostela, Spain

6Gynecological Oncology Department, Vall Hebron University Hospital, Barcelona, Spain

7Department of Natural Sciences, Colby-Sawyer College, New London, New Hampshire, United States of America

8Institut Curie, CNRS, Paris, France

9Present address: Université Paris Est, Faculté de Médecine, Créteil, France, INSERM, U955, Equipe 6, Créteil, France

10Gynecological Oncology Department, Hospital del Mar, PSMAR, Barcelona, Spain

11Pathology Department, Hospital del Mar, Barcelona, Spain

12Basic Sciences Department, International University of Catalonia, CIBERONC, Barcelona, Spain

*These authors have contributed equally to this work

Correspondence to:

Laura Devis, email: laura.devis@vhir.org

Antonio Gil-Moreno, email: agil@vhebron.net

Eva Colas, email: eva.colas@vhir.org

Keywords: ALCAM; endometrial cancer; myometrial invasion; MMP-9; ETV5

Abbreviations: EC: endometrial cancer; EEC: endometrioid endometrial cancer; SF: separation force; sALCAM: soluble ALCAM; ALCAMcytoless: ALCAM without the cytoplasmic tail

Received: October 26, 2017    Accepted: February 20, 2018    Published: March 30, 2018

ABSTRACT

Endometrial cancer (EC) is the sixth deadliest cancer in women. The depth of myometrial invasion is one of the most important prognostic factors, being directly associated with tumor recurrence and mortality. In this study, ALCAM, a previously described marker of EC recurrence, was studied by immunohistochemistry at the superficial and the invasive tumor areas from 116 EC patients with different degree of myometrial invasion and related to a set of relevant epithelial and mesenchymal markers. ALCAM expression presented a heterogeneous functionality depending on its localization, it correlated with epithelial markers (E-cadherin/β-catenin) at the superficial area, and with mesenchymal markers at the invasive front (COX-2, SNAIL, ETV5, and MMP-9). At the invasive front, ALCAM-negativity was an independent marker of myometrial invasion. This negativity, together with an increase of soluble ALCAM in uterine aspirates from patients with an invasive EC, and its positive correlation with MMP-9 levels, suggested that ALCAM shedding by MMP-9 occurs at the invasive front. In vivo and in vitro models of invasive EC were generated by ETV5-overexpression. In those, we demonstrated that ALCAM shedding was related to a more invasive pattern and that full-ALCAM recovery reverted most of the ETV5-cells mesenchymal abilities, partially through a p-ERK dependent-manner.


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