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Generation and characterization of orthotopic murine models for endometrial cancer

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Abstract

We describe the generation of two orthotopic murine models for endometrial cancer (EC).The first model is generated from endometrial Hec-1A cancer cells transfected with luciferase and injected directly into the uterus of female mice. This model allows a follow-up with bioluminescence imaging (BLI) along the experiment and generates abdominal dissemination and lymphatic and hematogenous metastases in high percentages, also detectables with BLI. The dissemination pattern of this model imitates the advanced stages of EC in patients, and its molecular profile corresponds to aggressive type 2 EC (p53 positive, hormone receptors negative, high percentage of Ki67 positive cells). The second model is derived from endometrioid human tissue collected from surgical pieces. By injecting this tissue inside the uterine cavity of a mouse we obtain orthotopic growth with pelvic dissemination and lymph node metastasis. The molecular pattern observed in human type 1 endometrioid EC (p53 negative, low Ki67 index, presence of hormone receptors) is conserved after the murine growth in orthotopic tumor and metastases. This model supposes a singular pre-clinical tool to study therapeutic agents, though it mimics clinical and molecular behavior of endometrioid EC, which is the most common histology in the patient.

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Abbreviations

EC:

Endometrial cancer

BLI:

Bioluminescence imaging

Hec1A:

Human endometrial carcinoma 1A

Fluc:

Firefly luciferase

Hec1A-Fluc:

Hec1A cells transfected with luciferase gen

FIGO:

International Federation of Gynecology and Obstetrics

i.p:

Intraperitoneal

ROI:

Region of interest

ph/s:

Photons/second

H&E:

Hematoxylin and eosin

IHC:

Immunohistochemical

ER:

Estrogen receptor

PR:

Progesterone receptor

MSH6:

MutS homolog 6 gene

MSH2:

MutS homolog 2 gene

MLH1:

MutL homolog 1 gene

SEM:

Standard errors of the mean

3D:

Three-dimensional

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Acknowledgments

The authors would like to thank Lisa Piccione for correction of the manuscript. This work has been supported by the Spanish Ministry of Science and Innovation (SAF 2005-06771; SAF 2008-03996; SAF 2010-10635-E; SAF2011-26548), the Spanish Ministry of Health (RTICC RD06/0020/0058, RD06/0020/1034; CP08/00142; PI08/0797), the Catalan Institute of Health (DURSI 2005SGR00553) and the Department of Universities and Research, Catalan Government (2009SGR00487, 2005SGR00553), the ACCIO program (RDITSCON07-1-0001), the Foundation La Marato de TV3 (grant 050431), the IV Grant Fundació Santiago Dexeus Font for Clinical Investigation Projects 2009, the National Programme of Biotechnology (FIT-010000-2007-26), and the European Commission Program Fondo Europeo de Desarrollo Regional (FEDER). M.LL. is recipient of a predoctoral fellowship from the Spanish Ministry of Innovation and Science (FI07/00423).

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Authors and Affiliations

  1. Unit of Gynecologic Oncology, Department of Gynecology, Hospital Vall d’Hebron, Passeig de la Vall d’Hebron 119, 08035, Barcelona, Spain

    Silvia Cabrera, Jordi Xercavins & Antonio Gil-Moreno

  2. Biomedical Research Unit, Vall d’Hebron Research Institute, Passeig de la Vall d’Hebron 119, 08035, Barcelona, Spain

    Marta Llauradó, Eva Colás, Anna Ruiz, Andreas Doll & Jaume Reventós

  3. Department of Pathology, Hospital Vall d’Hebron, Barcelona, Spain

    Josep Castellví

  4. CIBBIM-Nanomedicine, Hospital Vall d’Hebron, Barcelona, Spain

    Yolanda Fernandez & Simó Schwartz Jr.

  5. Department of Pathology, Hospital del Mar, Barcelona, Spain

    Francesc Alameda

  6. Department of Gynecology, Hospital del Mar, Barcelona, Spain

    Ramon Carreras

  7. Translational Oncology Laboratory, Instituto de Investigación Sanitaria de Santiago, Complexo Hospitalario Universitario Santiago de Compostela, Santiago de Compostela, Spain

    Miguel Abal

Authors
  1. Silvia Cabrera
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  2. Marta Llauradó
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  4. Yolanda Fernandez
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  6. Eva Colás
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  7. Anna Ruiz
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  8. Andreas Doll
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  11. Jordi Xercavins
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  12. Miguel Abal
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  13. Antonio Gil-Moreno
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  14. Jaume Reventós
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Corresponding author

Correspondence to Silvia Cabrera.

Additional information

Silvia Cabrera, Marta Llauradó, Antonio Gil-Moreno and Jaume Reventós have contributed equally to this study.

Electronic supplementary material

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10585_2011_9444_MOESM1_ESM.tif

Supplementary Figure 1. In vitro appearance and behavior of Hec-1A cell line and Hec-1A-Fluc clones. (A) Phase-contrast images and cell prolIferation assay of the Hec-1A cell line and clones 4, 5, 8 and 9 of the Hec-1A Fluc cells (20×). (B) Cell proliferation assay using the CellTiter 96® AQueous One Solution (MTS) (Promega) and cell invasion assay performed in triplicate using the Cytoselect 24-well cell migration assay (Cell Biolabs) for the clones 4, 5,8 and 9 of the Hec-1A Fluc cells. (C) Cell proliferation assay using the CellTiter 96® AQueous One Solution (MTS) (Promega) and cell invasion assay performed in triplicate using the Cytoselect 24-well cell migration assay (Cell Biolabs) for the non transfected Hec-1A cell line and the clone 5 of the Hec-1A Fluc cells, which was the selected clone to generate de murine model. (TIF 1.07 MB)

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Cabrera, S., Llauradó, M., Castellví, J. et al. Generation and characterization of orthotopic murine models for endometrial cancer. Clin Exp Metastasis 29, 217–227 (2012). https://doi.org/10.1007/s10585-011-9444-2

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  • DOI: https://doi.org/10.1007/s10585-011-9444-2

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