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Expression of the TGF-β coreceptor endoglin in epidermal keratinocytes and its dual role in multistage mouse skin carcinogenesis

Oncogene volume 22, pages 5976–5985 (2003)Cite this article

Abstract

Endoglin is an integral membrane glycoprotein primarily expressed in the vascular endothelium, but also found on macrophages and stromal cells. It binds several members of the transforming growth factor (TGF)-β family of growth factors and modulates TGF-β1-dependent cellular responses. However, it lacks cytoplasmic signaling motifs and is considered as an auxiliary receptor for TGF-β. We show here that endoglin is expressed in mouse and human epidermis and in skin appendages, such as hair follicles and sweat glands, as determined by immunohistochemistry. In normal interfollicular epidermis, endoglin was restricted to basal keratinocytes and absent in differentiating cells of suprabasal layers. Follicular expression of endoglin was high in hair bulb keratinocytes, but decreased in parts distal from the bulb. To address the role of endoglin in skin carcinogenesis in vivo, Endoglin heterozygous mice were subjected to long-term chemical carcinogenesis treatment. Reduction in endoglin had a dual effect during multistage carcinogenesis, by inhibiting the early appearance of benign papillomas, but increasing malignant progression to highly undifferentiated carcinomas. Our results are strikingly similar to those previously reported for transgenic mice overexpressing TGF-β1 in the epidermis. These data suggest that endoglin might attenuate TGF-β1 signaling in normal epidermis and interfere with progression of skin carcinogenesis.

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Acknowledgements

We thank Annette Düwell for helping with mice breeding and genotyping, and Cristina González for skilful technical assistance. This work was supported by grants from Ministerio de Ciencia y Tecnología (SAF2001-2362 to MQ, SAF2000-0132 to CB, and SAF2001/1701 to JML-N), Fondo de Investi-gacion Sanitaria (PI020200) and Comunidad Autónoma de Madrid (CAM) to CB.

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Author notes

  1. Miguel Quintanilla and Jose Ramón Ramirez: The first two authors contributed equally to this work

Authors and Affiliations

  1. Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), Arturo Duperier 4, Madrid, 28029, Spain

    Miguel Quintanilla, Eduardo Pérez-Gómez & Diana Romero

  2. Departamento de Anatomía Patológica, Hospital Gomez-Ulla, Glorieta del Ejercito, Madrid, 28047, Spain

    Jose Ramón Ramirez

  3. Centro de Investigaciones Biológicas, CSIC, Ramiro de Maeztu 9, Madrid, 28040, Spain

    Beatriz Velasco & Carmelo Bernabéu

  4. Blood and Cancer Research Program, The Hospital for Sick Children, Ontario, Canada

    Michelle Letarte

  5. Department of Immunology, University of Toronto, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada

    Michelle Letarte

  6. Departamento de Fisiología y Farmacología, Facultad de Medicina, Universidad de Salamanca, Salamanca, 37007, Spain

    Jose Miguel López-Novoa

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Correspondence to Miguel Quintanilla.

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Quintanilla, M., Ramirez, J., Pérez-Gómez, E. et al. Expression of the TGF-β coreceptor endoglin in epidermal keratinocytes and its dual role in multistage mouse skin carcinogenesis. Oncogene 22, 5976–5985 (2003). https://doi.org/10.1038/sj.onc.1206841

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