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A Role for Endoglin as a Suppressor of Malignancy during Mouse Skin Carcinogenesis

¹ Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas, ² Laboratorio de Genética Molecular Humana, Departamento de Biología, and ³ Hospital Universitario de la Princesa, Universidad Autónoma de Madrid; ⁴ DIGNA Biotech; and ⁵ Centro de Investigaciones Biológicas, CSIC, and Center for Biomedical Research on Rare Diseases, Madrid, Spain

Requests for reprints: Miguel Quintanilla, Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Arturo Duperier 4, 28029 Madrid, Spain. Phone: 34-9158-54412; Fax: 34-9158-54401; E-mail: mquintanilla{at}iib.uam.es.

Endoglin is a membrane glycoprotein that acts as a coreceptor for transforming growth factor-ß. We and others have previously suggested a function of endoglin as a tumor suppressor in epithelial cancer. Here, we study the expression of endoglin during chemical mouse skin carcinogenesis. We find that shedding of membrane endoglin, allowing the secretion of a soluble endoglin form, is a late event associated with progression from squamous to spindle cell carcinomas. Knockdown of endoglin in transformed keratinocytes activates the Smad2/3 signaling pathway resulting in cell growth arrest, delayed tumor latencies, and a squamous to spindle phenotypic conversion. Forced expression of the long endoglin isoform in spindle carcinoma cells blocks transforming growth factor-ß1 stimulation of Smad2/3 signaling and prevents tumor formation. In contrast, expression of the short endoglin isoform has no effect on spindle cell growth in vitro or in vivo. Our results show that endoglin behaves as a suppressor of malignancy during the late stages of carcinogenesis. Therefore, disruption of membrane endoglin emerges as a crucial event for progression to spindle cell carcinomas. [Cancer Res 2007;67(21):10268–77]