A role for endoglin as a suppressor of malignancy during mouse skin carcinogenesis.
Endoglin is a membrane glycoprotein that acts as a coreceptor for transforming growth factor-beta. 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-beta1 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.
Pérez-Gómez
Eduardo
E
Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain.
Villa-Morales
María
M
Santos
Javier
J
Fernández-Piqueras
José
J
Gamallo
Carlos
C
Dotor
Javier
J
Bernabéu
Carmelo
C
Quintanilla
Miguel
M
D000818:Animals; D015820:Cadherins / Q000235:genetics; D002465:Cell Movement; D000071063:Endoglin; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D015603:Keratinocytes / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D034741:RNA, Small Interfering / Q000235:genetics; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000473:pathology / Q000517:prevention & control*; D051899:Smad2 Protein / Q000502:physiology; D051900:Smad3 Protein / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000502:physiology*
D015820:Cadherins; D000071063:Endoglin; C502004:Eng protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D053773:Transforming Growth Factor beta1; D025521:Tumor Suppressor Proteins; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I