Expression of the TGF-beta coreceptor endoglin in epidermal keratinocytes and its dual role in multistage mouse skin carcinogenesis.
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)-beta family of growth factors and modulates TGF-beta(1)-dependent cellular responses. However, it lacks cytoplasmic signaling motifs and is considered as an auxiliary receptor for TGF-beta. 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-beta(1) in the epidermis. These data suggest that endoglin might attenuate TGF-beta(1) signaling in normal epidermis and interfere with progression of skin carcinogenesis.
Quintanilla
Miguel
M
Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Arturo Duperier 4, Madrid 28029, Spain. mquintanilla@iib.uam.es
Ramirez
Jose Ramón
JR
Pérez-Gómez
Eduardo
E
Romero
Diana
D
Velasco
Beatriz
B
Letarte
Michelle
M
López-Novoa
Jose Miguel
JM
Bernabéu
Carmelo
C
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000009:adverse effects; D000818:Animals; D015703:Antigens, CD; D002277:Carcinoma / Q000139:chemically induced / Q000209:etiology* / Q000473:pathology; D002478:Cells, Cultured; D000071063:Endoglin; D000078404:Epidermal Cells; D004817:Epidermis / Q000473:pathology / Q000502:physiology; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D009374:Neoplasms, Experimental / Q000209:etiology / Q000473:pathology; D010212:Papilloma / Q000139:chemically induced / Q000209:etiology* / Q000473:pathology; D011956:Receptors, Cell Surface; D012016:Reference Values; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000139:chemically induced / Q000209:etiology* / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate / Q000009:adverse effects; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism / Q000502:physiology*
D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface; D016212:Transforming Growth Factor beta; D019010:Vascular Cell Adhesion Molecule-1; D015127:9,10-Dimethyl-1,2-benzanthracene; D013755:Tetradecanoylphorbol Acetate