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

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)-b family of growth factors and modulates TGF-b 1 -dependent cellular responses. However, it lacks cytoplasmic signaling motifs and is considered as an auxiliary receptor for TGF-b. 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-b 1 in the epidermis. These data suggest that endoglin might attenuate TGF-b 1 signaling in normal epidermis and interfere with progression of skin carcinogenesis.

Endoglin expression in breast tumor cells suppresses invasion and metastasis and correlates with improved clinical outcome

“…This latter finding extends previous work in which MSP analysis was used to demonstrate ENG CpG island methylation in esophageal cell lines and two esophageal tumors (Wong et al, 2008) and indicates that this mechanism of ENG gene regulation may be utilized in multiple cancer types. Of interest, reduced endoglin expression enhances malignant progression in a mouse model of skin carcinogenesis (Quintanilla et al, 2003); however, the mode of endoglin downregulation is by shedding of the extracellular domain (Perez-Gomez et al, 2007). As the mouse Eng gene does not contain a CpG island this may reflect an alternative mechanism to regulate mouse Eng expression.…”

PRH/HHex inhibits the migration of breast and prostate epithelial cells through direct transcriptional regulation of Endoglin

“…Endoglin is a TGF-β coreceptor that modulates TGF-β-dependent cellular responses (14,15). Most studies on Endoglin have focused on its pro-angiogenic role in endothelial cells, its involvement in vascular remodelling and its role as a marker of the tumour vasculature, but it also plays a direct role in tumourigenesis (16).…”

Characterization of murine S-endoglin isoform and its effects on tumor development

“…Aside from its expression in endothelial cells, endoglin is also present in several nonendothelial tissues, mainly in cellular lineages within the vascular and hematopoietic systems and connective tissues (Fonsatti et al, 2001;Fonsatti and Maio, 2004). We have shown that endoglin is expressed in the epidermis and skin appendages, such as hair follicles and sweat glands (Quintanilla et al, 2003). Several tumor cells also express endoglin, including pre-B cell and monocytic leukemia (Quackenbush and Letarte, 1985;Haruta and Seon, 1986;Lastres et al, 1992;Zhang et al, 1996), choriocarcinoma (Letamendia et al, 1998a), ovarian carcinoma (Jindal et al, 1995), melanoma (Altomonte et al, 1996), prostate cancer (Liu et al, 2002) and basal and squamous cell carcinomas (Quintanilla et al, 2003).…”

“…We have shown that endoglin is expressed in the epidermis and skin appendages, such as hair follicles and sweat glands (Quintanilla et al, 2003). Several tumor cells also express endoglin, including pre-B cell and monocytic leukemia (Quackenbush and Letarte, 1985;Haruta and Seon, 1986;Lastres et al, 1992;Zhang et al, 1996), choriocarcinoma (Letamendia et al, 1998a), ovarian carcinoma (Jindal et al, 1995), melanoma (Altomonte et al, 1996), prostate cancer (Liu et al, 2002) and basal and squamous cell carcinomas (Quintanilla et al, 2003). The presence of endoglin in both cells and vasculature of tumors has stimulated studies on the role of endoglin in cancer Takahashi et al, 2001;Duff et al, 2003).…”