Increased levels of soluble endoglin (Sol-Eng) correlate with poor outcome in human cancer. We have previously shown that shedding of membrane endoglin, and concomitant release of Sol-Eng is a late event in chemical mouse skin carcinogenesis associated with the development of undifferentiated spindle cell carcinomas (SpCCs). In this report, we show that mouse skin SpCCs exhibit a high expression of hepatocyte growth factor (HGF) and an elevated ratio of its active tyrosine kinase receptor Met versus total Met levels. We have evaluated the effect of Sol-Eng in spindle carcinoma cells by transfection of a cDNA encoding most of the endoglin ectodomain or by using purified recombinant Sol-Eng. We found that Sol-Eng inhibited both mitogen-activated protein kinase (MAPK) activity and cell growth in vitro and in vivo. Sol-Eng also blocked MAPK activation by transforming growth factor-β1 (TGF-β1) and impaired both basal and HGF-induced activation of Met and downstream MAPK. Moreover, Sol-Eng strongly reduced basal and HGF-stimulated spindle cell migration and invasion. Both Sol-Eng and full-length endoglin were shown to interact with Met by coimmunoprecipitation experiments. However, full-length endoglin expressed at the plasma membrane of spindle carcinoma cells had no effect on Met signaling activity, and was unable to inhibit HGF-induced cell migration/invasion. These results point to a paradoxical suppressor role for Sol-Eng in carcinogenesis.
Elevated levels of a circulating form of the transforming growth factor-β (TGF-β) coreceptor endoglin correlate with poor clinical outcome in different types of cancer. Soluble endoglin (Sol-Eng) is primarily produced by cleavage of cell-surface endoglin by the transmembrane metalloprotease MMP14 that releases most of its extracellular domain. Sol-Eng has been found to contribute to different cardiovascular pathologies, including preeclampsia, a severe hypertensive syndrome of pregnancy. While the anti-angiogenic and pro-hypertensive functions of Sol-Eng appear well established, its role in cancer has not been fully investigated. Recently, we reported that Sol-Eng strongly inhibits signaling through the hepatocyte growth factor (HGF) tyrosine kinase receptor Met in mouse skin spindle carcinoma cells. Sol-Eng also blocked basal and HGF-mediated stimulation of carcinoma cell proliferation, migration and invasion. Taken together, the above results and the anti-angiogenic function exerted by Sol-Eng suggest a suppressor role for Sol-Eng in cancer. This conclusion is discussed in the paradoxical context of Sol-Eng as a marker of poor prognosis and as a potential contributor to the decreased risk of preeclamptic mothers to develop breast cancer later in life.
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