@article{902c73a3e6824a30ae1529a5cc19a3cc,
title = "Endoglin suppresses human prostate cancer metastasis",
abstract = "Endoglin is a transmembrane receptor that suppresses human prostate cancer (PCa) cell invasion. Small molecule therapeutics now being tested in humans can activate endoglin signaling. It is not known whether endoglin can regulate metastatic behavior, PCa tumor growth, nor what signaling pathways are linked to these processes. This study sought to investigate the effect of endoglin on these parameters. We used a murine orthotopic model of human PCa metastasis, designed by us to measure effects at early steps in the metastatic cascade, and implanted PCa cells stably engineered to express differing levels of endoglin. We now extend this model to measure cancer cells circulating in the blood. Progressive endoglin loss led to progressive increases in the number of circulating PCa cells as well as to the formation of soft tissue metastases. Endoglin was known to suppress invasion by activating the Smad1 transcription factor. We now show that it selectively activates specific Smad1-responsive genes, including JUNB, STAT1, and SOX4. Increased tumor growth and increased Ki67 expression in tissue was seen only with complete endoglin loss. By showing that endoglin increased TGFβ-mediated suppression of cell growth in vitro and TGFβ-mediated signaling in tumor tissue, loss of this growth-suppressive pathway appears to be implicated at least in part for the increased size of endoglin-deficient tumors. Endoglin is shown for the first time to suppress cell movement out of primary tumor as well as the formation of distant metastasis. It is also shown to co-regulate tumor growth and metastatic behavior in human PCa.",
keywords = "Circulating tumor cells, Endoglin, Metastasis, Prostate cancer, Transforming growth factor β",
author = "Minalini Lakshman and Xiaoke Huang and Vijayalakshmi Ananthanarayanan and Borko Jovanovic and Yueqin Liu and Craft, {Clarissa S.} and Diana Romero and Vary, {Calvin P.H.} and Bergan, {Raymond C.}",
note = "Funding Information: We also show for the first time that endoglin suppresses human PCa tumor growth, and went on to demonstrate that this was due to changes in cell proliferation. Further, we identified a mechanism by which endoglin could regulate the growth of cells in tumor tissue by demonstrating that loss of endoglin led to a loss of TGFβ-mediated inhibition of cell proliferation in vitro. This mechanism is also supported by additional facts. First, TGFβ is ubiquitous in tissue and is an important suppressor of human PCa cell proliferation [35]. Second, we demonstrated in the current study that loss of endoglin led to a loss of TGFβ signaling in tissue, just as it did in vitro. By examining the effect of endoglin upon MMP-2 and -9 gene expression in tissue, we pursued a rigorous examination of endoglin{\textquoteright}s effect upon TGFβ signaling. This is because these MMPs are recognized mediators of cell invasion, and their expression has been shown to increase in invading human prostate cells [14, 36]. Therefore, it would be expected that their expression would increase with progressive endoglin loss and the associated progressive increase in cell invasion. However, the opposite was observed. As the expression of both MMP genes is increased by TGFβ, this finding directly supports the notion that loss of endoglin decreased TGFβ signaling in tissue. Third, the increased tumor growth in NO-ENG mice was not due to decreased cell death, but was associated with increased Ki67, a measure of increased cell proliferation. This is consistent with in vitro findings that demonstrate that endoglin loss leads to a loss of TGFβ-mediated inhibition of cell proliferation. Funding Information: Acknowledgments This work was supported by grants from the National Institutes of Health to RCB, CA122985 and Prostate SPORE CA90386.",
year = "2011",
month = jan,
doi = "10.1007/s10585-010-9356-6",
language = "English (US)",
volume = "28",
pages = "39--53",
journal = "Clinical and Experimental Metastasis",
issn = "0262-0898",
publisher = "Springer Netherlands",
number = "1",
}