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Maintaining endometrial epithelial barrier function

The cell surface protein CD73 is overexpressed in a variety of human tumors and is essential for the generation of extracellular adenosine. Adenosine has been shown to dampen T cell-mediated immune responses and is generally considered to promote tumor growth. Jessica Bowser and colleagues at the University of Texas MD Anderson Cancer Center determined that CD73 is markedly downregulated in poorly differentiated and advanced stage endometrial cancers. In endometrial epithelial cells, CD73 localized to membrane areas of cell-cell contacts and filopodia, and CD73 deficiency increased paracellular permeability under hypoxic conditions. CD73-generated adenosine activated the adenosine A1 receptor to induce actin polymerization through a pathway involving the RHO-GTPase CDC42, N-WASP, and the ARP2/3 complex, thereby maintaining cell-cell adhesion and epithelial barrier integrity. Pharmacological inhibition or genetic loss of CD73 attenuated actin polymerization, thereby reducing cellular adhesion and promoting migration and invasion. Together, these data identify a mechanism by which loss of CD73 promotes cancer progression and indicate that CD73 has a complex role in cancer. The accompanying image is an electron micrograph of human endometrial cancer cells exposed to hypoxia and treated with the adenosine analog NECA. Ruthenium red straining shows that membrane integrity is maintained in these cells and the formation of interdigitating filopodia between cells. These structures and membrane integrity are compromised in cells lacking CD73 (not shown).

Published December 7, 2015, by Corinne Williams

Scientific Show StopperOncology

Related articles

Loss of CD73-mediated actin polymerization promotes endometrial tumor progression
Jessica L. Bowser, … , Kenneth Dunner Jr., Russell R. Broaddus
Jessica L. Bowser, … , Kenneth Dunner Jr., Russell R. Broaddus
Published January 4, 2016; First published December 7, 2015
Citation Information: J Clin Invest. 2016;126(1):220-238. https://doi.org/10.1172/JCI79380.
View: Text | PDF
Categories: Research Article Oncology

Loss of CD73-mediated actin polymerization promotes endometrial tumor progression

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Abstract

Ecto-5′-nucleotidase (CD73) is central to the generation of extracellular adenosine. Previous studies have highlighted a detrimental role for extracellular adenosine in cancer, as it dampens T cell–mediated immune responses. Here, we determined that, in contrast to other cancers, CD73 is markedly downregulated in poorly differentiated and advanced-stage endometrial carcinoma compared with levels in normal endometrium and low-grade tumors. In murine models, CD73 deficiency led to a loss of endometrial epithelial barrier function, and pharmacological CD73 inhibition increased in vitro migration and invasion of endometrial carcinoma cells. Given that CD73-generated adenosine is central to regulating tissue protection and physiology in normal tissues, we hypothesized that CD73-generated adenosine in endometrial carcinoma induces an innate reflex to protect epithelial integrity. CD73 associated with cell-cell contacts, filopodia, and membrane zippers, indicative of involvement in cell-cell adhesion and actin polymerization–dependent processes. We determined that CD73-generated adenosine induces cortical actin polymerization via adenosine A1 receptor (A1R) induction of a Rho GTPase CDC42–dependent conformational change of the actin-related proteins 2 and 3 (ARP2/3) actin polymerization complex member N-WASP. Cortical F-actin elevation increased membrane E-cadherin, β-catenin, and Na+K+ ATPase. Together, these findings reveal that CD73-generated adenosine promotes epithelial integrity and suggest why loss of CD73 in endometrial cancer allows for tumor progression. Moreover, our data indicate that the role of CD73 in cancer is more complex than previously described.

Authors

Jessica L. Bowser, Michael R. Blackburn, Gregory L. Shipley, Jose G. Molina, Kenneth Dunner Jr., Russell R. Broaddus

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