title: Loss of CD73-mediated actin polymerization promotes endometrial tumor progression.
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.forename: Jessica L
authors.initials: JL
authors.lastname: Bowser
authors.forename: Michael R
authors.initials: MR
authors.lastname: Blackburn
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Shipley
authors.forename: Jose G
authors.initials: JG
authors.lastname: Molina
authors.forename: Kenneth
authors.initials: K
authors.lastname: Dunner
authors.forename: Russell R
authors.initials: RR
authors.lastname: Broaddus
mesh_terms: D015720:5'-Nucleotidase / Q000502:physiology*; D000199:Actins / Q000378:metabolism*; D000818:Animals; D002450:Cell Communication; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D018450:Disease Progression; D016889:Endometrial Neoplasms / Q000209:etiology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D058851:GPI-Linked Proteins / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D055503:Protein Multimerization; D011554:Pseudopodia / Q000502:physiology; D043682:Receptor, Adenosine A1 / Q000502:physiology; D020764:cdc42 GTP-Binding Protein / Q000502:physiology
chemical_list: D000199:Actins; D058851:GPI-Linked Proteins; D043682:Receptor, Adenosine A1; D015720:5'-Nucleotidase; C548241:NT5E protein, human; D020764:cdc42 GTP-Binding Protein