Loss of CD73 shifts transforming growth factor-β1 (TGF-β1) from tumor suppressor to promoter in endometrial cancer

Cancer Lett. 2021 May 1:505:75-86. doi: 10.1016/j.canlet.2021.01.030. Epub 2021 Feb 17.

Abstract

In many tumors, CD73 (NT5E), a rate-limiting enzyme in adenosine biosynthesis, is upregulated by TGF-β and drives tumor progression. Conversely, CD73 is downregulated in endometrial carcinomas (EC) despite a TGF-β-rich environment. Through gene expression analyses of normal endometrium samples of the uterine cancer TCGA data set and genetic and pharmacological studies, we discovered CD73 loss shifts TGF-β1 from tumor suppressor to promoter in EC. TGF-β1 upregulated CD73 and epithelial integrity in vivo in the normal endometrium and in vitro in early stage EC cells. With loss of CD73, TGF-β1-mediated epithelial integrity was abrogated. EC cells developed TGF-β1-mediated stress fibers and macromolecule permeability, migration, and invasion increased. In human tumors, CD73 is downregulated in deeply invasive stage I EC. Consistent with shifting TGF-β1 activity, CD73 loss increased TGF-β1-mediated canonical signaling and upregulated cyclin D1 (CCND1) and downregulated p21 expression. This shift was clinically relevant, as CD73Low/CCND1High expression associated with poor tumor differentiation, increased myometrial and lymphatic/vascular space invasion, and patient death. Further loss of CD73 in CD73Low expressing advanced stage EC cells increased TGF-β-mediated stress fibers, signaling, and invasiveness, whereby adenosine A1 receptor agonist, CPA, dampened TGF-β-mediated invasion. These data identify CD73 loss as essential for shifting TGF-β activity in EC.

Keywords: Adenosine; CD73; Endometrial cancer; TGF-β; Tumor suppressor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5'-Nucleotidase / physiology*
  • Adenosine / physiology
  • Adult
  • Aged
  • Animals
  • Cell Differentiation
  • Cell Line, Tumor
  • Endometrial Neoplasms / pathology*
  • Female
  • GPI-Linked Proteins / physiology
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Neoplasm Staging
  • Transforming Growth Factor beta1 / physiology*
  • Tumor Suppressor Proteins / physiology*

Substances

  • GPI-Linked Proteins
  • TGFB1 protein, human
  • Transforming Growth Factor beta1
  • Tumor Suppressor Proteins
  • 5'-Nucleotidase
  • NT5E protein, human
  • Adenosine