Mesenchymal stem cell-derived interleukin-28 drives the selection of apoptosis resistant bone metastatic prostate cancer

Nat Commun. 2021 Feb 1;12(1):723. doi: 10.1038/s41467-021-20962-6.

Abstract

Bone metastatic prostate cancer (PCa) promotes mesenchymal stem cell (MSC) recruitment and their differentiation into osteoblasts. However, the effects of bone-marrow derived MSCs on PCa cells are less explored. Here, we report MSC-derived interleukin-28 (IL-28) triggers prostate cancer cell apoptosis via IL-28 receptor alpha (IL-28Rα)-STAT1 signaling. However, chronic exposure to MSCs drives the selection of prostate cancer cells that are resistant to IL-28-induced apoptosis and therapeutics such as docetaxel. Further, MSC-selected/IL-28-resistant prostate cancer cells grow at accelerated rates in bone. Acquired resistance to apoptosis is PCa cell intrinsic, and is associated with a shift in IL-28Rα signaling via STAT1 to STAT3. Notably, STAT3 ablation or inhibition impairs MSC-selected prostate cancer cell growth and survival. Thus, bone marrow MSCs drive the emergence of therapy-resistant bone metastatic prostate cancer yet this can be disabled by targeting STAT3.

Publication types

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

MeSH terms

  • Adenocarcinoma / secondary*
  • Aminosalicylic Acids / pharmacology
  • Aminosalicylic Acids / therapeutic use
  • Animals
  • Apoptosis / drug effects
  • Benzenesulfonates / pharmacology
  • Benzenesulfonates / therapeutic use
  • Bone Neoplasms / drug therapy
  • Bone Neoplasms / secondary*
  • Cell Differentiation / drug effects
  • Cell Line, Tumor
  • Cell Proliferation
  • Culture Media, Conditioned / metabolism
  • Disease Models, Animal
  • Docetaxel / pharmacology
  • Docetaxel / therapeutic use
  • Humans
  • Interferons / genetics
  • Interferons / metabolism
  • Male
  • Mesenchymal Stem Cells / pathology*
  • Mice
  • Mice, Knockout
  • Osteoblasts / pathology
  • Primary Cell Culture
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / pathology*
  • RNA, Small Interfering / metabolism
  • Receptors, Interferon / genetics
  • Receptors, Interferon / metabolism*
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • STAT1 Transcription Factor / metabolism
  • STAT3 Transcription Factor / antagonists & inhibitors
  • STAT3 Transcription Factor / metabolism
  • Tibia / pathology

Substances

  • Aminosalicylic Acids
  • Benzenesulfonates
  • Culture Media, Conditioned
  • IFNLR1 protein, human
  • IFNLR1 protein, mouse
  • Ifnl3 protein, mouse
  • NSC 74859
  • RNA, Small Interfering
  • Receptors, Interferon
  • Recombinant Proteins
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Stat1 protein, mouse
  • Stat3 protein, mouse
  • Docetaxel
  • Interferons