Enhanced shedding of extracellular vesicles from amoeboid prostate cancer cells Potential effects on the tumor microenvironment

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review

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Author(s)

  • Jayoung Kim
  • Samantha Morley
  • Denis Bedoret
  • Dale T. Umetsu
  • Dolores Di Vizio
  • Michael R. Freeman

Detail(s)

Original languageEnglish
Pages (from-to)409-418
Journal / PublicationCancer Biology and Therapy
Volume15
Issue number4
Publication statusPublished - Apr 2014
Externally publishedYes

Abstract

The gene encoding the cytoskeletal regulator DIAPH3 is lost at high frequency in metastatic prostate cancer, and DIAPH3 silencing evokes a transition to an amoeboid tumor phenotype in multiple cell backgrounds. This amoeboid transformation is accompanied by increased tumor cell migration, invasion, and metastasis. DIAPH3 silencing also promotes the formation of atypically large (>1 μm) membrane blebs that can be shed as extracellular vesicles (EV) containing bioactive cargo. Whether loss of DIAPH3 also stimulates the release of nano-sized EV (e.g., exosomes) is not established. Here we examined the mechanism of release and potential biological functions of EV shed from DIAPH3-silenced and other prostate cancer cells. We observed that stimulation of LNCaP cells with the prostate stroma-derived growth factor heparin-binding EGF-like growth factor (HB-EGF), combined with p38MAPK inhibition caused EV shedding, a process mediated by ERK1/2 hyperactivation. DIAPH3 silencing in DU145 cells also increased rates of EV production. EV isolated from DIAPH3-silenced cells activated AKT1 and androgen signaling, increased proliferation of recipient tumor cells, and suppressed proliferation of human macrophages and peripheral blood mononuclear cells. DU145 EV contained miR-125a, which suppressed AKT1 expression and proliferation in recipient human peripheral blood mononuclear cells and macrophages. Our findings suggest that EV produced as a result of DIAPH3 loss or growth factor stimulation may condition the tumor microenvironment through multiple mechanisms, including the proliferation of cancer cells and suppression of tumor-infiltrating immune cells. © 2014 Landes Bioscience.

Research Area(s)

  • AKT1, Amoeboid, EMT, Extracellular vesicles, Immune cells, Microvesicles, miR125a, Prostate cancer

Citation Format(s)

Enhanced shedding of extracellular vesicles from amoeboid prostate cancer cells Potential effects on the tumor microenvironment. / Kim, Jayoung; Morley, Samantha; Le, Minh; Bedoret, Denis; Umetsu, Dale T.; Di Vizio, Dolores; Freeman, Michael R.

In: Cancer Biology and Therapy, Vol. 15, No. 4, 04.2014, p. 409-418.

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review