Bi-directional exosome-driven intercommunication between the hepatic niche and cancer cells

Molecular Cancer

Research

Bo Ma¹  Colin H. Beckwitt¹  Nikolina Dioufa¹  Amanda M. Clark¹  Alan Wells² 

[1] Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA;Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA;McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA;University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA;Pittsburgh VA Medical Center, VA Pittsburgh Healthcare System, S713 Scaife Hall, 3550 Terrace St, 15261, Pittsburgh, PA, USA;

关键词: Exosomes;    Microphysiological system;    E-cadherin;    Mesenchymal-to-epithelial-reverting-transition;   

DOI  :  10.1186/s12943-017-0740-6

 received in 2017-07-06, accepted in 2017-11-06,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundOur understanding of the multiple roles exosomes play during tumor progression is still very poor and the contribution of the normal tissue derived exosomes in distant seeding and tumor outgrowth has also not been widely appreciated.MethodsUsing our all-human liver microphysiological system (MPS) platform as a model to closely recapitulate the early metastatic events, we isolated exosomes from both tumor cells and liver microenvironment.ResultsWe observed that while priming of the hepatic niche (HepN) with MDA-231 breast cancer derived exosomes facilitated seeding of the cancer cells in the liver, subsequent tumor outgrowth was diminished; this was consistent with increased entry into dormancy. We found that hepatic niche (HepN) derived exosomes contribute significantly to the exosome pool and are distinguished from cancer derived exosomes based on their size, protein and miRNA content. By Ingenuity Pathway Analysis (IPA) of the miRNA content of the HepN, MDA-231/HepN and MDA-231 cells we showed that the HepN derived exosomes affect the breast cancer cells by suppressing pathways involved in cancer cell proliferation and invasion. More importantly exposure of MDA-231 and MDA-468 cells to purified normal HepN derived exosomes, induced changes in the cells consistent with a Mesenchymal to Epithelial reverting Transition (MErT). miRNA arrays performed on MDA-231 treated with Hum Hep/NPC derived exosomes showed significant changes in the levels of a select number of miRNAs involved in epithelial cell differentiation and miRNAs, such as miR186, miR23a and miR205, from our top and bottom bins have previously been reported to regulate E-cadherin transcription and MErT induction in various cancer types. Consistently HepN derived exosome treatment of breast and prostate cancer lines lead to a transient induction of E-cadherin and ZO-1 at the protein level and a more epithelial-like morphology of the cells.ConclusionsCollectively our data revealed a novel mechanism of regulation of the metastatic cascade, showing a well-orchestrated, timely controlled crosstalk between the cancer cells and the HepN and implicating for the first time the normal tissue/HepN derived exosomes in enabling seeding and entry into dormancy of the cancer cells at the metastatic site.

【 授权许可】

CC BY   
© The Author(s). 2017