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

Abstract

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.Electronic supplementary materialThe online version of this article (10.1186/s12943-017-0740-6) contains supplementary material, which is available to authorized users.

Does Direct and Indirect Exposure to Ionising Radiation Influence the Metastatic Potential of Breast Cancer Cells

“…Another study by Dioufa et al (2017) showed that priming the hepatic niche with exosomes exuded from MDA-231 breast cancer cells facilitated seeding of the cancer cells in the liver. Intriguingly, the same study also showed a difference in a certain set of miRNA contents in the tumour-derived exosomes compared with exosomes from normal cells (which happened to be a set of miRNAs involved in epithelial cell differentiation) [135]. It was also shown that bone-derived exosomes can stimulate proliferation in tumour cells, as well as mediate communication between cancer cells and bone cells [136].…”

Ceramide and Exosomes: A Novel Target in Cancer Biology and Therapy

“…A study on human breast cancer MDA-MB-231 cells settling into a premetastatic niche in the liver showed that exosomal communication can be bi-directional. Upon priming of HepN liver cells with cancer cell-derived exosomes, liver cells secrete exosomes that turn down migratory gene expression and induce mesenchymal-to-epithelial reverse transition (MET) in cancer cells (Dioufa, Clark, Ma, Beckwitt, & Wells, 2017). As the result of this bi-directional communication, HepN-derived exosomes enhance cancer cell seeding, but also suppress cell outgrowth, which renders cancer cells temporarily dormant once settled into their niche.…”

The great escape: How metastases of melanoma, and other carcinomas, avoid elimination

“…The tumor signals that enable intercalation within a tissue (including extracellular vesicles (EV)) [30][31][32][33] leads to reverse signaling (including EV) from the receptive organ that imparts the cMErT and initial dormancy. 34,35 The state of the tumor cell in dormancy is unknown, with one model positing quiescence versus another of balanced proliferation and death. In silico modeling determined that it is highly unlikely that micrometastases exist in a state of balanced proliferation and death, but rather either grow out or enter quiescence.…”

“…The quantitative nature of this balance is noted in tumor cells producing greater numbers of EV than the host parenchymal cells, but with this being counterbalanced by the numerically vaster numbers of host cells upon single cell seeding. 35 Similarly, the growth factor-rich milieu of tumor cells may also overwhelm the death signals from the innate immune response to foreign bodies/cells, enabling greater survival of mesenchymal aggressive tumors. This is important in studying resistance to therapy if the surviving and outgrowing 'metastatic' tumor cells have not upregulated key molecules and behaviors that normally function to enable metastatic seeding, and thus would appear as falsely sensitive growths.…”