Exosome-Mediated Metastasis: From Epithelial–Mesenchymal Transition to Escape from Immunosurveillance

doi:10.1016/j.tips.2016.04.006

Trends in Pharmacological Sciences

Volume 37, Issue 7, July 2016, Pages 606-617

https://doi.org/10.1016/j.tips.2016.04.006 Get rights and content

Trends

Tumour-derived exosomes (TDEs) contain prodigious amounts of epithelial–mesenchymal transition (EMT) inducers, and transduce EMT characteristics in recipient epithelial cells.

Exosomes are being implicated in the aetiology of organotropic metastasis owing to their target-homing ability and capacity to form a premetastatic niche at specific organ sites.

Exosomes may be hijacked by tumour viruses and may confer oncogenic potential or induce malignant transformation in recipient cells.

TDEs have potent immunomodulatory effects that likely foster tumour escape from immunosurveillance.

Pharmacological agents that directly or indirectly modulate tumour exosome biogenesis, secretion, and function have also shown promising antimetastatic activity.

Exosomes are extracellular signalosomes that facilitate eukaryotic intercellular communication under a wide range of normal physiological contexts. In malignancies, this regulatory circuit is co-opted to promote cancer cell survival and outgrowth. Tumour-derived exosomes (TDEs) carry a pro-EMT (epithelial–mesenchymal transition) programme including transforming growth factor beta (TGFβ), caveolin-1, hypoxia-inducible factor 1 alpha (HIF1α), and β-catenin that enhances the invasive and migratory capabilities of recipient cells, and contributes to stromal remodelling and premetastatic niche formation. The integrin expression patterns on TDEs appear to dictate their preferential uptake by organ-specific cells, implying a crucial role of this pathway in organotropic metastasis. Through the expression of immunomodulatory molecules such as CD39 and CD73, TDEs modify the immune contexture of the tumour microenvironment, which could have implications for immunotherapy. Hence, targeting TDE dysregulation pathways, such as the heparanase/syndecan-1 axis, could represent novel therapeutic strategies in the quest to conquer cancer.

Section snippets

A Framework for Exosome-Mediated Metastasis

Metastatic outgrowths are the predominant cause of death from cancer. Since the late nineteenth century, when Paget formulated his enduring ‘seed-and-soil’ hypothesis [1], comparing disseminated tumour cells and the organ microenvironment with the ‘seed’ and ‘soil’, respectively, research on the mechanisms of cancerous metastasis has focused on the interaction between tumour and host. In recent years, this field has been enlivened with the exciting possibility that a newly described mode of

Initiation of Metastasis: Epithelial–Mesenchymal Transition

The formation of life-threatening metastases at distant organs requires the invasion of primary tumours through the basement membrane and dissemination via the circulation. Epithelial cells at the invasive front of carcinoma surmount this physical barrier by acquiring migratory and invasive properties through EMT [20].

Recently there have been compelling suggestions that TDEs may serve as conduit for EMT-initiating signals, owing to the observations that they (i) appear to deliver prodigious

Organotropic Metastasis: New Leads to an Old Mystery

Organotropic metastasis–the proclivity of certain primary tumours to spawn secondary neoplasia in specific organs–has been an age-old enigma in cancer biology [1]. Whereas EMT may support the dissemination of metastatic cells, incoming tumour stem cells would then need to engraft in a permissive foreign tissue microenvironment to proliferate and establish successful secondary outgrowths. Several recent studies suggest that cancers engender this congenial turf through exosomes, which in turn

Immune-Modulating Effects

The notion that the successful proliferation of disseminated clones to clinically manifest outgrowths hinges on the ability of tumour cells to escape natural or therapy-induced immunosurveillance has found widespread acceptance, and in this section it is our goal to assemble some of the emerging insights that implicate tumour exosomes in cancer immunoediting and subversion.

Firstly, TDEs arbitrate the generation of an immunosuppressive environment by blunting the response of immune effector

Pharmacological Strategies against Exosomal Dysregulation

As might be inferred from the preceding discussions, exosomal-mediated metastasis encompasses an intricate sequence of coordinated events, each of which may be amenable to therapeutic targeting (Figure 4), and collectively potentially represent a new paradigm to guide future development of antimetastatic therapeutic strategies.

Concluding Remarks

Recent developments in cancer biology require us to reconsider long-held assumptions about the pathobiology of metastases. Exosomes are evidently versatile and critical intercellular messengers employed by tumours to architect the local and distant microenvironment. These extrinsic signalling cues orchestrate the initiation of metastasis, which may occur through EMT, the synchronised preparation of a premetastatic niche, as well as escape from immunosurveillance to allow tumours to propagate

Acknowledgments

This research is supported by the National Research Foundation Singapore and the Singapore Ministry of Education under their Research Centres of Excellence (RCE) Initiative; Clinician Scientist Individual Research Grant-New Investigator Grant (CS-IRG-NRG) Award by the National Medical Research Council (NMRC) for Validation of Candidate Biomarkers in Plasma for Diagnosis and Prognosis of Lung Cancer; and Clinician Scientist Award (Senior Investigator Category) by the NMRC for Translational

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Trends in Pharmacological Sciences

ReviewExosome-Mediated Metastasis: From Epithelial–Mesenchymal Transition to Escape from Immunosurveillance

Trends

Section snippets

A Framework for Exosome-Mediated Metastasis

Initiation of Metastasis: Epithelial–Mesenchymal Transition

Organotropic Metastasis: New Leads to an Old Mystery

Immune-Modulating Effects

Pharmacological Strategies against Exosomal Dysregulation

Concluding Remarks

Acknowledgments

Lancet

Cancer Cell

Cancer Cell

Cell

Cell

Cancer Lett.

Curr. Biol.

Cell

Adv. Drug Deliv. Rev.

Biochim. Biophys. Acta

J. Control. Release

Blood

J. Biol. Chem.

J. Biol. Chem.

Cell Rep.

Biochim. Biophys. Acta

J. Biol. Chem.

Mol. Ther.

Modulation of B-cell exosome proteins by gamma herpesvirus infection

Proc. Natl. Acad. Sci. U.S.A.

MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response

Proc. Natl. Acad. Sci. U.S.A.

Exosomal HIF1α supports invasive potential of nasopharyngeal carcinoma-associated LMP1-positive exosomes

Oncogene

RNA trafficking by acute myelogenous leukemia exosomes

Cancer Res.

Neoplastic reprogramming of patient-derived adipose stem cells by prostate cancer cell-associated exosomes

Stem Cells

Tumor-derived exosomes are enriched in ΔNp73, which promotes oncogenic potential in acceptor cells and correlates with patient survival

Hum. Mol. Genet.

Matrix metalloproteinase 13-containing exosomes promote nasopharyngeal carcinoma metastasis

Cancer Sci.

Urothelial cells undergo epithelial-to-mesenchymal transition after exposure to muscle invasive bladder cancer exosomes

Oncogenesis

Quantitative proteomics of fractionated membrane and lumen exosome proteins from isogenic metastatic and nonmetastatic bladder cancer cells reveal differential expression of EMT factors

Proteomics

Interaction and uptake of exosomes by ovarian cancer cells

BMC Cancer

Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET

Nat. Med.

Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis

Cancer Res.

Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver

Nat. Cell Biol.

Tumor-derived exosomes promote tumor progression and T-cell dysfunction through the regulation of enriched exosomal microRNAs in human nasopharyngeal carcinoma

Oncotarget

Cancer exosomes express CD39 and CD73, which suppress T cells through adenosine production

J. Immunol.

Exosome proteomics reveals transcriptional regulator proteins with potential to mediate downstream pathways

Cancer Sci.

Molecular characterization of exosome-like vesicles from breast cancer cells

BMC Cancer

KRAS-dependent sorting of miRNA to exosomes

Elife

Exosomes secreted under hypoxia enhance invasiveness and stemness of prostate cancer cells by targeting adherens junction molecules

Mol. Carcinog.

Exosomes reflect the hypoxic status of glioma cells and mediate hypoxia-dependent activation of vascular cells during tumor development

Proc. Natl. Acad. Sci. U.S.A.

Exosome transfer from ovarian cancer cells to mesothelial cells promotes cell invasion by upregulating MMP-9 secretion and increasing clearance of mesothelial cells

Cancer Res.

The tetraspanins CD151 and Tspan8 are essential exosome components for the crosstalk between cancer initiating cells and their surrounding

Oncotarget

Review
Exosome-Mediated Metastasis: From Epithelial–Mesenchymal Transition to Escape from Immunosurveillance