Forbeck Focus Meeting 2014 - Extracellular Vesicles: Promises and Pitfalls

April 12-14, 2014, La Jolla, CA

Organizer:
Clark C. Chen, MD, Ph.D., University of California San Deigo (Forbeck Scholar 2009)

Participants:
Xandra O. Breakefield, Ph.D. - Massachusetts General Hospital
Bob Carter, MD, Ph.D. - University of California San Diego
Emanuele Cocucci, MD, Ph.D. - Harvard Medical School
Crislyn D'Souza-Schorey, Ph.D. - University of Notre Dame
Carsten Fruhbeis - Johannes Gutenberg Universitat Mainz
Stephen Gould, Ph.D. - Johns Hopkins University
Fred Hochberg MD - Massachusetts General Hospital
Hakho Lee, Ph.D. - Massachusetts General Hospital
Hon Leong, Ph.D. - London Health Sciences Centre
David Lyden MD, Ph.D. - Weill Cornell Medical College
Johan Skog, Ph.D. - Exosome Diagnostic
Alissa Weaver MD, Ph.D. - Vanderbilt University


Outcome:
In the most recent Forbeck retreat, the topic of exosomes surfaced in presentation by scholars of different generation. To me, this was impressive since scholars are selected based on a wide spectrum of interests. It was the reason behind the surprising finding that certain nuclear proteins are found on the cell surface. It was also the reason why certain mRNA and miRNA can be isolated from patient derived bio-fluids, such as serum, urine, and cerebrospinal fluid. Exosome as a recurrent theme in distinct biologic domains suggests it as an entity of general interest to laboratory and clinical investigations. Exosomes are small secreted vesicles that contain select proteins, mRNAs, and miRNAs. 

The available data suggest that exosomes serve as a mean by which glioblastoma can communicate with and modify its neighboring cells and the microenvironment. I am interested in the clinical application of exosomes in terms in neuro-oncology as it pertains to both biomarker and therapeutic development. It is known that glioblastoma cells secrete exosomes containing select tumor protein, mRNA, and miRNAs. The lipid bi-layer of the exosome protects these molecules from degradation in the hostile environment of the various bio-fluids (e.g. urine, serum, cerebrospinal fluid). As such, development of methods for purifying glioblastoma specific exosomes constitutes an attractive strategy for biomarker development. This is particularly important for brain cancers where repeated biopsy is associated with significant surgical and thus not practical in clinical practice. Additionally, fusion of exosomes with peri-tumor stroma or with neighboring tumor cells results in the delivery of exosome contents into these cells. This delivery can significantly alter the biology of the target cell and induce changes in tumor behavior and response to therapy. 

While there is general agreement that exosomes are small secreted vesicles that contain select proteins, mRNAs, and miRNAs, there is little agreement in terms of the specific definition of exosomes. The confusion in literature is largely related to a lack of understanding basic exosome biology. In general, exosomes are purified by size based criteria whereby cells and large cellular debris are removed by either centrifugation or size exclusion. In this context, it is not surprising that there are disagreements as to the definition of exosomes. Some authors define exosomes as vesicles of 30-90 nm and vesicles larger vesicles as ectosomes. Others define the upper limits of exosomes as 120-140 nm. While a size-based definition of exosomes will, by nature, be somewhat arbitrary, a more important issue in the field is that there are significant molecular heterogeneity within exosomes purified based on size criteria. It would be greatly advance the field if we come to a consensus of exosome markers that define the exosomes based on the mechanism of formation , the source of origin (urine, serum, cerebrospinal fluid), and aberrant cell states (tumor versus normal). It is further helpful to identify the molecular pathways required for exosome formation. Inhibition of these pathways may hamper communications within the tumor microenvironment and prohibit glioblastoma growth. I hope to address these issues by assembling a panel of exosome investigators. The proceedings from this meeting will be organized into a review article for consideration of publication. The contents of the article will be submitted for publication consideration.