A New Horizon in Oncology: Identifying and Disrupting Tumor Exosomes

Biologics

Large lipid vesicles which appear similar to exosomes. Source: Wikipedia

Most biologists and clinicians will be very familiar with membranous vesicles, but the concept of exosomes is less prevalent, despite being characterized 30 years ago.1 Exosomes are nanovesicles which are roughly 50 nm in size and are thought to be produced by most cells—even tumor cells—for intercellular signaling purposes.2 Much like other vesicles, exosomes bud off of their host’s lipid bilayer, then, after travel, integrate into their target’s lipid bilayer and disburse their cargo into the target’s cytosol. See where this is going? A new review published in the Journal of Cell Adhesion & Migration makes a compelling case that tumor exosomes traverse the tumor microenvironment, contributing to or perhaps starting tumor progression via the delivery of their cargo to noncancerous cells.3 To further investigate the role of tumor exosomes within cancer progression, a powerful molecular simulation software suite will be necessary.

Closing in on the Mechanism of Tumor Progression

With a title like “Exosomes in cancer theranostic: Diamonds in the rough,” it’s clear that the authors of the review have high expectations for the future of tumor exosome research, and it’s no secret why. Exosomes produced by tumors carry tumor-spreading cargo such as angiogenic switches and immune escape mechanisms which convert the healthy cells that they dump their cargo into. Genetic material also easily travels in exosomes, though in limited quantities due to their small size.

In a way, tumor exosomes behave like micro viruses, spreading the cancerous state from one cell to another, resulting in its reproduction and subsequent future “infection.” Interestingly, exosomes can actually one-up real viruses, because they can reprogram other cells to produce more of themselves, whether or not they actually contain genetic material, via their protein mixture cargo.

The review focused on the role of exosomes within cancer progression in a diagnostic context, assuming that tumor-generated exosomes would have molecular motifs which could be detected and then quantified to predict progression as a sort of biomarker—a conclusion verified by other research.4=7638&pubmed-linkout=1″>http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=7638&pubmed-linkout=1] In particular, the review cited other research which measured levels of heat shock proteins (HSPs) derived from exosomes isolated from serum. Excitingly, other researchers have jumped onto the possibility of utilizing exosomes in oncology as well, noting that their ability to carry mRNA, DNA, small molecules, and proteins makes them potent and programmable delivery vehicles, again recalling the theme of a pseudo-virus.5

Exosomal Signaling Systems Are Complicated

Thinking a step ahead, tumor exosomes could also be targeted via a variety of methods to interrupt their ability to bind to their target membrane—stopping progression in its tracks. Whether researchers intend to study tumor exosomes, produce new exosomes of their own, or attempt to intercept tumor exosomes to stop progression, they’ll need to characterize the following proteins, systems, and structures:

  • Surface markers or molecular motifs of exosomes produced by healthy cells
  • Cargo molecules contained in exosomes produced by healthy cells
  • Homing marker for exosomes on healthy cells intended for reception of exosomes produced by healthy cells
  • Alternative homing markers on healthy cells which aren’t used by healthy cell exosomes but may be used by tumor exosomes
  • Method of packaging and introduction of cargo molecules produced by healthy cells
  • Method of delivery and unpacking (if any) of cargo produced by healthy cells into other healthy cells
  • Method of delivery and unpacking (if any) of cargo produced by healthy cells into tumor cells
  • Surface markers or molecular motifs of exosome produced by tumor cells
  • Cargo molecules contained in exosomes produced by tumor cells
  • Homing marker specific to exosomes produced by tumor cells on tumor cells (if any)
  • Method of packaging and introduction of cargo molecules produced by healthy cells
  • Method of delivery and unpacking (if any) of cargo produced by tumor cells into other tumor cells as well as healthy cells

Characterizing each of these components and determining their interaction with each other is critical to understanding potential drug targets—every single component above has a cornucopia of points at which a biologic or small molecule therapy could conceivably be effective at slowing or stopping tumor progression. It’s clear that “screen-n-dream” shotgun style small molecule testing will be a waste of time and resources now that researchers have access to more refined molecular simulation tools which can be used to tailor biologics to their intended target.

Researchers’ technological capabilities weren’t always advanced enough to take the focused route rather than a molecular fishing expedition, though. In the days of exosomes’ first discovery, this kind of planned and targeted deep investigation simply wasn’t possible due to the sheer number of various moving parts that exosomal transmission has; characterizing the structure of a single homing marker might take years. Simulating the entire system was out of the question—even until very recently. As an apt comparison point, researchers were only able to fully simulate a virus’ interaction with the phospholipid bilayer in late 2016.6 Though exosomes are much smaller, simpler, and likely easier to simulate than entire viruses, the point stands: making simulations isn’t trivial.

Tools for Hunting Tumor Exosomes

Given the hot-off-the-press nature of the latest tumor exosome research and the demonstrated utility of molecular modeling, grant money for further research utilizing both is all but guaranteed. This poses a problem, though: how can researchers hope to study the potentially minute differences between tumor exosomes and healthy exosomes without a next-generation simulation suite to guide their efforts? Good thing there is one, designed specifically for research and drug development of biologics.

BIOVIA Biologics is the modeling, simulation, and data analytics suite that will allow you to explore complex exosomic systems with confidence and accuracy. With Biologics, you’ll be able to individually characterize homing markers and receptors, then quantitatively develop new biologics to target whichever you please. Contact us today to find out how you can use Biologics to crack into the mechanism of tumor progression.

  1. “Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes).” July 1987, https://www.ncbi.nlm.nih.gov/pubmed/3597417
  2. “Exosomes and HIV Gag bud from endosome-like domains of the T cell plasma membrane.” March 2006, https://www.ncbi.nlm.nih.gov/pubmed/16533950
  3. “Exosomes in cancer theranostic: Diamonds in the rough.” February 2017, http://www.tandfonline.com/doi/abs/10.1080/19336918.2016.1250999?journalCode=kcam20
  4. “Exosomes isolation and characterization in serum is feasible in non-small cell lung cancer patients: critical analysis of evidence and potential role in clinical practice.” 2016, “Modulation of tissue tropism and biological activity of exosomes and other extracellular vesicles: New nanotools for cancer treatment.” July 2016, http://www.sciencedirect.com/science/article/pii/S1043661816306521
  5. “First accurate simulation of a virus invading a cell.” September 2016, http://news.psu.edu/story/425297/2016/09/12/research/first-accurate-simulation-virus-invading-cell