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Page 60 Hunt et al. Extracell Vesicles Circ Nucleic Acids 2020;1:57-62 I http://dx.doi.org/10.20517/evcna.2020.04

including breast cancer and hepatocellular carcinoma, among others [20-25] . Additionally, several ongoing clinical
trials are testing anti-adrenergic medications as an adjuvant or stand-alone therapy in prostate and pancreatic
[18]
cancers (NCT03152786, NCT02944201, NCT03838029, NCT04245644). Within this study, Amit et al.
found that Carvedilol, which non-selectively blocks α1, β1, and β2 adrenergic receptors, dramatically
decreased tumor growth and proliferation rates when compared to tumors within vehicle-treated mice
null
harboring patient-derived xenografted p53 OCSCC tumors. Supporting the use of anti-adrenergic
therapies in humans, this group found that the level of TH staining in human OCSCC samples was an
independent predictor of increased tumor recurrence and decreased patient survival. Thus, this work
argues for an increased focus on anti-adrenergic approaches for treating OCSCC as well as other cancers.

[1]
[18]
Similar to the findings by Amit et al , Magnon et al. found an increased density of TH-positive adrenergic neurons
within the tumor microenvironments of patients with high-risk prostate adenocarcinomas . This group showed
[1]
that the number of adrenergic neurons within the tumor microenvironment was an independent predictor of
tumor recurrence. They also found a similar relationship between tumor aggression and the amount of
parasympathetic vesicular acetylcholine transporter (VAChT)-positive staining within the tumor body.
However, they were not able to determine whether this increase in autonomic innervation was due to
neurogenesis, neuritogenesis, neuron-type switching, or some other mechanism. Additionally, they were
not able to determine if the tumor was driving this increase in autonomic neurite number, and by what
means these aggressive tumors were communicating with local neurons. In contrast, the findings presented
[18]
by Amit et al. shed light on possible mechanisms of communication between prostate tumors and local
innervating autonomic neurons. These experiments add to the already rich literature describing the role
that EVs play in regulating the tumor microenvironment and cancer metastasis. Future work in prostate
adenocarcinoma should examine the EVs released by these tumors, and the miRNA contents that may be
manipulating local neurons. A recent report systematically demonstrated the importance of EV contents
[26]
in the development and growth of a variety of cancers . Though small RNA messengers and regulators
were found to be important in mediating tumor growth in this study as well, this group provided ample
evidence supporting damage-associated molecular patterns (DAMPs) and other cancer-associated proteins
as essential mediators of neuron-tumor trophic interactions. These findings point to the possibility that
protein messengers are important in establishing and maintaining the trophic relationships between
prostate adenocarcinomas and local autonomic fibers, as well as p53 OCSCC tumors and local sensory/
null
adrenergic neurons.
[18]
Though the mechanisms governing neuron-tumor relationships described by Amit et al. were worked
out between OCSCC tumors and sensory/adrenergic neurons of the oral cavity, many of these principles
might be generalizable to other tumor types and neuronal subtypes. Already, increased neuritogenesis and
sensory-autonomic neurotype switching has been reported in pancreatic nerves in the context of pancreatic
[27]
cancer . However, the findings presented here also differ from those published in previous work. In
[1]
contrast to the findings of Magnon et al. , Amit et al. found no increase in parasympathetic VAChT-
[18]
null
positive neurites in p53 OCSCC tumors. Thus, it is possible that for each tumor type and each region
of local autonomic fibers, a balance of sympathetic and parasympathetic neurons guides tumor growth
and survival. Future work will need to examine these balancing forces within each tumor type and the
corresponding microenvironment.

This work describes novel mechanisms of EV-mediated regulation of tumor activity, which highlights new
hypotheses regarding the biology underlying these mechanisms. Differential delivery of miR-34a vs. miR-21
and miR-324 to local neurons could be the result of differential loading of miRNAs into EVs. Alternatively,
the differing contents of these cancer-derived EVs could be dictated strictly by expression changes within
WT
null
WT
p53 and p53 cancer cells. Specific analysis of transcriptional changes in p53 and p53 cancer cells,
null
combined with detailed profiling of EV contents will allow for a deeper understanding of the mechanisms
null
governing this described specificity of EV contents. In tandem with this, specific subpopulations of p53