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Klingeborn et al. Page 13

troubling is the risk of mistakenly using findings in the apical RPE exosome proteome to
guide research into basolateral-specific biological processes such as lipoprotein particle flux,
waste disposal, and nutrient transport, all of which may play a role in sub-RPE deposit and
drusen formation under pathological conditions. The next step in these studies will be to
study potential changes in the protein cargo in exosomes derived from RPE cells under
conditions of stress relevant to the AMD disease process, such as photo-oxidative stress and
dysregulation of lipid metabolism, to mention a few. Identified proteomic changes may
result in novel targets for therapy.
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5. Exosomes in ocular angiogenesis

5.1. Angiogenesis in Cancer
The involvement of exosomes and small EVs in angiogenesis in cancer has been the focus of
intense research in the last couple of years (Kalluri, 2016; Whiteside, 2016b). Exosomes and
small EVs have been shown to modulate angiogenesis in tumors by both pro- and anti-
angiogenic pathways (Ribeiro et al., 2013). For example, exosome release is increased by
hypoxia that often occurs in tumors, and these exosomes stimulate angiogenesis, when taken
up by endothelial cells (Hong et al., 2009; Park et al., 2010; Skog et al., 2008; Umezu et al.,
2013). The vascular remodeling induced by tumor-derived exosomes likely affects not only
tumor growth, but also metastasis. One of the ways tumor cell-derived exosomes may impair
the structural integrity of endothelial cells and cause leakiness, is via the exosomal
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microRNA, miR-105, which downregulates the expression of the tight junction associated
protein, ZO-1. Downregulation of ZO-1 enhances vascular permeability and thereby
metastatic dissemination (Zhou et al., 2014). Two recent studies determined the miRNA
content of exosomes derived from uveal melanoma (UM; an ocular cancer) (Eldh et al.,
2014; Ragusa et al., 2015). Ragusa and colleagues showed that an exosome-associated
miRNA (miR-146a) was upregulated in the vitreous humor of UM patients compared to
controls. They also demonstrated that miR-146a was upregulated in serum exosomes from
those same patients. Interestingly, the study by Eldh et al. found that UM-derived exosomes
from UM metastases in the liver could be recovered from the liver circulation (liver
perfusates). Both of these studies exemplify approaches to recover eye-specific exosomal
diagnostic markers from tissues and/or fluids that are peripheral to the eye, and thus more
easily accessible. It represents encouraging proof-of-concept for identifying eye disease-
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specific biomarkers outside the eye.

In the eye, both the cornea and the retina maintain very strict homeostatic control over
angiogenesis, when left unchecked neovascularization severely affects vision (Abdelfattah et
al., 2016; Eichler et al., 2004). Exosomes may play an important role in maintaining this
homeostasis under normal conditions.

5.2. Cornea
The transparency of the cornea is critical for vision. The healthy cornea is an avascular
tissue and during normal wound healing, repair occurs within hours without the formation of
new blood vessels (Chang et al., 2001). In some cases however, imbalance between pro- and
anti-angiogenic factors during wound healing can lead to corneal neovascularization. These
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Prog Retin Eye Res. Author manuscript; available in PMC 2018 July 01.