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Page 53 Racchetti et al. Extracell Vesicles Circ Nucleic Acids 2023;4:44-58 https://dx.doi.org/10.20517/evcna.2023.03

In addition to their interaction with MVB, autophagosomes interact with their established vesicles, the
exosomes. The process of this interaction is highly complex; it could be established in target cells, where
exosomes of original cells are taken up, or in the extracellular space, where exosomes and autophagosomes
are present as EVs [72,89,90] . Autophagy and exosome crosstalk are complex processes. They are beginning to be
recognized and documented [86,89-92] . These interactions, considered protective of cells, including neurons ,
[80]
have been shown to play an essential role in cancers, discussed in the following subsection 5D.

Subsection 5C: Secretory autophagy. Autophogasome secretion occurs by UPS. Processes of this type are
also frequent with exosomes, ectosomes, and lysosomes [7,34-36] . With autophagosomes that govern many
cytoplasmic proteins, UPS is critical, leading to toxic protein disposal, immune signaling, and pathogen
surveillance. For decades UPS was the only type of secretion active in autophagosomes for decades.
Recently, based on their endoplasmic reticulum-translocation process, about 30% of the autophagy-
dependent proteins have been reported to be possibly secreted by conventional processes . In other words,
[93]
many (but not all) secreted autophagic proteins operate by UPS, while a smaller fraction appears to be
operated by conventional forms of secretion [93,94] . Various proteins secreted by UPS have been identified.
Some participate in the extracellular navigation of EVs, which is essential for various functions [20,75,76,85] .
Among autophagosome EVs, many contain cytokines, granules (including FGF2, TGFβ), and proteins (α-
synuclein, HMGB1, matrix metalloproteases, and many others) [89,95,96] , also relevant for diseases as discussed
in the subsection 5D.

Subsection 5D: Autophagosome diseases. The role of autophagosomes in diseases has been reported in
[97]
various organs, for example, cerebral neurodegeneration . For immune diseases, autophagosomes have
been investigated more extensively; however, the state of knowledge remains limited . Regarding therapy,
[98]
the studies of autophagosome EVs are preliminary [80,81,92] .

More established is the state of cancer. A consistent property of cancer cells is their substantial generation of
exosomes and (thus) of their EVs, which interact extensively with autophagosomes, contributing to some
forms of cancer. Specifically, the exosomes secreted by cancer cells modulate autophagy in recipient cells,
while autophagy influences exosome biogenesis [89,91] . The promising approach is based on the anti-cancer
effects induced by autophagy inhibitors, which significantly impact in terms of EV quantity and their
content, with profound therapeutic activity [20,99,100] . Reinforcement of autophagosome effects can be induced
by agents such as nuclear factors and G protein-coupled receptors [10,101] . Therefore, interest is currently
focused on developing inhibitors of various properties. Results appear based on the interaction of
autophagosomes with exosomes and other factors that, in many cancers, are essential for adapting patients
to tumor microenvironments [20,89,99-101] .

Another mechanism that controls cancer growth is a property typical of endo-lysosomes reported in
subsection 4A, i.e., the expression of TRP channels. These channels, absent from general lysosomes, are
often maintained by the endo-lysosomes fused to autophagosomes, with or without MVBs. Therefore,
cancer growth can be reduced by specific anti-channel treatments [65,102] . In this case, the therapy can be
attempted based on current autophagosome knowledge.

CONCLUSION
We illustrated the initial steps of vesicle processes leading to EV navigations and intercellular
communications. Most illustrations concern cytoplasmic areas where specific vesicles are generated. For
many years, no function had been attributed to the original membrane-bound structures of vesicle origin.
The discovery of the first two types of specific structures, MVBs (visible in all cells) and ectosomes