Dear Editor,
Terminology matters. After all this is the basis of the formal code that allows investigators
to communicate, compare notes and use computational tools to access molecular databases.
If the same term is assigned different or inconsistent meanings, or different terms
are used to describe the same entity, communications degenerate. This is why occasional
debate on what specific terms mean, where they came from, and what is their best use
is a healthy exercise.
Few scientific communities experienced this problem more acutely than those of us
who work on what is now collectively described as extracellular vesicles (EVs). The
underlying biological complexity, technical considerations, historical reasons and
cultures of different parental research fields have stimulated semantic creativity
to produce a mind numbing plethora of descriptors, including terms such as exosomes,
ectosomes, microvesicles, microparticles, shed vesicles, prostasomes, promininosomes,
tolerosomes, apoptotic bodies, nanovesicles and several others, the meaning of which
is only recently being more rigorously considered (1–3).
The case in point are EVs known as “oncosomes.” At the time of this writing, there
were at least 26 PubMed citations and a handful of authoritative review articles,
in which the term “oncosomes” has been used (including as key word) to highlight different
aspects of EV release by cancer cells (4–7). In spite of its intuitive usefulness
and convenient “ring,” this term is often applied in ways that have little to do with
its intended meaning, circumstances under which it has been coined in our respective
laboratories, ontologic efficiency or any consensus in the field. Therefore, some
context may be useful in putting things in perspective towards establishing meaningful
definitions.
In 2008, we described the first piece of experimental evidence that the oncogenic
form (variant III) of the epidermal growth factor receptor (EGFR), EGFRvIII, which
is relatively specific to human glioblastoma (GBM), is released from brain tumour
cells as cargo of EVs that range between 100 and 400 nm in diameter and carry phosphatidylserine
on their surfaces (8). While the biogenesis of these EVs was initially unknown, this
observation signified the ability of EVs to mediate the extracellular exit of structurally
and functionally abnormal, mutant and potentially transforming macromolecules (oncogenes).
This feature fundamentally and qualitatively distinguishes such oncogene-containing
EVs from all of their counterparts that may be produced by transformed or non-transformed
cellular populations, regardless of the state, function and origin of such cells.
Indeed, this is the basis of the contention that EVs could serve as reservoir of cancer-specific
biomarkers recoverable from biological fluids. To highlight this uniqueness of oncogene-carrying
EVs, one of us (B.M.) coined the term “oncosomes,” which was included in the related
manuscript (8) and reiterated in subsequent writings (9, 10). Again, in this case
the root particle “onco-” refers to the oncogenic molecular cargo of cancer-derived
EVs.
In 2009, one of the co-authors (D.D.V.) described a process whereby amoeboid migration
of metastatic prostate cancer cells triggered production of gigantic EVs (>1,000 nm
to >10,000 nm) found to emanate from large protrusions of the cellular plasma membrane
(11). Formation of these EVs was dependent on cellular transformation, including activation
of AKT1 and EGFR pathways, and was associated with abnormal assembly of molecular
cargo, including proteins and nucleic acids. This process also reflected both the
oncogenic transformation and a transition to a fast migratory and highly metastatic
amoeboid phenotype of cancer cells (12). These EVs were also initially referred to
as “oncosomes” but were clearly structurally and morphologically unique, beyond their
molecular content. To capture this cancer-related abnormal structure and content of
these highly unusual EVs, they were subsequently described as “large oncosomes” (LOs),
a term that has since been consistently used in original contributions on this subject
(12–14).
Interestingly, LO-like EVs may have gone underreported. For example, structures with
similar characteristics (microparticles or cytoplasts) have recently been implicated
in modulating innate immunity at metastatic cancer sites (15), and were also observed
during formation of invadopodia and cancer cell extravasation (16). Again, in this
case the distinguishing feature was the biogenetic process leading to formation of
very large EVs by specific types of cancer cells. Indeed, as a corollary, it may also
be useful to consider additional specific terms to describe large EVs produced by
non-transformed cells as discussed by Kowal et al. (1). Perhaps in this case terms
such as large EVs, “megavesicles” or shed cytoplasts could be far more appropriate
than “oncosomes.”
Thus, terms “oncosomes” and “large oncosomes” are not synonymous or interchangeable.
They have different origins, conceptual contexts, EV size reference and contents,
and were introduced at different times and for very different specific reasons by
different research groups. In none of these instances, the term “oncosomes” simply
refers to the fact that these EVs emanate from cancer cells as such. Instead, these
descriptors are meant to highlight two different unique consequences of malignant
transformation, as it intersects with cellular vesiculation processes, namely the
emission of oncogenic macromolecules and abnormalities in the EV biogenesis, respectively.
Arguably both of these features are important and the related terms may retain their
original usefulness, but only as long as they are applied in a purposeful, meaningful
and consistent manner.
Brian Meehan
Child Health and Human Development ProgramThe Research Institute of the McGill University
Health CentreMontreal, Quebec, Canada
Janusz Rak
Department of Pediatrics, Biochemistry, and Experimental Medicine McGill UniversityChild
Health and Human Development Program, The Research Institute of the McGill University
Health CentreMontreal, Quebec, CanadaEmail: janusz.rak@mcgill.ca
Dolores Di Vizio
Division of Cancer Biology and TherapeuticsDepartments of Surgery, Biomedical Sciences
and Pathology and Laboratory MedicineSamuel Oschin Comprehensive Cancer InstituteCedars-Sinai
Medical CenterLos Angeles, CA, United StatesEmail: Dolores.Divizio@cshs.org