Exosomes and small vesicles, less than 100 nm, released by
cells and containing parts of DNA or RNA, miRNAs, proteins, and other matter
released by the cell. They become free in the extracellular areas and can find
their way to other cell sites. The exosomes with miRNA may find other cells,
attach, enter, and activate the cell in such a manner to result in the damage
in the originating cell.
This paper is a combination of fact and speculation. It
attempts to refer to many significant works presented in the literature while attempting
to knit together an alternative view of metastasis. There is a great deal of
evidence for this new paradigm, but the reader should be warned that there is
no definitive acceptance. Thus the speculation. Paradigm shifts are always
difficult. Kuhn and his followers have posited ways in which this occurs. I am
hardly suggesting that there is any sudden or great insight, I am merely
suggesting an alternative view. This view looks at the exosome and miRNA.
One could look at this as an example of a cancer cell of
origin and metastatic cells at distant points. In this paradigm the cancer stem
cell, "cell of origin", just sends out exosomes of miRNA which somehow
float about until the find a cell to attach to. If one accepts this paradigm,
it changes in material ways how we see metastasis and more importantly how we
see possible therapeutics. Namely if a melanoma mets to the lung, does it do so
via an miRNA in an exosome and moreover is it the lung because the lung tissue
has a receptor that allows the entry of the miRNA.
Thus exosomes with miRNA can be powerful transmitters of
cancers. The actual malignant cell does not have to move, it just has to send
out the right miRNA.
As Rak noted regarding the work of Leyden and his Lab:
The metastatic dissemination of cancer cells from their
site of origin through the bloodstream to distant organs is a major cause of
cancer-related deaths. This process is not random1; instead, certain
populations of cancer cells preferentially seek out and colonize specific
organs, under the control of a range of molecular programs. Such homing
implicitly involves interactions between cancer cells that escape the primary
tumour, sometimes known as seeds, and the microenvironment, or ‘soil’, of target
sites.
But less intuitive is the discovery by Hoshino et al. that
seeds can influence the soil before their arrival, sending out extracellular
vesicles called exosomes that precondition specific organs for metastatic
invasion. There is growing support for the provocative notion that a build-up
of systemic responses to a primary tumour might precede, and even enable, the
eruption of metastatic cancer.
These responses might involve complex alterations in the
body’s vascular, coagulation and inflammatory systems — for example,
cancer-related changes in the composition of soluble proteins, in cell
populations or in the characteristics of exosomes5in the blood. Hoshino et al.
define exosomes as small extracellular vesicles — membrane-bounded compartments
that transport proteins, lipids and nucleic acids from one cell to another, and
which can travel considerable distances in bodily fluids or the bloodstream.
This information- transfer process has attracted
considerable interest in cancer research, because some extracellular vesicles
carry cancer causing genes called oncogenes, or oncogenic proteins that promote
cancer formation and disease progression. The involvement of extracellular
vesicles, including exosomes, in metastasis has been studied for some time, and
contributes to several key events that prepare a distant site for colonization
— a process called premetastatic niche formation.
Simply stated, it could be postulated that it is the exosome
that initiates and facilitates metastatic growth, not necessarily the flow of
the cells to new locations.
A great deal of effort is underway to resolve the extent of
the functions of EVs in cancer metastasis and in turn the possibility of
targeting them as a therapeutic.
There are two paradigms that we now work with in metastasis.
The classic involves the movement of the malignant cell across the body. The
second, the EV model, is the movement of EVs across the body, influencing
distant phenotypes. The EV model makes sense in many cancers, because of the
ease of the EV going into and out of the circulatory systems; blood and lymph.
We demonstrate these two paradigms below:
The classic paradigm is shown below. It fundamentally
assumes that a single cell mutates and becomes malignant and then that cell
proliferates as a cell and enters and leaves the blood system and finds a
location where it can again proliferate, perhaps undergoing additional genetic
changes. The key here in the classic paradigm is that the malignant cell is the
mechanism for proliferation. The literature here is significant.
Key to this Classic Paradigm, is the belief that it is the malignant
cell itself which migrates, and even more so, the cell is a stem cell. Namely
it can migrate and do so in a manner that allows it to establish its own outpost
of a malignancy. The cell maintains and carries with it the identical genetic
flaws which made it what it is at its site of origin. Then as part of this
paradigm, it is this cell which must go into and out of the blood stream. This
behavior of the Classic Paradigm is a complex and oftentimes highly
questionable type of behavior.
The new EV paradigm is shown below. It is not the actual
cell but elements of the cell such as miRNA which go forth and multiplies. Note
it first does a phenotype change still requiring fueling and then may actually
have a genotype change resulting in the classic "whack a mole"
results in metastasis.
The essence of the Neo Classical paradigm conjecture is
severalfold:
1. A malignant cell is changed and produces exosomes which
contain, for want of a better alternative, miRNAs which if and when absorbed by
target cells are oncogenetic in nature. The malignant cell can best be called a
stem cell.
2. The target cells absorbing and activating the miRNAs
phenotypically become malignant. Their genetic structure has not changed but
they are responding to the miRNA exosome. The target cells may be local or
distant.
3. The target cells are targeted by ligands or receptors on
the exosome that match those of the target cells. Thus there is a specificity
of targeting, much like what we see in many metastatic events.
4. The exosomes are small enough and unencumbered with
surface proteins that they are easily sent into and out of the blood stream. In
addition they are almost invisible to the immune system.
5. Long term exposure is inducive to a genotypic change of the
target cell, thus enabling it to become its own stem like cell.
6. Properly characterize exosomes may be targetable.
7. Early extraction of the stem cell before genotypic change
can be curative. Once the target cell genotypically changes that cell must be
excised or deactivated.
8. However, if the exosome itself is identifiable then
perhaps an immune targeting may be achieved.
If the above conjecture, which we argue may have some
validity, is correct, it argues for a dramatically different approach to cancer
treatment.
Exosomes have become a significant factor in examining
cancer metastasis. One could argue that they are paradigm shifting. Our focus
herein is to examine exosomes as a significant if not primary diver of many
metastases. This is a dramatically different view of cancer progression. It
does allow for the explanation of many of the issue that we see in examining
such progression.
We use the literature to examine the exosomes and its
kindred spirits. Exosomes are fundamentally ad double wall lipid carriers of
cellular elements, predominantly parts of DNA, RNA, proteins, and most
importantly miRNA.
What is metastasis and how does it work. Again in a
simplified sense, metastasis if the propagation of malignant behavior to other
sites in addition to the primary site. Now trees and other plants get tumors.
But these tumors do not spread. Large galls on the sides of trees are
compartmentalized tumors plus viral materials. Thus what makes animals have
such diseases and how do they function?
Micro RNAs are small RNA strips, about 22 base pairs in length,
that can target and suppress mRNA inhibiting translation.
Epigenetic factors such as the impact of miRNAs can be
significant. They silence or activate genes, they can also impact histones
which in turn may silence or activate genes. We examine both to a degree. There
is a complex network of positive feedback where miRNAs can induce via other
genes favorable growth environments.
In the Classical model we have the mutation of genes, the creation
of a putative cancer stem cell, and the movement from one place to another via
initially an EMT and then intra and extra-vasation. Now the Neo-Classical model
assumes that it is the exosome and its contents, putatively the miRNA, that
moves about. This can be a fundamental paradigm shift but arguably verifiable.
Thus how then does one consider the dynamics of metastasis in this case?
Dealing with the exosomes one considers ways to block them
via multiple therapeutics. If one can block them after initial tumor
recognition then is there a way to mitigate metastasis?
Immunotherapy has made great strides however to be effective
the cells targeted must be recognizable. Thus understanding the surface of the
exosomes or even more so to be able to target them and insert markers may be
effective. One wonders if CAR-T approaches may be effective.
This is a key question which may be easier to deal with. We
can now access many of the exosomes, examine their contents and then assess the
specific malignancy and ascertain its progression.
We proceed to review, examine, and consider these issues.
This is not a fundamental research paper since it relies on the work of others,
it is not a review paper since it does not present a summary of others, but it
is an attempt to consider a new paradigm. This may or may not prove to have
sustainable capacity but the author believes it is worth the consideration in
light of recent investigations.
We have published a paper discussing this topic in detail.
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