The movement of cancer cells from the initial site of development and to distant sites is a complex problem. We have previously provided a high level model for this process but it makes significant assumptions of the movement parameters which may not necessarily be reflective of the prime biochemical processes actually involved[1]. In a recent paper by Chen et al the authors have modeled the movement from the blood stream into distant organs.
The metastatic process is a complex concatenation of loss of
cell localization and cell survival and proliferation in new environments.
Generally as cells mature into specific cell types they become localized to
their environment, such as in melanocytes and the E cadherin binding[2].
Cells also work within their own environment via communications with the extra
cellular matrices[3].
The authors state:
We demonstrate tight endothelial cell–cell junctions,
basement membrane deposition and physiological values of vessel permeability. Employing
our assay, we demonstrate impaired endothelial barrier function and increased
extravasation efficiency with inflammatory cytokine stimulation, as well as
positive correlations between the metastatic potentials of MDA-MB-231, HT-1080,
MCF-10A and their extravasation capabilities. High resolution time-lapse microscopy reveals the highly
dynamic nature of extravasation events, beginning with thin tumor cell
protrusions across the endothelium followed by extrusion of the remainder of
the cell body through the formation of small ( 1 mm) openings in the
endothelial barrier which grows in size ( 8 mm) to allow for nuclear
transmigration. No disruption to endothelial cell–cell junctions is discernible
at 60 X, or by changes in local barrier function after completion of
transmigration. Tumor transendothelial migration efficiency is significantly
higher in trapped cells compared to non-trapped adhered cells, and in cell
clusters versus single tumor cells.
Specifically the investigators have developed a mechanical
model of the vasculature, one they can manipulate for analytical purposes, and
then they demonstrate the movement of the malignant cells across the interface
into a quasi-cellular environment.
As Chu states:
Now researchers at MIT have developed a microfluidic
device that mimics the flow of cancer cells through a system of blood vessels.
Using high-resolution time-lapse imaging, the researchers captured the moments
as a cancer cell squeezes its way through a blood vessel wall into the
surrounding extracellular matrix.
She continues:
As tumor cells make their way through the circulatory
system, some “arrest,” or pause at a particular location, adhering to a blood
vessel’s wall — the first stage of extravasation. Scientists have thought that
this cell arrest occurs in one of two ways: A cell may send out sticky
projections that grab onto the vessel lining, or it may be too big to pass
through, literally becoming trapped within the vessel. To investigate which possibility is more likely, the
researchers grew a network of tiny blood vessels from a solution of human
umbilical-cord endothelial cells. They injected a solution containing vascular
cells into a small microfluidic device containing a reservoir of hydrogel,
along with growth factors normally present in the developing circulatory
system. Within days, an intricate system of microvessels took shape, with each
about one millimeter long and 10 to 100 microns in diameter — dimensions
similar to the body’s small capillaries. The group then pumped tumor cells through the vascular
network, using a line of breast cancer cells known to be particularly invasive.
Using high-resolution confocal microscopy, the team watched as tumor cells
flowed through the miniature circulatory system. They observed that the
majority of cells that arrested along a vessel did so due to entrapment — that
is, they simply became stuck.
The observations are unfortunately in vitro and in a
constructed environment and lack much of the biochemical elements that often
make up for the transport. Although this is interesting in principle it fails
to substantiate all of the elements which make up an in vivo process.
Then she concludes:
In addition to observing the extravasation of single
tumor cells, the group also looked at the behavior of cell clusters — two or
more cancer cells that accumulate in a blood vessel. From their observations,
the researchers found that almost 70 percent of cell clusters broke through a
blood barrier, compared with less than 10 percent of single cells. But some cells that make it out of the circulatory system
may still fail to metastasize. To see whether a cell’s ability to extravasate
correlates with its metastatic potential, the group compared the efficiency of
extravasation of different cancer cell lines. The lines included breast cancer
cells, cells from fibrosarcoma (a cancer of the connective tissue), and a line
of nonmetastatic cancer cells. Sure enough, the team observed that the most metastatic
cells (fibrosarcoma cells) were also the most likely to extravasate, compared
with breast cancer and nonmetastatic cells — a finding suggesting that
targeting drugs to prevent extravasation may slow cancer metastasis.
The problem is that the cancer cells move in and out. There
is a continual flow and at the same time they have the problem of mutating as
well.
Observations
This is an interesting and strongly visual result. However,
there are several observations:
Mutations: Cancer cells are
continually mutating. Mutations results oftentimes in new surface receptors due
to the changes in the internal proteins. The cell surface receptors may respond
differently to the passage through such a cellular membrane. Thus this model
may be reflective of itself but not of reality.
Localization: One of the most intriguing things about
cancers is the localization of the metastases. Why, for example, do we so often
see prostate cancer go to the bone, melanoma to the brain, across the blood
brain barrier, and the same with so many other cancers. There is a
predisposition to transfer at specific sites. How does this approach deal with
such localization effects?
Stem Cells: Stem cells are a potential significant factor in
understanding metastasis. One question is; do stem cells move as easily as
others or more so? Or, are stem cells just active wherever they are and their
products are carried through the blood stream to sites where they can continue
cellular proliferation, and possibly induce a new set of stem cells there?
In and Out Flows: One of the questions one must ask when
looking at cancer cells in the blood, as has been done recently, is if the cell
is coming or going? Namely is the cell going from a source site, a primary, to
a remote or metastatic site, or from an already metastatic site to another new
one? The tagging of such cells would be important. The understanding of the
genetic changes would also be of critical importance.
Biochemical Drivers: The nature of cell surface markers,
receptors and the like, often dominate how the cells behaves, interacts with
the ECM, and can move to the blood system and exit from it as well. We have
argued that the cancer cell just flows and diffuses in the blood system and
that there is no growth. That is just gross speculation but it is open to
debate. Moreover the interaction of the cell with the cell way, and the
localization effects of the cell way by organ specificity may be an attractive
basis for organ specific metastasis. Or possibly not. But, having all these
elements at play in vivo is better than in vitro.
Immune System: Then also is the impact of the immune system
as the cells flow through the vessels. The cells are in a massive amount of
immune system interactions, and how does this impact the cells?
These are but a few of the unanswered questions elicited by
this paper. The simulation is well worth looking at the paper, but taking its
results as fact is stretching it a bit too far.
References
Chen, M., et al, Mechanisms of tumor cell extravasation in
an in vitro microvascular network platform, Integ Bio, 2013, http://pubs.rsc.org/en/content/pdf/article/2013/ib/c3ib40149a
Chu, J., Watching tumors burst through a blood vessel, MIT
News, http://web.mit.edu/newsoffice/2013/watching-tumors-burst-through-a-blood-vessel-0920.html
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