[If ideas are entities that trade from mind to mind, then writing is their currency. And disjointed writing, like soiled currency, often does not serve its purpose. The objective of these pages is to induce the habit of writing, aiming for efficient technical communication amongst our research-scholars. These writings are unedited and therefore open to direct feedback.
In this, very first article of our Commentary-series, Privita Edwina (PhD scholar) discusses metastasis and the importance of dormant tumor cells in context of cancer progression. We invite readers to send in their comments/critique using the contact-form to the left.]
In solid-tissues such as skin or liver, cells are connected to the neighbouring cells or the extracellular matrix (ECM) through the transmembrane proteins known as cell adhesion molecules. These connections help the cell/tissue maintain its form and function. The communication between the cell and its neighbours happens in the form of biophysical and/or biochemical signalling. It is a two-way process in which the cell generated signals are transferred to the surrounding matrix or the neighbouring cells which in turn respond by signalling downstream effectors and vice versa. When the cell signalling is altered it results in diseases such as metabolic disorders, tissue fibrosis, cancer etc.
Cancer and cells
Cancer is a leading cause of death worldwide, accounting for nearly 10 million deaths in 2020. The major cause of death due to cancer is its ability to “metastasize”. Metastasis is a process in which the cells dislodge from a primary tumour, gain entry into the blood-circulation, travel along the blood vessel, gain entry into the tissue parenchyma at a distant site and establish a new colony which eventually forms a secondary tumour. Though it appears as a straightforward process there are several obstacles that these travellers must overcome in order to reach a new site and flourish. Sadly, only 0.01% of the escaped cells survives the process.
Nevertheless, the
metastatic cells are hard to diagnose and harder to treat since they exist in
many different phenotypic states. It is often said that metastasis begins with
Epithelial-to-Mesenchymal transition (EMT) in which the cells acquire
characteristics suitable for invasion such as increased motility, loss of
apical-basal polarity, loss of cell-cell contacts, ability to degrade the ECM
etc. But what exactly is “metastasis”,
and how does it progress?
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| The (not-so) long road to metastasis |
Stages of metastasis
The first step
of metastasis begins with the dissemination of the tumour cells from the
primary tumour. The cells can travel either as clusters or as single cells. If
the cells were to travel in clusters it has already failed to comply with the
EMT prerequisite which disallows the cell-cell contacts. However, it has been
clearly documented in breast and lung tumour that cells move in clusters.
Therefore, a complete EMT is not a prerequisite for the metastatic process.
Rather the cells exist in multiple intermediate states lying between epithelial
and mesenchymal pool. Another line of thought is that, among the escaping cohort,
the leader cells (cells in the front of the cluster) might be on the terminal
side of EMT with more destructive traits (ability to degrade the matrix by
proteases) to enable the evasion. The follower cells can therefore follow the
path of the leader cells.
In the next
stage, the cells enter the circulation to travel to a distant site. These
travellers, known as circulating tumour cells (CTCs), may migrate individually
or as clusters. Life in circulation is equally difficult for these CTCs, for
they need to withstand multiple obstacles on their way in the form of
hydrodynamic flow, shear stress, loss of adhesion to substrate that makes them
vulnerable to clearance by the body’s immune system. Having said that, CTCs shield
themselves by befriending the cells of the circulatory system such as
neutrophils, monocytes, macrophages as well as endothelial cells. These circulatory
cells act as a protective cloak for the CTCs and facilitate their survival.
Now that the
CTCs have survived their life in circulation, the next step is to invade the
new tissue parenchyma and establish the colonies. This process is known as
extravasation. During extravasation, CTCs traverse the endothelial wall in
process termed as trans endothelial migration. In some cases, CTCs take the
company of the resident cells, especially the monocytes to facilitate
extravasation.
The propensity
for a particular cell to metastasize to a particular organ may be dependent
upon the tissue of origin, the mechanical and biochemical properties of the new
tissue site, cues for survival advantage.
For example, CTCs entering liver or bone may have a passive entry owing
to their fenestrated architecture whereas those that aim for the brain must
prepare to navigate the tortuous blood-brain barrier which will require a
different set of adaptations. The choice of the distant organ may also be
dependent on the design of the circulatory system. For instance, the metastasis
of colorectal cells to the liver is favoured because the portal vein from gut
empties directly to the liver.
End of metastatic-journey
Having completed
the arduous metastatic journey, the CTCs cannot immediately proliferate in the
new tissue. Instead, they exist as dormant tumour cells (DTC) since they are in
an unfamiliar environment and they lack native signals to continue
proliferation. These DTCs may continue to stay quiescent for weeks to years
before they can get survival signals. Being quiescent can also protect the DTCs
from being recognized by the immune system as well as confers chemoresistance
to the cells. Therefore, understanding the dormancy time period may help us
target the quiescent cells that may pose a threat many years later.
Reports say that
those DTCs that embody traits of cancer stem cells (CSCs) have the survival
advantage since they can rapidly revamp their genetic programs to adapt to the
new environment. The metastatic microenvironment also adds to the ability of
DTCs to establish new colonies. Especially, the fibroblast can signal the DTCs
to engage their integrins for stromal support. In addition, the local ECM
composition and arrangement, stiffness and hypoxia also contribute to the
ability of previously dormant cells to colonize the organ. On the whole, DTCs
stumble through trial and error on different gene expression programs and
adaptive behaviours to effectively survive in the tissue in which they have
landed.
Though tumour
originates as a result of genetic mutations, the non-genetic adaptive programs of
the native as well as the distant microenvironment should act in concert in order
for the success of the invasion-metastatic cascade.