When I was young and my father had returned from the Navy in
WWII he had a phrase he used frequently to admonish my at times less than nest
tendencies. Namely: "a place for everything and everything in its
place". I thought I knew what he was saying but it was not until I started
to understand cancer metastasis that this truly rang a bell. Cancer is not
"neat". It just drops stuff all over the place, sending cells hither
and thither, never putting things back where they belong.
We examine another process which is linked to cancer andmetastasis, namely the Epithelial to Mesenchymal Transition, EMT. As we have
noted in many other areas we have examined this has been argued to have
significant therapeutic interest. There has been some examination here as of
later but there is limited clinical application. What this area does do is
shine a light on the issue of cell location and lost of location stability as
an integral part of cell carcinogenesis.
Cells express genes in different ways depending when and
where they are. Epithelial cells generally express genes that allow the cell to
perform a specific function and to do so at a specific location. However from
time to time, such as in the growth phase of an organism, this stable phenotype
is suppressed and the cell has a characteristic that allows it to move freely
as a mesenchymal cell. Thus transitions from mesenchymal to epithelial phenotypes
are stabilizing transitions in a maturing organism (called MET). The reverse,
EMT, are generally destabilizing transitions. For example a melanocyte with E
cadherin expressed binds to the other keratinocytes and remain stable in the
skin. When E cadherin is not expressed but N cadherin is, the melanocytes bind
together and then wander, often first upward creating a carcinoma in situ, then
downward creating a melanoma. Thus as expression of genes is effected the
process of EMT allows for movement and thus metastasis.
In this note, we examine some of the recent advances
understanding this process, especially as applied to several somatic
malignancies. There is also the consideration of using EMT mechanisms as a
means to target therapeutics to mitigate metastasis. The state of the art is
still somewhat early but it does provide an interesting alternative. This paper
is not meant to be comprehensive but suggestive.
Weinberg presents a detailed description of the EMT as a
part of metastasis[1].
As Heerboth et al note:
EMT and MET comprise the processes by which cells transit
between epithelial and mesenchymal states, and they play integral roles in both
normal development and cancer metastasis. This article reviews these processes
and the molecular pathways that contribute to them.
First, we compare embryogenesis and development with
cancer metastasis.
We then discuss the signaling pathways and the
differential expression and down-regulation of receptors in both tumor cells
and stromal cells, which play a role in EMT and metastasis.
We further delve into the clinical implications of EMT
and MET in several types of tumors, and lastly, we discuss the role of
epigenetic events that regulate EMT/MET processes.
We hypothesize that reversible epigenetic events regulate
both EMT and MET, and thus, also regulate the development of different types of
metastatic cancers.
The above is more of an outline of the issues that can be
considered. Namely: (i) benign EMT processes versus malignant, (ii) downregulation
and control of EMT pathways, (iii) specific EMT effects in specific cancers,
and (iv) reversible controls regulating metastasis.
As Radisky notes:
The epithelial-mesenchymal transition (EMT) is an
orchestrated series of events in which cell-cell and cell-extracellular matrix
(ECM) interactions are altered to release epithelial cells from the surrounding
tissue, the cytoskeleton is reorganized to confer the ability to move through a
three-dimensional ECM, and a new transcriptional program is induced to maintain
the mesenchymal phenotype.
Essential for embryonic development, EMT is nevertheless
potentially destructive if deregulated, and it is becoming increasingly clear
that inappropriate utilization of EMT mechanisms is an integral component of the
progression of many tumors of epithelial tissues. Structural integrity is a key
property of epithelial tissues: external epithelia serve as protective barriers
against environmental hazards, and internal epithelia create defined and
physiologically controlled subdomains within the organism. Epithelial structure
is maintained by cell-cell interactions.
These involve tight junctions, cadherin based adherens
junctions that are connected to the actin cytoskeleton, gap junctions that
allow direct chemical interactions between neighboring cells, and desmosomes
connected to the intermediate filament cytoskeleton, and cell-ECM interactions
mediated by integrins and other molecules.
In this paper we address the following:
1. What is EMT and how does it function?
2. What are the critical drivers of the EMT process?
3. How does EMT effect a cancerous process?
4. What are the pathway elements involved in EMT?
5. What are the specifics of various cancers and EMT?
6. What is the interaction between the immune system and the
EMT process?
7. What role does chronic inflammation play in EMT activation
and in turn cancer?
8. What are the therapeutic opportunities available in the EMT
context?
9. Does the presence of blood borne EMT markers present a
diagnostic, prognostic, and therapeutic opportunity?
EMT is a process whereby a cell changes from a stable cell
in a well defined matrix to a cell which has the ability to move about in a
relatively unstructured manner. In essence the EMT process enables a metastatic
change. We summarize some of these features herein.
EMT is simply the process whereby cells lose the ability to
be at the right place at the right time. From Kalluri and Weinberg we have a
definition:
An epithelial-mesenchymal transition (EMT) is a biologic
process that allows a polarized epithelial cell, which normally interacts with
basement membrane via its basal surface, to undergo multiple biochemical
changes that enable it to assume a mesenchymal cell phenotype, which includes
enhanced migratory capacity, invasiveness, elevated resistance to apoptosis,
and greatly increased production of ECM (extra cellular matrix) components.
The completion of an EMT is signaled by the degradation
of underlying basement membrane and the formation of a mesenchymal cell that
can migrate away from the epithelial layer in which it originated.
Thus many cells are organized in a certain manner to effect
certain functions. In the prostate, a glandular organ, there are basal and
luminal cells surrounding the glands wherein secretion occurs. In the case of
high grade PIN for example, the cells start to proliferate and no longer align
properly. Then they slowly depart and create for wont of a better term, move
out. They continue:
A number of distinct molecular processes are engaged in
order to initiate an EMT and enable it to reach completion. These include
activation of transcription factors, expression of specific cell-surface
proteins, reorganization and expression of cytoskeletal proteins, production of
ECM-degrading enzymes, and changes in the expression of specific microRNAs. In
many cases, the involved factors are also used as biomarkers to demonstrate the
passage of a cell through an EMT..
The pioneering work of Elizabeth Hay first described an
“epithelial mesenchymal transformation” using a model of chick primitive streak
formation. In the intervening time, the term “transformation” has been replaced
with “transition,” reflecting in part the reversibility of the process and the
fact that it is distinct from neoplastic transformation.
The phenotypic plasticity afforded by an EMT is revealed
by the occurrence of the reverse process — a mesenchymal- epithelial transition
(MET), which involves the conversion of mesenchymal cells to epithelial
derivatives. Relatively little is known about this process; the best-studied
example is the MET associated with kidney formation, which is driven by genes
such as paired box 2 (Pax2), bone morphogenetic protein 7 (Bmp7), and Wilms
tumor 1 (Wt1).
From Kalluri and Weinberg we have three types of MET cells
are discussed:
(A) Type 1 EMT is associated with implantation and embryonic
gastrulation and gives rise to the mesoderm and endoderm and to mobile neural
crest cells. The primitive epithelium, specifically the epiblast, gives rise to
primary mesenchyme via an EMT. This primary mesenchyme can be re-induced to
form secondary epithelia by a MET. It is speculated that such secondary
epithelia may further differentiate to form other types of epithelial tissues
and undergo subsequent EMT to generate the cells of connective tissue,
including astrocytes, adipocytes, chondrocytes, osteoblasts, and muscle cells.
(B) EMTs are re-engaged in the context of inflammation
and fibrosis and represent the type 2 EMTs. Unlike the type 1 EMT, the type 2
EMT is expressed over extended periods of time and can eventually destroy an
affected organ if the primary inflammatory insult is not removed or attenuated.
(C) Finally, the secondary epithelia associated with many
organs can transform into cancer cells that later undergo the EMTs that enable
invasion and metastasis, thereby representing type 3 EMTs.
Namely this details the three types; (i) those involved in a
developing organism, (ii) those involved in a repairing organism, and (iii)
those involved in a metastasizing organism. There is a similarity amongst these
three.
As Kong et al have noted:
Cancer stem cells (CSCs) are cells within a tumor that
possess the capacity to self-renew and maintain tumor-initiating capacity
through differentiation into the heterogeneous lineages of cancer cells that
comprise the whole tumor. These tumor-initiating cells could provide a resource
for cells that cause tumor recurrence after therapy. Although the cell origin
of CSCs remains to be fully elucidated, mounting evidence has demonstrated that
Epithelial-to-Mesenchymal Transition (EMT), induced by different factors, is
associated with tumor aggressiveness and metastasis and these cells share
molecular characteristics with CSCs, and thus are often called cancer stem-like
cells or tumor-initiating cells.
The acquisition of an EMT phenotype is a critical process
for switching early stage carcinomas into invasive malignancies, which is often
associated with the loss of epithelial differentiation and gain of mesenchymal
phenotype. Recent studies have demonstrated that EMT plays a critical role not
only in tumor metastasis but also in tumor recurrence and that it is tightly
linked with the biology of cancer stem-like cells or cancer-initiating cells.
Here we will succinctly summarize the state-of-our-knowledge regarding the
molecular similarities between cancer stem-like cells or CSCs and
EMT-phenotypic cells that are associated with tumor aggressiveness focusing on
solid tumors.
We now consider several observations resulting for the above
analysis. We examine four areas:
1. We look at the issue of cancer stem cells and their
relationship to the EMT process. CSC are interesting targets of interest since
targeting them may be much more effective than targeting bulk tumors. All too
often removing a bulk tumor without regard to a CSC presence just means
recurrence. It is often the case where a surgeon gets a clear margin on an
excision and declares victory while a CSC has escaped.
2. Circulating tumor cells or parts thereof have become of
significant interest in what has been termed liquid biopsies. Namely
constituents of tumor cells in the blood can be detected and analyzed. Here we
look at markers for excess EMT process.
3. There has been an evolving understanding of the EMT
process. We briefly discuss this change.
4. The arear of new therapeutics is key. One specific area
we have tried to open is based upon the following logic.
a)
EMT is related to and a
putative driver of metastatic growth.
b)
EMT as a process is heavily
influenced by immune system drivers
c)
Perhaps immunotherapeutic
approaches to mitigating EMT processes may be effected and this down regulate
any metastatic results.
Thus studying the EMT process can add significantly to our
understanding of a multiplicity of cancers.
1. Cancer Stem Cells
Stem cells have been discussed at length in the context of
many cancers. They are often closely associated with the EMT process. As Mitra
et al note:
Tumor relapse and metastasis are the primary causes of
poor survival rates in patients with advanced cancer despite successful
resection or chemotherapeutic treatment. A primary cause of relapse and
metastasis is the persistence of cancer stem cells (CSCs), which are highly
resistant to chemotherapy. Although highly efficacious drugs suppressing
several subpopulations of CSCs in various tissue-specific cancers are
available, recurrence is still common in patients. To find more suitable
therapy for relapse, the mechanisms underlying metastasis and drug-resistance
associated with relapse-initiating CSCs need to be identified. Recent studies
in circulating tumor cells (CTCs) of some cancer patients manifest phenotypes
of both CSCs and epithelial-mesenchymal transition (EMT).
These patients are unresponsive to standard chemotherapies
and have low progression free survival, suggesting that EMT-positive CTCs are
related to co-occur with or transform into relapse-initiating CSCs.
Furthermore, EMT programming in cancer cells enables in
the remodeling of extracellular matrix to break the dormancy of relapse-initiating
CSCs. In this review, we extensively discuss the association of the EMT program
with CTCs and CSCs to characterize a subpopulation of patients prone to
relapses.
Identifying the mechanisms by which EMT-transformed CTCs
and CSCs initiate relapse could facilitate the development of new or enhanced
personalized therapeutic regimens.
We have discussed the CSC construct especially in the case
of PCa. It could be argued that identifying the PCa and removing them would
then make any of the other cells indolent.
CSC development still is a complex area. Just how a CSC is formed and
how it manages to survive and prosper is complex. Perhaps the nexus with the
EMT process may assist in better understanding.
Circulating Tumor Cells, CTC, and parts therefrom, such as
RNA fragments, even DNA fragments, are also a current topic of interest in
detecting and monitoring cancers. Since EMT is considered an essential part of
the metastatic process, then it would seem logical to also look for EMT markers
as well.
As Heerboth et al note:
Another exciting area of research is the use of EMT
markers in the analysis of circulating tumor cells (CTC). Diagnostically, CTC
has been a mainstay of clinical practice in assessment of metastasis and
prognosis. The presence of CTC in a patient’s blood can be measured using the
AdnaTest, a PCR assay for markers of EMT such as Twist, Akt, and Pi3k. The test
employs a method for enriching the CTCs in a blood sample using antibodies
conjugated to magnetic beads. Once the tumor cells have been pulled down, the
mRNA can be isolated and expression of EMT markers determined. The test is
reported to be sensitive enough to detect two CTCs in a 5 mL sample of blood.
Recent works have indicated that consideration of CTC EMT
status is critical to achieve a more accurate prognosis. In studies of
metastatic breast cancer, CTC were found to express known EMT regulators,
including TGF-β pathway components and the FOXC1 transcription factor. These
data support a role for EMT in the blood-borne dissemination of human breast
cancer. Classical markers of EMT, Twist, and vimentin, have been identified in
breast cancer patients and specifically show elevated expression in patients with
metastatic cancer relative to patients with early stage cancer, supporting the
hypothesis that EMT controls the metastatic potential of CTCs
Thus we see that a more complex set of blood borne markers
may be identified and profiled to establish cancer diagnosis, prognosis and
arguably even fine tuning on therapeutics and therapeutic targeting.
From Lee et al we have a list of putative markers. Whether
any of these are specifically appropriate will take time to study. The issue
one assumes is to better understand EMT as it pertains to a malignancy. For
example, for decades in breast cancer, in melanoma, and other cancers, removal
of lymph nodes was considered standard practice even if no overt sign of
metastasis was present. The resulting morbidity was often significant. If
however one seeks EMT processes then perhaps one may attain a more viable and
specific alternative.
There has been a debate over the years regarding the nature
of EMT and cancer. As Tian (2005) notes in an earlier paper:
Epithelial mesenchymal transition has been postulated as
a versatile mechanism which facilitates cellular repositioning and redeployment
during embryonic development, tissue reconstruction after injury,
carcinogenesis, and tumor metastasis. The hypothesis originates from parallels
drawn between the morphology and behavior of locomotory and sedentary cells in
vitro and in various normal and pathologic processes in vivo.
This review analyzes data from several studies on
embryonic development, wound healing, and the pathology of human tumors,
including work from our own laboratory, to assess the validity of the proposal.
It is concluded that there is no convincing evidence for conversion of
epithelial cells into mesenchymal cell lineages in vivo and that the biological
repertoire of normal and malignant cells is sufficient to account for the
events and processes observed, without needing to invoke radical changes in
cell identity.
The author then goes on with a detailed "on the other
hand" discussion of EMT relevance. This is always a worthwhile analysis to
come back to from time to time.
However Roche (2018) notes some thirteen years later:
The epithelial-to-mesenchymal transition (EMT) occurs
during normal embryonic development, tissue regeneration, organ fibrosis, and
wound healing. It is a highly dynamic process, by which epithelial cells can
convert into a mesenchymal phenotype. However, it is also involved in tumor
progression with metastatic expansion, and the generation of tumor cells with
stem cell properties that play a major role in resistance to cancer treatment.
EMT is not complete in cancer cells, and tumor cells are
in multiple transitional states and express mixed epithelial and mesenchymal
genes.
Such hybrid cells in partial EMT can move collectively as
clusters, and can be more aggressive than cells with a complete EMT phenotype.
EMT is also reversible by the mesenchymal-to-epithelial transition (MET),
thought to affect circulating cancer cells when they reach a desirable
metastatic niche to develop secondary tumors. The EMT process involves the
disruption of cell–cell adhesion and cellular polarity, remodeling of the
cytoskeleton, and changes in cell–matrix adhesion. It is associated with
improvement in migratory and invasive properties.
In cancers, EMT inducers are hypoxia, cytokines, and
growth factors secreted by the tumor microenvironment, stroma crosstalk,
metabolic changes, innate and adaptive immune responses, and treatment with
antitumor drugs. Switch in gene expression from epithelial to mesenchymal
phenotype is triggered by complex regulatory networks involving transcriptional
control with SNAI1 and SNAI2, ZEB1 and ZEB2, Twist, and E12/E47 among
transcriptional factors, non-coding RNAs (miRNAs and long non-coding RNAs),
chromatin remodeling and epigenetic modifications, alternative splicing,
post-translational regulation, protein stability, and subcellular localization.
EMT is becoming a target of interest for anticancer
therapy. However, more knowledge about the role of EMT in metastasis, its
control, and its reversion is necessary. Indeed, alternative modes of
dissemination, colonization via a MET-independent pathway, and investigation of
circulating cancer cells in the blood support a more nuanced view of the role
of EMT and MET in cancer metastasis.
The above argument seems to strengthen the assertion of the
significance of EMT and as importantly the MET reversal process which we have
discussed.
The understanding of the EMT process presents opportunities
for therapeutic development. Mladinich et al have noted:
Cancer stem cell (CSC) has become recognized for its role
in both tumorigenesis and poor patient prognosis in recent years. Traditional
therapeutics are unable to effectively eliminate this group of cells from the
bulk population of cancer cells, allowing CSCs to persist posttreatment and
thus propagate into secondary tumors. The therapeutic potential of eliminating CSCs,
to decrease tumor relapse, has created a demand for identifying mechanisms that
directly target and eliminate cancer stem cells. Molecular profiling has shown
that cancer cells and tumors that exhibit the CSC phenotype also express genes
associated with the epithelial-to-mesenchymal transition (EMT) feature.
Ample evidence has demonstrated that upregulation of
master transcription factors (TFs) accounting for the EMT process such as
Snail/Slug and Twist can reprogram cancer cells from differentiated to
stem-like status. Despite being appealing therapeutic targets for tackling
CSCs, pharmacological approaches that directly target EMT-TFs remain
impossible. In this review, we will summarize recent advances in the regulation
of Snail/Slug and Twist at transcriptional, translational, and
posttranslational levels and discuss the clinical implication and application
for EMT blockade as a promising strategy for CSC targeting.
Thus there may be avenues of access to controlling the CSC
via the EMT process. The authors conclude:
These studies indicate that approaches which inhibit
protein expression or activity upstream of EMT-TFs will have a better chance to
achieve CSC eradiation. Extensive work as reviewed above shed light on new approaches
for the targeting of EMT-TFs. As our understanding of protein regulation of
EMT-TFs advances, the ability to generate or repurpose new candidate molecules
to target CSCs increases.
Specific inactivation of EMT-TFs in combination with
chemotherapy will likely enhance patient survival long-term via targeting of
both CSCs and differentiated tumor cells. We have reasons for optimism that
future studies on structural information of upstream regulators of EMT-TFs and
on the crosstalk between upstream regulators and EMT-TFs would yield new CSC
therapeutics.
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