More on Rosa

In an interesting paper by Benjamin Zachariah the author notes from her writings:

Rosa Luxemburg's central statement on the national question came in a series of articles written for a Polish public in 1908-1909. The issue of national self-determination had arisen in Russia after the 1905 revolution, before which it was mainly an 'urgent' question in the Austro-Hungarian empire. 

The occasion for her writing in this context was her criticism of the programme of the Social Democratic Labour Party (RSDLP) of Russia. 

In the tradition of Karl Marx's Critique of the Gotha Programme of the German Social Democratic Party, she explored the contradictory impulses of this programme. 

Its 9th point read 'that the party demands a democratic republic whose constitution would ensure “that all nationalities forming the state have the right to self-determination.”'

She also drew attention to the 7th point, 'which demands the abolition of classes and the full legal equality of all citizens without distinction of sex, religion, race or nationality', and 

the 8th, 'which says that the several ethnic groups of the state should have the right to schools conducted in their respective national languages at state expense, and the right to use their languages at assemblies and on an equal level with the state language in all state and public functions.' 

And she cited in addition the 3rd, which asked for local self-government for those areas with special conditions or living conditions of the population. 

She pointed out that those who formulated the programme clearly felt that 'the equality of all citizens before the law, linguistic rights, and local self-government were not enough to solve the nationality problem' and had therefore added another clause on national self-determination.

Now let us consider what she said over a century ago.

1. Self determination means that the groups so formed can select by themselves, as a collective, what rules they live by

2. That distinctions of people based upon religion, sex etc be abolished. This is much more that non discrimination.

3. Rights to their own language, superseding any "national" common language

4. Local self government

Sound familiar? Indeed, the Marxist agenda of Rosa and her allies have been here before, and it is here again. This is not Socialism of the 1910s in the US, Debs and my grandmother, it is what they rebelled against, Marxism.

History has examined and approached these domains before, and somehow the politicians rediscovering them are doing so devoid of any historical or economic perspective.

Have we no Prisons, Have we no Jails?

When I see the overflowing trash in Washington as shown graphically by the NY Times I think little of the Government worker but all of the people who dumped it there. This demonstrates a clear issue of physical causality.

The "cause" of the trash is not the political battle but the people who dumped it there. Now the DC police are not on strike, so why not hand out littering tickets. Why not enforce these misdemeanors with picking up of the trash. A self solving system. Not only that but one can then fine them as well and have a self funding system.

Causality is an important concept. It is a critical principle in understanding our very existence. Showing an overflowing trash heap and stating a false cause is not only poor journalism but is "fake news".

Now let me take it a step further. Look at the NY subways, often filled with trash. If one were to use facial recognition to identify the trash disposers then perhaps we could do the same here. Send them down on the tracks and fine them. Perhaps a bit harsh, but it is causality again.

But the overflowing trash is emblematic of politics in general, and unfortunately of the press in particular.

I Am Spartacus!

In the late 1960s when I was in Cambridge (Massachusetts not England) there were massive political and antiwar assemblies. If I recall correctly one was the Rosa Luxemburg chapter of SDS. Now as a young Instructor and grad student in the technical space I had no idea who Rosa Luxemburg was, but the name was intriguing. Go some thirty years hence in a bar in Moscow and my Polish partner, a former member of Solidarity and imprisoned by the Soviets, ranted about Rosa. I was still ignorant.

But over the years I have become acquainted with the person. You see Rosa was a founder of the Spartacists, a group of Marxists in Germany in the early 20^th century who were Communists in Germany but not fully aligned with the Bolsheviks such as Lenin. Yet Lenin expressed his loss at the time of her assassination by the Freikorps in 1919. Thus 100 years ago Rosa was shot and dumped into the river in Berlin.

Her beliefs were true blue Marxist. One of particular interest today is Rosa and the National Question. Rosa was a bright Polish Jew working in Germany and having a doctorate from the University in Zurich. She viewed society as demanding an overhaul and it was her ideas as promulgated in the papers she wrote for that stated her positions. In many ways she was a pure Marxist and set apart from the Soviet Communists. She was argumentative, aggressive, assertive, and a promulgator of her social message.

Now the National Question I believe can be simply stated by Rosa herself:

“Nation-states” are today the very same tools and forms of class rule of the bourgeoisie as the earlier, non-national states, and like them they are bent on conquest. The nation-states have the same tendencies toward conquest, war, and oppression – in other words, the tendencies to become “not-national.” Therefore, among the “national” states there develop constant scuffles and conflicts of interests, and even if today, by some miracle, all states should be transformed to “national,” then the next day they would already present the same common picture of war, conquest, and oppression."

But Lenin was a promulgator of the "right of self-determination" Yet Rosa noted:

'“The right of nations to self-determination” is at first glance a paraphrase of the old slogan of bourgeois nationalism put forth in all countries at all times: “the right of nations to freedom and independence.”

She felt such a "right" was controlled by the bourgeois. For Rosa there should be no boundaries, no borders. Borders were artificial means of control of the proletariat.

Thus the Spartacists were a group of Marxists disavowing borders, against nations as false constructs.

Thus when one looks at Washington today we may readily see many Spartacists and many Luxemburg look alikes.

One should recall what this battle did to Germany and regrettably what happened to Rosa.

Technology Transfer?

NIH had completed a Director's conference wherein an interesting issue was discussed.

They noted:  

ACD member and working group cochair Dr. M. Roy Wilson walked the assembly through the former topic, outlining the scope of a problem that involves intramural as well as extramural intellectual property potentially targeted for misappropriation by organizations outside the United States. Failure of visiting scientists to report financial conflicts and establishing so-called “shadow labs” that illegally copy U.S. resources are just two types of undue influence that have been documented by recent federal investigations. After taking a look at his own institution (Wayne State University), Wilson said he found warning flags of a similar threat within the research community there. He cautioned ACD members and NIH leaders to be vigilant about protecting the scientific enterprise from those who would take advantage of its culture of open information-sharing for their own personal gain. “The main message is that it’s real,” Wilson said. “There are significant breaches that are occurring at our universities…At the same time, when you look at the large number of investigators that are funded by the U.S. government in one way or another, [the problems account for] a relatively small amount. However it’s enough that it’s just not a random occurrence here and there. It seems to be more systematic and in some cases concentrated at certain institutions. It certainly warrants concern and a response.”

This is, was, and will continue to be a serious issue. Our universities are open to many international students and researchers and as such they all too often have access to the latest technology as well as poorly protected intellectual property. Also these individuals are funded by the US Taxpayer.

The technology is then often taken back to country of residence. There it is often used to compete with US entities.

This is ever more critical in the bio domain because of the IP in therapeutics as well as the use of the bio IP as a weapon.

MOOCS, Not The Smashing Success

Back when MOOCs first started I was highly skeptical. As they evolved I became convinced that my initial assessment was correct. Now there are some good ones, yet they are far and few between. Science published a review of them in its recent issue.

They note:

It was clear from the first few years of MOOC research that MOOCs disproportionately drew their learners from affluent countries and neighborhoods, and markers of socioeconomic status were correlated with greater persistence and certification. In 2012 to 2013, 80% of learners came from countries rated with high or very high United Nations Human Development Index ratings. That proportion grew slightly through 2015 to 2016, so that the majority of new registrations and certifications came from the world's most affluent countries. Rather than creating new pathways at the margins of global higher education, MOOCs are primarily a complementary asset for learners within existing systems. Last, MOOCs' low completion rate has barely budged, despite 6 years of investment in course development and learning research. A strategy that depends on bringing new learners into higher education cannot succeed if educational institutions cannot support learners in converting their time and financial investment into completing a course to earn a credential with labor market value....MOOCs will not transform higher education and probably will not disappear entirely. Rather, they will provide new supports for specific niches within already existing education systems, primarily supporting already educated learners. The 6-year saga of MOOCs provides a cautionary tale for education policy-makers facing whatever will be the next promoted innovation in education technology, be it artificial intelligence or virtual reality or some unexpected new entrant. New education technologies are rarely disruptive but instead are domesticated by existing cultures and systems.

Here are my observations:

 1. My first one was an MIT course which I had actually taught decades before. The problem was that the software for the exams was defective, the information for using it was not there, and the overall structure was banal at best.

2. I took an Epigenetics course. After overcoming the language issue, Australian versus US, the most disturbing part was the usage of "peer evaluation" This means one is evaluated by those who know less and are often motivated to suppress those they feel are superior. The worst of the culture exploitation. The instructor was clearly in my opinion clueless on this dynamic. Peer Evaluation is one of the worst concepts in education.

3. Some instructors in courses were totally incomprehensible. Totally. One chemistry course had a few folks rambling across a board of stuff and one wondered if they just wanted to have a MOOC presence.

On the positive side:

1. A Hong Kong medical course was spot on, as was a US chemistry course, as was a Harvard Med Immunology course.

2. In contrast the Harvard Med Genetics course was driven by cartoons, yes real cartoons. It was as costly as the immunology one bust in my opinion targeted for the millennial. 

Overall I have tried well over two dozen of these. A recent couple from Mt Sinai in New York was exceptionally well done. The were short, on a specific topic, well articulated, and kept on topic. 

I found Cousera much better whereas EdX was all too often an overdone attempt as a semester level course. Often missing the target.

The drop rate is significant yet there does not seem to any attempt to find out why.  With such an attitude one sadly sees them going by the wayside.

The best course was the MIT one on introductory Biology with Eric Lander. It was just a well done recording of his lectures with exceptionally well thought out problems. In contrast when a colleague tried a genetics course it lacked the vibrancy of the Lander lectures.

Epithelial to Mesenchymal Transitions and Cancer

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.

2. Circulating Tumor Cells

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.

3. Contradictions

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.

4. Therapeutics

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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[1] Weinberg pp 657-669