Tuesday, April 26, 2016

What is the Future of Education and the Workforce in the United States

In recent years certain parties have begun to question the economic value of a college education based on changes in both the available number of jobs as well as the success rates for those of various majors acquiring their intended and/or desired job. Overall it seems foolish to argue that a college education does not have any value. In fact one could argue that a college education has never been more valuable relative to the ability to acquire a “quality” job. For example a recent Pew Research Center study determined that an individual with only a high school graduate level education will only earn, on average, about 62% of what an individual with a four-year degree will earn down from the high school graduate earning 77% back in 1979.1

Of course statistics like this appear impressive; typically significant problems come from the utilization of averages. Few will argue that certain jobs have significantly higher financial windfalls than other jobs both of which may require an individual to have at least a bachelor’s degree. Basically the wage curve for jobs in the United States has not increased in a linear manner; the wages associated with the top portion of “quality” jobs have dramatically increased over the years leaving the rest behind in the proverbial dust. Therefore, if one were to remove the top 5% and bottom 5% of wages for jobs held by those with four-year degrees it stands to reason that this 62% number would significantly increase to a number much closer to the 1979 derived 77%. Overall due to education displacement and college graduates taking jobs they are “over-educated” for, it would not be surprising if overall bachelor’s degree wages have decreased in recent years, especially since wage growth in general has been so poor.

This element is an important consideration when contemplating the economic value of a college degree. One of the problems in modern society is the rise of the “gig” economy; basically due to a much lower pool of full time jobs with benefits, individuals now must instead engage in numerous part-time short-term tasks/opportunities with few to no benefits at much less money both in total value and consistency of acquisition. This trend bucks those of the past where the advancement of technology would facilitate increased job growth both in number and salary.

Unfortunately technology may have begun to reach the tipping point where it is a net detriment to job growth instead of a net benefit. Combining this reality with the continued outsourcing of jobs by numerous corporate interests to lower cost environments in other countries, it becomes fair to question the panacea of education that some tout with respects to job prospects. For example there is still this simplistic notion that when individual A loses a job to another individual in a lower cost environment or to a piece of technology, then that individual A simply needs to acquire new skills and that education will “magically” produce a new quality job for this person. Clearly this belief is not supported by reality for numerous well-educated individuals do not have quality jobs despite their determination and skill sets and this trend appears to be worsening not improving.

Based on these conditions instead of “upgrading” one’s position in the job market, the college degree has almost become a prerequisite to compete for a quality job, thereby making the college degree important even for those who are not prepared to excel in college. Strangely enough the “importance” of a college degree has evolved rather inexplicably for even those jobs that in the past were filled by those without college degrees. The general expectations and duties of these jobs have not changed, yet a larger number of companies expect applicants to have college degrees for jobs that involve secretarial or simple logistics work. Why, what does the college degree bring in modern society that in the past was “excluded”? Overall unfortunately with this increase in the general employment “importance” of a college degree the costs associated with acquiring one have also increased, thereby dramatically increasing the risks associated with failure, not only in acquiring the degree, but also in acquiring a job after earning the degree.

To better identify these new risks one looks to the old adage that education is akin to investing in one’s future. In the past one could view going to college as investing 10 dollars for a 80% chance at making 50 dollars (a high quality job) otherwise one could frequently, but not always, still acquire 15 dollars (a lower quality job) even upon failure versus the ability to acquire 15 dollars without having invested that 10 dollars. Now going to college is akin to investing 30 dollars for a 50% chance at making 50 dollars otherwise one is limited to a lower probability than in the past at making 10 dollars (lower quality job with lower acquisition probability). While simplistic this analogy basically demonstrates the almost irrational change that has occurred in the job market in modern society within the United States, more money must be invested for a lower probability of success at achieving a smaller average payday. Note that success is not only acquiring a degree, but also acquiring a job that is appropriate for that degree.

One interesting aspect of this degree acquisition are those who feel community colleges should no longer be used as jumping off points for traditional four-year educations, but instead should focus more on becoming vocational schools to train individuals for specific jobs. Such a strategy is inherently questionable because the purpose of education in general is to produce individuals that can effectively rationalize, make positive contributions to society and responsibly participate in government whether it is as an elected official or a voting citizen. A narrow educational experience in a vocational institution hardly has the capacity to aid in the achievement of such a goal. Thus, converting community colleges into “cogs in the machine” educational environments does not appear to be a responsible choice at this point.

Furthermore it is the second portion of this equation that has failed in the modern economy. Acquiring college degrees is not the problem with more degrees awarded, both proportionally and in total number, than at any other time; the problem is that such accomplishment has lost significant meaning for outsourcing and technology have shrunk the “quality” job pool. Thus, numerous individuals with four-year degrees have had to settle for jobs below what would be expected of individuals with such a level of education.

In fact the unemployment rate for recent college graduates remains higher than years before the Great Recession in 2008 and higher for all other age groups. For those graduates that have jobs they are more likely to be underemployed than past younger college graduates as well as other age groups.2 Wages are also down for them relative to other age groups and their past peers.2 Further exasperating these problems is that these types of jobs seem to no longer have an effective and transparent advancement track. Basically the ability to steadily advance in the company both in responsibilities and salary have ceased to exist in part due to the “gig” economy and in part due to unknown reasons (maybe in the name of more profits).

Some might argue that this conclusion of a shrinking quantity of “quality” jobs is erroneous due to continuous claims of the need for qualified individuals in the STEM (science, technology, engineering, mathematics) fields. Unfortunately this counter-argument is complicated by the expected requirements of those jobs. First, not everyone is attending college for the purpose of receiving a STEM-based degree. Basically the “quality” job demand is not large or widespread, thus should everyone simply attempt to acquire one of these degrees even if it is not in their field of interest or expertise? The problem with chasing the “hot” or “trending” degree, especially for some the very specific fields within the STEM umbrella, is that those areas can contract in a blink of an eye based on changes in market conditions leaving individuals with a near worthless degree (as far as the job market is concerned). Part of the problem in this respect is that not surprisingly the public typically only hears about the successful individuals in these fields not those who struggle or fail.

Second, and more importantly, the limiting factor for acquiring a vast majority of the available STEM-based jobs is not education, but experience. Basically these jobs are reserved for individuals who have degrees in the appropriate field as well as at least 5 years of experience in that field. The problem is that there are not enough entry-level jobs in advanced fields so individuals can acquire this desired experience. Another problem is that the entry-level jobs that exist do not shut out those with experience. Thus, there can be individuals with 3 or less years experience vying for these entry-level jobs as well and not surprisingly they have a higher probability of getting them over one without any experience. In short a young graduate can receive the necessary education, but will still lack the most desired element, experience. Overall the fad in the early 21st century was referencing this glut of demand for STEM qualified individuals and a cooling science and tech environment has reduced this demand, yet the public line has yet to acknowledge this reduction.

This new mindset of a college degree being a prerequisite for a quality job, both in the present and in the future due to the lack of advancement opportunities, has hurt the process of education itself. Education has become a means to an end or a de facto commodity instead of a tool to enrich the life of an individual, thereby turning education into a rote activity with reduced levels of creativity, fun and enjoyment for a number of individuals. This issue is further complicated by the fact that if everyone is acquiring an advanced education then its value becomes diluted psychologically in that it is not viewed as a boon or achievement, but instead as “just something that you do” stripping even more enjoyment from the educational process, especially for those who are not naturally motivated to learn. A side issue is that so many people have advanced degrees employers are less likely to reward applicants for having one in addition to it being expected.

With education becoming more of a commodity it is treated more deterministically, in that people attempt to devise the “optimal” way to provide education forgetting that the students, especially in their formative years, do not learn the same way and have their own strengths and weaknesses. This mindset produces a “one size fits all” methodology, which due to the aforementioned differences will inherently produces winners and losers based on who is best supported by this universal education method. Also this mindset has the significant potential to produce a single blueprint for the future of society, which is dangerous for inherent flexibility and diversity is superior to rigidity. This new mindset is demonstrated in the new testing culture that has arisen in the last 15 years in public education as well as the quasi-retreat from public schools to private and specialized charter institutions by wealthier families.

This testing culture also facilitates a sprinter’s mindset where the only thing that matters is preparing and succeeding on the next test or the next quiz, thus focusing on skills that are only relevant to acquire in the “now” instead of a marathoner’s mindset where long term retention of knowledge and skills is important in order to provide foundations to build upon when acquiring new and more complicated skills (i.e. the basis of quality learning and education). This mindset has also seeped over to the “future” of education in MODO courses and micro-degrees, which can be largely viewed as “cram” courses where 1-2 years of knowledge is comprised into a 2-3 month period. One wonders how effectively this strategy will be in the long-term, but it is difficult to see it as a net positive.

Not only are students hurt by this new culture both in education and the job market, but so are teachers. The single mindset of “make sure students can pass the test” and the seemingly incessant testing schedule has fostered the idea of teachers as simple “cogs in the machine” as well, further eroding the importance placed on the position and diminishing unique and inventive teaching methodologies. Groups like Teach for America and their supporters contribute to this mindset by selling the idea that quickly trained amateurs, most of whom will be out of teaching in five years, can be as successful, if not more successful, than fully trained and/or experienced teachers by simply following “the playbook”.

A sad state of affairs is that these programs, in addition to charter schools, on average have not produced higher test scores or even more “educated” students with the exception of those privately funded institutions with much more money than public schools that hand-pick their student body ensuring high student quality and potential from the start. Failing to produce improved results is not the only accomplishment of these institutions; they have also driven a continuing public and private lack of respect for the professional teaching position, which when combined with continuing negative elements of institutional control as well as negative financial incentives, has created an environment where fewer individuals want to be teachers, thereby inherently reducing the total number of quality teachers in the educational pool.

Not surprisingly teachers, like any occupation, gravitate towards the best financial, occupational and social environments and with less quality teachers entering and remaining in the profession society has created small concentrated environments of universal teaching quality leaving other areas significantly devoid of this element. The current environment regarding education has only exacerbated this division. This exodus of quality teachers and administrators to environments that frankly do not need their talents combined with the lack of respect for the process of teaching has created a serious financial issue for a number of schools. The idea that “anyone can teach” has created the erroneous philosophy of “schools can operate on shoestring budgets”.

This philosophy is dangerous for two reasons: 1) a teaching environment with limited resources place unnecessary pressures on the staff and limits their ability to evolve and grow; evolution that would create a more positive and meaningful educational environment; 2) limited resources place psychological burdens on students, which will commonly result in less motivation, shorter attention spans and greater levels of misbehavior because such an environment facilitates the idea of future prospects seeming so bleak that the overarching mindset is “what is the point?”;

The idea that outside environment matters is a convenient and common exclusion made by teacher critics. When students are motivated, work hard and follow instruction, as well as are curious and ask questions because they want to learn, then even a mediocre teacher appears to be a great and inspirational teacher. When students are frustrated, starving, concerned for their safety, do not respect the institution or its instructors, then even a creative and visionary teacher appears to be a failure unable to “reach” his/her students.

This above discussion has raised two unquestionable issues regarding future job markets and education. 1) the number of available quality jobs relative to the number of applicants is trending downwards in both respects (fewer quality jobs and more applicants) and it is difficult to see a scenario in which this trend changes in the near future if government does not act; 2) the demand of a college degree and the deemed “tools to succeed in college” for even a sufficient opportunity to acquire a “quality” job has produced a single-mindedness relative to the educational process destroying teaching diversity, prestige, and importance; this loss makes the evolution and maturation of a divergent number of intelligent personalities much more difficult, thus diminishing the overall quality of society;

Focusing on the second issue first, some argue that the problems associated with any quality teacher exodus can be overcome by technology. Proponents of MODO and other online instruction methods are already hyping its transformational potential, especially in the avenue of lowering class sizes. However, applying these mediums to education raises questions regarding personal instruction. For example what happens when a student has a question? Basically what is the dynamic of how a teacher is supposed to interact with a classroom of 20 students and other 10-15 “tele-educating” from their homes? What happens if the teacher is the one “tele-educating”? It is difficult to scale any success at the college level to the middle or high school level.

While this is one a single issue of many involving “tele-education”, an interesting element is how does this inherent increased complexity of student/teacher interaction reflect the new modern narrative/trend in education of “anyone can teach”. Others talk of providing personalized education through technology. Such a goal seems incredibly ambitious and complicated, especially since proponents do not provide a clear definition for what a personalized education or personalized educational experience is supposed to represent.

At the moment there are two significant problems facing the incorporation of technology into the current educational system. First, the incorporation of technology appears to be following an inverted need curve, basically the communities that could benefit the most from technology are the least likely to incorporate it due to lack of finances and lack of specialists; instead more wealthy communities have and will continue to incorporate technology while poorer and more rural communities will not. Therefore, instead of acting as an equalizing force in education narrowing the education gap between the rich and the poor or between whites and non-whites, as envisioned, technology is turning out to be simply another means in which the “haves” separate themselves from the “have nots”. Unfortunately for technology adopters this general funding issue appears to be semi-permanent until the financial culture surrounding the importance of education changes.

Second, the utilization of technology as a negative force on education has been widely demonstrated numerous times already. Simply ask almost any teacher to name the most detrimental device to teaching and it stands to reason that a vast majority will reply “the smart phone”. Not only are smart phones huge sources of distraction during class both for the directly interacting student and any others he/she may choose to communicate with via text, but they have also been demonstrated to be useful tools for those who attempt to cheat on assignments and tests. Unfortunately most of the “expertise” that the younger generations are supposed to possess regarding the application of technology appears front-loaded in the entertainment field and lacking in the education and enlightening discovery fields.

For example it could be successfully argued that technology as a whole has fostered an increased level of laziness and carelessness as students simply plagiarize from online pieces regardless of their accuracy. A number of students seem to believe that because something is online then it must be true; or just “Wikipedia” something and call it a day refusing to engage in any deeper level of analysis and understanding. Understand that Wikipedia can be a valuable resource for background as a jumping off point, but too many students view it as the only needed reference. Part of the reason for this increased detrimental behavior in education is the fact that, as mentioned above, education itself has been marginalized to a results-only system, thus the actual process or methodology behind education is viewed as irrelevant, just “getting it down” is important. Overall before technology can actually become a boon in education these problems must be address for technology cannot solve them, only exacerbate them.

So what can be done about the marginalization of education? If one of the hallmark traits of the United States is the idea that anyone can rise from nothing to be something and that education is a central element increasing the probability of such success then establishing a firm set of rules to foster an educational environment that favors some and opposes others, the system that current exists, flies directly in the face of such an ideal. The overall solution is not a difficult one in that successful change needs to involve re-establishing education as a meaningful learning and growth experience, not as a means to an end (i.e. a job).

The first step is to grant methodological freedom back to teachers decoupling their wages and tenure from standardized testing results. Instead evaluations can take place through exit interviews, written student evaluations and final test performance. Finals in given subjects should represent a cumulative knowledge and retention of what was supposed to be taught, thus final grades would be a meaningful measurement element regarding both teaching and learning success. Remember education is a two-way street between the teacher and students, quality instruction and quality reception/retention.

Another part of accomplishing this larger goal is to reintroduce the value of previously vilified as meaningless elements like recess for elementary school level students and a wider array of liberal and performing arts for older students. Basically make education a more global and involved process rather than systematic rote analysis of narrow topics that for most students have little excitement, i.e. create a situation where individuals see value in actually going to school rather than having an environment that could be easily replicated at home through simple focal study.

A meaningful element to stimulate the above process is for both schools and families to better identify the passions and interests of the students and then correlate those elements into the learning process by demonstrating how learning “perceived” mundane things like math and chemistry tie into those passions. This way education becomes an amplifying force for that passion rather than one that detracts and potentially changes it to something that may be more ill-suited for the individual.

Another important element is to psychologically prepare students to embrace the discomfort of learning. Some argue that learning is not fun and education needs to reflect that, but it can be counter-argued that such an environment for a number of students has already been attained; this is a major problem for if students acknowledge learning and education as painful then they will be less interested in engaging in the process and will look for shortcuts (i.e. cheating). Instead one must focus on the discomfort of learning in the context that it is frustrating when one does not know something one wants to know, but proper instruction and hard/smart work makes that frustration ephemeral.

Basically learning is only not fun when no progress is being made. If progress is being made (i.e. some knowledge being acquired) then learning produces a noticeable sense of accomplishment and pain/frustration is limited and short-term. Therefore, one of the chief strategies in the educational process is to focus on why someone is not making progress and rectify it. This is not to say that education and learning is always effortless, but there is always a purpose to the effort.

In summary some of the most important first steps to resolving the second problem… on its face at least, is to increase the value for students in attending school itself, couple individual passions with more perceived mundane topics to demonstrate their overall value, and enhance the educational process by psychologically prepping students that learning is short-term frustrating long-term satisfying and that adversity makes the process worth it. Also while not discussed above it is important to honest evaluate students as well, if they are not ready to move on to the next level then they should not move on to the next level. However, while these goals are noteworthy and commendable, one could question if they even meaningful?

A central problem in education is the influence of the future job market for the sad reality is if one’s education cannot be parlayed into meaningful employment then most will look unfavorably upon that education. The current dictum of society has deemed that diversity in education is not applicable to “maximizing” output efficiency for future employment, thus diversity in education is not properly funded. Another concern is that just having a degree may not be enough as studies have shown that most employers in the “quality” job fields focus on candidates with degrees from elite institutions foregoing even quality well-known and regarded public universities. So how can the process of education be decoupled from the job market?

The most obvious solution is the return of a number of “quality” jobs that do not require a college degree, which would allow more freedom in education instead of degree chasing and resume padding, especially at the high school level (in order to gain entry into those elite colleges). Unfortunately achieving this solution appears very unlikely due to the continuing march of technology and the reduced spending power of young adults limiting the further expansion of the last holdouts of quality jobs not requiring an advanced degree, jobs in the entertainment industry.

There was an initial belief for a significant resurgence in domestic manufacturing, a past bastion of “quality” jobs, at some time in the future driven by dramatically increasing oil prices born from supply issues (i.e. peak oil), which would increase transportation costs to the point where cheaper outsourced manufacturing environments would become prohibitively expensive. However, the surprising significant drop in oil prices in recent years has dramatically decreased the probability of this hope coming to pass, in the near future at least. Overall as long as capitalism fuels the idea of chasing profits as the most important thing to a corporation, it is difficult to anticipate a change in the trend of fewer “quality” jobs available to those without advanced degrees.

A second option is significantly increasing the salaries for various service jobs and the like (the “non-quality” jobs) until those jobs become “quality” jobs. There has been a significant movement towards increasing minimum wages in various cities and a smaller movement for increasing the Federal minimum wage up to $12-$15 an hour. However, while California recently boasted the greatest success for this movement, it is difficult to see any type of major Federal legislation regarding wages in the near future and a number of states are taking steps to neutralize the ability of cities to independently change wage policy. Incidentally the new law in California will be an interesting test case for the viability of increasing wages on service jobs, but because the increase is incremental quality data will probably not be available until the early 2020s. Overall though regardless of the results from California it is difficult to conclude that increasing minimum wage is a valid overarching strategy, it will take hold in certain regions, but not others, which unfortunately may further complicate income inequality.

A third option is changing the admissions process for college by lessening the value of standardized testing and grades and increasing the value of interviews and critical thinking questions. Some would argue that such a process has taken hold in certain universities with optional weighting of SAT or ACT scores and more “holistic” admissions methods. This weighting change would also make sense with regards to grades; for example grades are significantly arbitrary based on some numerous uncontrollable environmental and academic circumstance; i.e. an A at high school x does not always carry the same weight as an A at high school y and some high schools allow students greater amounts of extra credit which conceal their actual knowledge of the subject through grade inflation.

However, the chief problem with these current holistic methods is that universities are not transparent in their application, thus stripping significant credibility from the methods themselves. Also one could argue that these holistic methods are not tangible enough to identify individuals with distinctive and valuable viewpoints in order to validate selecting a high achiever from a less difficult environment versus a lower achiever from a more difficult and/or diverse environment, which could create problems. Whether this problem corrects the “degree value” issue is questionable, but it can aid educational diversity and creativity at the middle and high school level, which is an important element in solving the overall problem between education and employment.

It must be noted that changing the admissions process does nothing to manage increasing tuition costs, especially at elite universities, which is another problem unto itself. However, due to the inherent economic demand detriments associated with most universities due to difficulties meeting enrollment goals from less interest in college and higher levels of competition, it is highly unlikely that significant drops in tuition will be seen in the near future. Government intervention may come from lower interest rates on various student loan programs, but without changes in the general economic system, increasing government grant programs seems wasteful.

Another possible solution is to significantly limit the risk associated with taking more indirect educational pathways that society may find “inefficient”. One of the easiest ways to accomplish this diversification of educational philosophy is by ensuring individuals have available resources to pursue their own educational identities. The chief aspect of risk in modern society is financial; the idea of absorbing risk is one of the elements that produces unbalance in society between rich and poor individuals where individuals with connections and/or resources are typically not punished when engaging in risky ventures and failing whereas those without connections are commonly severely punished when engaging in the exact same behavior and also failing.

One can point out numerous instances when an individual has talent in subject matter x, but needs to take a job in a much less desired and low talent field in order to “pay the bills” because the potential risk associated with attempting to gain employment in the talent field is too great, in part to “secret handshake” connections having nothing to do with skills or education. People like to believe that talent eventually wins out, but modern society has demonstrated too many times that such is not the case.

The most direct way of limiting the negative repercussions of risk is establishing a guaranteed basic income (GBI) which would provide basic living resources for all adult citizens with minor to clean criminal histories within a certain income bracket eliminating the need to take jobs solely to survive. A GBI creates freedom that will increase the probability that individuals will maximize their educational opportunities, talents and passions because of a mitigation of risk. While increasing wage is a nice idea there is question to how much it will actually affect poverty due to potential reduced work hours and the possibility of increased taxes due to tax bracket changes whereas a GBI will definitely eliminate poverty on a meaningful level.

Some may attempt to argue that a GBI will foster laziness and a lack of ambition if individuals receive a certain amount of money for simply existing, but such arguments fail to acknowledge that a GBI will only contribute to survival, it would be very difficult to live comfortably, enjoy luxury and make a mark on the world by forgoing a job only to live on the GBI. Also without things to do, individuals would quickly become board and would look to accomplish things to productively fill their time. Finally a GBI will allow individuals to better “invest” in themselves by providing them the necessary seed money to get started. Realistically there is no accuracy in the argument that a GBI would “corrupt” the work ethic of society and anyone who argues that such corruption would occur is simply wrong.

While the application of a GBI would be the most effective means to decouple the restrictions and risks of employment on education, it would definitely be a significant task to accomplish due to the preconceived notions regarding the application of capitalism in human society. This perception is a problem, for a number of individuals only regard a task as having value when someone is paid to do it, which is a dangerous attitude to have. Overall despite a GBI making sense to all major political parties and supporting most of their fundamental philosophical economic beliefs, its actual passage is presumed to be difficult, in part because no one has the guts to try.

A concerning element with the issue of employment and education is that it should be clearly obvious to anyone that the current method is not productive, does not benefit most individuals or society as a whole and cannot hold. So why did the current method ever rise in the first place and why does anyone actually support it? A cynic might think that such a system is desired by the powerful, those who have championed it in the first place by passing legislation like No Child Left Behind or Race to the Top, because it benefits their children, but provides far less benefit and even potential detriment to less wealthy families and children. Therefore, in such a system individuals who could become competition for these wealthier children are handicapped before the competition really begins. Hopefully this is not the intent of the supporters of the current system, but unfortunately there have been too many scenarios in human history where one individual/group has had no problems “screwing over” another to get ahead even when they do not need to.

In the end a change needs to be made at the basic economic level because even if the appropriate changes are made at the educational level at this point in time, the end result will simply be a society filled with a larger number of well-educated under-employed, if employed at all, frustrated and even possibly angry individuals. Overall it does not appear that the form of capitalism currently practiced by the United States will be able to properly manage this trend and therefore, must evolve in some manner. Whether this evolution is the administration of a GBI, the re-localization of manufacturing, the general abandonment of the “absolute profit above all else” mindset for most corporations or some other significant change is uncertain, except for the fact that such a change must happen. The increasing detrimental economic link between employment and education should simply be viewed as a significant and early warning signal.

Citations –

1. The Rising Cost of Not Going to College. Pew Research Center. Feb 11, 2014.

2. Davis, A, Kimball, W, and Gould, E. “The Class of 2015: Despite an Improving Economy, Young Grads Still Face an Uphill Climb.” Economic Policy Institute. May 27, 2015. http://www.epi.org/publication/the-class-of-2015/

Wednesday, March 23, 2016

Why is Society Ignoring the Easiest Path to a Low Carbon Energy Infrastructure by Rejecting Nuclear Power

For decades certain parties have dreamed of the reality of “renewable” energy generation with the sun and/or wind providing the lion’s share, if not all, of the energy for a given society. Unfortunately decades removed from those initial dreams, society is little closer to that reality. Solar and wind proponents would argue that such a statement is foolhardy for the total percentage of energy generation from these sources rises ever higher year after year. However, these same proponents fail to acknowledge, or even realize, that neither solar or wind have had to face any real test supporting their viability as the chief energy generator. Can one say that an individual is really closer to passing a test when his percent correct has increased from 1% to 6%?

The lack of sufficient penetration has tabled effective identification of what type of integration methodologies will be required to evade consistent brown outs due to the intermittency of these technologies. However, it is known that battery technology for storage is still in its infancy, especially on a mass scale, and little discussion is given towards the significant shortfall in numerous rare earths to ensure solar and wind economic viability relative to the scale demanded; for solar economic viability is questionable even with these rare earths. Also there is a lack of general understanding regarding the required levels of redundancy to create the storage reserve. Despite these real unanswered questions where theory is stacked against solar and wind supporters, groups like ARPA-E continue to search for the “next energy breakthrough” commonly to support the expansion of wind and solar while seemingly ignoring the fastest and most stable route to a no/low carbon emission energy future… nuclear power.

No one can dispute the stability, low to no carbon emission and base-load power generation ability of nuclear power. The failures associated with the widespread adoption of fission based nuclear technologies, including the development of breeder reactors, have not be the result of technical flaws, roadblocks produced by the laws of physics, safety profiles or even overall capital and operational costs, but instead has been the result of a direct campaign against nuclear power based only upon paranoia, overreaction, fear and opposing economic interests.

Some may argue against nuclear power by citing certain projects that experienced large delays in construction and cost overruns. This criticism has valid and invalid points. The problem with simply citing a construction delay or cost overrun is that almost no construction project in the history of humanity be it a complex structure like a nuclear power plant or wind farm or a more simplistic structure like a corner grocery store have come in on-time and on-budget. The entire predictive process for the construction is consistently fraught with optimistic estimations and assumptions in effort to win the “bid” for the project either through associated agencies like subcontractors or to win approval for the project as a whole. Therefore, time and cost overruns should be treated as the norm, not the exception for any construction project.

However, optimistic estimations cannot explain all of the cost overruns. Another reason nuclear power appears more expensive than it actually should be is the lack of uniformity/standardization in design. For example when considering breeder reactors several different reactor prototypes have been proposed and even had initial construction periods. Anyone with any design experience knows that the most expensive type of product is the first working prototype (i.e. version 1.0). Due to the lack of coordination and cooperation between nations, instead of six or seven countries working together on one universal reactor design, economic competition has created an environment with numerous high level generation II to generation III breeder reactor version 1.0s, which has further increased costs.

Another rationality for cost increases with regards to nuclear power, especially breeder reactors, is simple short-sighted analysis regarding long-term cost benefit analysis. Basically breeder reactors remain more expensive (i.e. not directly cost-competitive) with more standard thermal reactors because research and development into breeders was quasi-sabotaged for decades by cheap uranium prices and corresponding economic incentives. So instead of acknowledging a time in the future when uranium may not be cheap due to potential shortages or more expensive extraction methods or simply understanding that nuclear power needed to evolve to be more effective in general and preparing for this reality with proper planning, both private corporations and government elected to take advantage of short-term gains that have now created long-term losses.

Basically capital costs associated with breeder reactors have been heavily influenced by the lack of standardization and the lack of a devotion to the continuous evolution of their design and construction. Any economist will sing the praises of assembly line and scale economics at dramatically reducing costs. Nuclear, especially breeders, has not been able to engage in these types of processes because of this “start-stop” mentality due to uranium prices, lack of long-term thinking, which is still plaguing the energy environment with so much short-term focus on solar and wind, and lack of cooperation among companies and governments.

Another issue that has been blown out of proportion is the danger of reprocessed material being siphoned off and/or stolen for the production of nuclear weapons. One of the original reprocessing methodologies, PUREX, certainly warranted concern because it is able to produce concentrations of pure plutonium after completion; however, PUREX is certainly not the only reprocessing method. There are a number of other methods most of which make plutonium isolation and extraction nearly impossible, thus making weaponizing the reprocessed material nearly impossible. Also appropriate safety measures can easily be applied to eliminate the potential seizure of any “weaponized” material. If terrorists acquire nuclear weapons it would be from some secret lab in Iran or from North Korea over a modern nuclear breeder reactor.

The final issue is the most depressing one when it comes to nuclear opposition, the overreaction to a meltdown. Overall there have only been two legitimate meltdowns in history, Chernobyl and Fukushima Daiichi. The events on Three Mile Island actually demonstrated what is supposed to happen when safety procedures are properly applied. The “demonization” of nuclear power at the hands of Chernobyl is especially ridiculous when considering both the technology at the time and the circumstances of the meltdown. If similar consideration was given to the airline industry then modern aviation would shutdown because a Wright Brothers’ era plane happened to crash. Of course that would never happen, which demonstrates the serious bias towards nuclear power possessed by certain entities.

Concerning Fukushima Daiichi, a power plant from the 50s built in one of the worst regions of the county it could have been relative to safety, it still required a once in a 1000-year natural disaster event to produce any negative outcome, which was in large part thanks to a lack of basic contingency safety protocols; yet these failures were heavily unjustifiably propagandized as inherent to nuclear technology instead of what they actually were: simple economic laziness/greed.

If nuclear power is the answer to addressing global warming what does that make of the other contenders? Clearly anything that produces significant quantities of CO2 or other greenhouse gases is out due to global warming issues, thus coal, oil and natural gas are non-starters. The idea of natural gas as a “bridge” from coal to a low-CO2 emission source may have been an option two or three decades ago, but is certainly not a cost-effective transition option now, despite the money the U.S. is wasting, relying on natural gas is a fool’s errand.

Geothermal is an option that would have been interesting to study regarding the enhanced geothermal systems (EGS) methodology as a realistic competitor to nuclear, but with the pertinent issue involving the potential progression of tectonic activity (periodic 2-3 Richter scale earthquakes under initial EGS tests, with time would this magnitude increases?) there does not appear to be adequate time to return to the start so to speak if earthquake magnitude progression was indeed a feature of EGS. Pipe dreams like tidal power and microwave/satellite solar are either boondoggles or do not have nearly enough momentum and potential to even be considered viable responses. Fusion, either of the hot or cold variety, seems no significantly closer now than two/three decades ago. Thus, the only valid competitors for nuclear appear to be terrestrial solar and wind power.

The biggest problem with both wind and solar is the intermittency associated with their energy generation. Try as they might to mitigate its importance, wind and solar proponents cannot in good conscious ignore the additional costs, maintenance, storage and redundancies required to compensate for this deficiency, which raise the costs associated with both solar and wind to levels that far exceed nuclear power. Without the need for storage and redundancy capacity to fill that storage then solar and wind are cheaper, which is the story solar and wind proponents sell the public; however, without storage and fill redundancy, it is logical to suggest that solar and wind will do nothing but produce rolling brownouts to blackouts as the principal energy provider. Unfortunately the current penetration structure of wind and solar does not provide any test cases to demonstrate these realities.

Another problem associated with wind and solar is that measuring their production via nameplate capacity commonly results in optimistic to unrealistic analysis. For example a wind farm reporting a nameplate capacity at 200 MW means that it produces 200 MW when functioning at optimal capacity. Unfortunately to actually achieve this maximum generation result, the wind needs to be blowing within the optimum speed range over the entire farm simultaneously, which is a meaningful statistical achievement; can it happen… yes; does it happen frequently, not even close. Furthermore the statistical probability of this occurring over multiple wind farms is even more unlikely. Basically the greater nameplate capacity built into this type of system, either within a single farm or throughout multiple farms, will result in an overall reduction in the expected maximum capacity that can be feasibly attained relative to the actual nameplate capacity.

In short it is unrealistic for a large wind producer to ever reach 100% nameplate at any given time and the more capacity that exists the lower percentage of the maximum that can actually be reached. For example (note these numbers are for explanation purposes not empirically derived, but accurately demonstrate the trend) a wind system with 3000 MW of nameplate will be able to achieve an average maximum generation of 2500 MW (83%) whereas a wind system with 4000 MW of nameplate will be able to achieve an average maximum generation of 3100 MW (77.5%). Of course these are only maximum values that are attained for a few seconds to minutes at a time; actual average wind capacity values for days to months range from 25-35% and have remained within this range for decades and show little sign of changing, despite certain levels of hype, hence the need for storage and redundancy to fill that shortage.

Another concern with both wind and solar generation is that their production potential changes significantly during winter months. The loss of solar during the winter is of no surprise to anyone that actually pays attention to general climate patterns; however, wind is trickier because while the overall average “amount” of wind does not seem to have any significant level of variance between seasons, its daily levels typically vary more during the winter than other months. Basically during winter months there is a higher probability that wind values depart from the mean both in magnitude and direction (i.e. positively or negatively). These larger departures place greater pressure on plant operators to smooth power curves and properly incorporate the energy produced from wind into the mix with other energy mediums. Remove those other more stable energy mediums and integration becomes even more difficult.

A number of solar and wind proponents have put forth the idea that smart grids will act as a panacea of sorts for the issues associated with integration addressing load balancing, peak curtailment and demand response among other potential problems. However, the scale of application associated with smart grids has been much lower than expected over the last decade despite attempts to invest billions of dollars in the process. Part of this significant delay is that some communities are rebelling against the installation of smart meters, central elements to the smart grid, even when costs of maintenance and installation are deferred to the utility company. While most of the reasons for the rejection of smart meters are thought to be questionable, it does not appear that smart meter detractors will be easily convinced off of their current position.

For example a portion of this resistance is the concern about the safety of potential electromagnetic and/or radiation that could emanate from the smart meter. Unfortunately smart meters may have entered that cell phone zone when it comes to radiation in that even if they are safe it may be impossible to convince some people of that fact and you can easily have an environment of “dueling” experts. Also unlike cell phones, smart meters do not have that “necessary for existence in society” reputation that cell phones seem to have.

Another problem for smart meters is a resistance by utility companies themselves to install them unless someone else is paying the bill due to a lack of standards through how the devices are connected to grid and communicate with each other. Basically no utility company wants to commit to a given format/design because that format may not be the one that “wins”, thus that preemptive commitment will result in significant financial losses. The situation is similar to the problem with the expansion of electric cars. Currently the existing infrastructure to support electric cars is basically non-existent outside of certain areas in California because those responsible for building it are waiting for electric car sales to increase to the point that justify building it, but without an infrastructure few individuals have interest in buying an electric car in part due to the worry that the infrastructure will never be built to support the purchase. One side has to take the leap, but neither side is willing to do so.

Even if smart meter installation was as widespread as hoped, smart grid proponents have acknowledged the problems associated with securing the flow of information and energy within the system. Currently there are valid concerns regarding how prone the system is to being hacked, which raises questions regarding the long-term security and safety of a smart grid. This is not to say that smart meters, and in large part a smart grid, do not have a role to play or cannot be safe, but the issues associated with their adoption and safety place a burden on their speedy application and mass testing that significantly damages the viability of a dominant wind and solar energy infrastructure.

Another issue with wind power that is not commonly considered is whether or not the general price of wind power is close to its minimum in that with a vast majority of the high-value wind collection land masses already being utilized, newer wind turbines will have less naturally efficient areas to generate power. Realistically this issue should not produce an environment were traditional wind power will significantly start increasing in price, but instead it would counteract any cost savings from any further technological advancement in wind turbines. The real question regarding future costs associated with wind power is storage level and medium.

Further problems for solar/wind supporters is even some of the “champion countries” of renewables are not seeing the carbon emission reduction numbers theory and general behavior would suggest. While in isolation Denmark’s wind generation numbers look impressive, they are not consistent, to the point where Denmark relies heavily on energy transfers to and from neighboring countries. Basically if these transfers did not exist Denmark would be in a state of constant brownout due to wind intermittency.

Currently this transfer process is stable because of the more consistent generation mediums possessed by other European countries, most notably natural gas and Swedish and Norwegian hydropower. At the current time and in the foreseeable future the ease of transfer to reduce volatility in Denmark’s energy markets would become incredibly difficult, if not impossible, if Europe adopted similar wind percentage generation profiles. Basically while wind proponents like to cite Denmark as the poster child for “what wind can do for you” its close proximity to Swedish and Norwegian hydropower provides a very unique environment that is not technically or economic replicable for other countries.

Also despite investing heavily in wind and solar power over the last decade Germany has not meaningfully reduced the level of coal and natural gas derived energy production. In fact for Germany CO2 emissions in the energy sector, the most critically relevant area for judging the impact of renewables, have increased relative to the past year (2012 vs. 2011, etc.) in 3 (2012, 2013 and 2015) of the last 4 years for when information is available. The reduction of CO2 emissions in 2014 relative to 2013 is also somewhat marred for it is highly probable that these reductions occurred because of lower energy consumption during the winter due to much warmer than average temperatures over that winter. So while the share of renewable sources of energy in Germany continue to expand, the CO2 emissions from its represented sector are not dropping, which speaks poorly towards the ability of renewables like solar and wind to quickly drop energy derived CO2 emissions, which is exactly what needs to occur to combat global warming.

Note that the issue concerning winter temperatures is also a big deal in Germany because of the lack of available renewables during that time period; solar is almost non-existent in Germany during the winter netting a typical average capacity of 10-11% and wind generation is rather erratic.

Some could argue that this result has been heavily influenced by the decision to suspend operation of the German nuclear power plant fleet with the intent of its future decommission. While this decision certainly has resulted in greater coal and natural gas use, the problem is that there was little reduction of energy derived carbon emissions even before the decision to suspend nuclear power use in Germany instead most of the overall reduction stemmed from the measurement point being 1990 right after the integration of heavily industrialized East Germany into West Germany producing an artificially high point of reference.

Finally one of the troubling aspects of the solar and wind proponent argument is a questionable interpretation of time. They properly acknowledge that ceasing carbon emissions must occur quickly, yet do not acknowledge that creating the type of solar/wind energy infrastructure to actually accomplish this reality will take a long time. Part of this apparent contradiction is that supporters are emboldened by the solar and especially wind percentage growth rates over the last decade as justification for the superiority of wind and solar despite these growth rates not representing meaningful penetrations into global energy markets. Basically wind and solar are still at best small supplemental energy producing elements.

Furthermore another problem, as mentioned before, is a number of proponents believe that once society “actually” commits to a solar/wind energy infrastructure future, the problems and issues associated with this system will magically disappear with Master Plan #1 succeeding without qualm or fail. It is akin to attempting to build a railroad track ahead of a speeding train… everything must go perfectly for it to work and anyone who thinks that any of the current infrastructure plans pushed by solar and wind proponents is anywhere remotely viable is, quite frankly, a fool.

At the present time the best idea to combat global warming is for the entire global community to agree on a single design for a nuclear fission breeder reactor and then allocate resources to begin the specialization required for manufacturing the required components and training the necessary construction and operational personnel. The simple fact is that too many questions and inefficiencies exist in any feasible plan to defeat global warming via the utilization of mass solar and wind energy generation; so much so that foregoing nuclear in favor of solar and wind is a recipe for disaster. Overall global cooperation through the initiation of a real and new nuclear renaissance is the most effective, economical and direct way to combat global warming while maintaining a consistent and reliable energy infrastructure in the developed world as well as allowing energy impoverished nations the ability to advance their energy consumption profiles without endangering the environment.

Tuesday, February 9, 2016

Treating Cancer Through Metastasis Neutralization and Possible Activation

While cancer in any form is potentially dangerous to a patent, it is widely acknowledged that only a small percentage of primary tumors are threatening to the life of a patient in the interim. A vast majority of cancer patient deaths occur due to cancer metastasis. Metastasis is a complex pathway of molecular interactions that produce an end result that involves the departure of a group of tumor cells from the primary tumor into the bloodstream and eventual invasion into other tissues resulting in the formation of additional tumors. Not surprisingly the process is governed by a number of complex pathways that are not fully understood. Despite this lack of knowledge regarding metastasis, is it clear that one of the best strategies for addressing cancer would be to create a therapeutic regimen that would prevent metastasis from occurring in the first place allowing physicians ample time to eradicate the primary tumor with no legitimate threat of reoccurrence.

Of the agents thought to be involved in cancer metastasis chemokine receptor CXCR4 is a promising agent of study and potential therapeutic target. Chemokines are a group of low molecular weight cytokines that induce chemotaxis, most of the time as chemoattractants, largely in leukocytes, endothelial and epithelial cells.1 Chemokines are commonly classified into CC, XC, CXC or CX3C designations based on the positioning of their respective conserved cysteine residues.1 One of the key normal functions of chemotaxis is to facilitate the movement of pro-inflammatory cells to the site of inflammation, including immune cells, normally after some form of injury. CXCR4 is an attractive target because of both strong anecdotal and experimental evidence regarding its overall expression and role in tumor malignancy and metastasis.1-5

CXCR4 functions as a G protein-coupled receptor (GPCR) that principally binds stromal cell-derived factor 1 (SDF-1), which is also known as CXCL12. With regards to cancer, CXCR4 plays a significant role in directional migration though activation of actin polymerization6,7 as well as invasion and adhesion, which influence the overall level of aggression for a tumor. There is also some evidence suggesting that CXCR4 plays a role in angiogenesis as well.4,5

CXCR4 can undergo four major changes to influence its functionality: homo or heterodimerization (with CCR2, CCR5, CXCR7 or CD4), phosphorylation, glycosylation, or sulfation.8-14 Unfortunately limited information is known about functional changes associated with dimerization in cancer for almost all studies involving CXCR4 dimerization relate to HIV, but it is thought that such changes enhance CXCL12 binding. It is also believed that dimerization typically occurs internally before CXCR4 is expressed on the cell surface, typically as oligomers. This oligomeric structure persists in the plasma membrane.14

Phosphorylation occurs principally at serine residue number 339 (Ser339) after exposure to either CXCL12, epidermal growth factor (EGF), or phorbol ester and it is believed that phosphorylation may also occur to a much smaller extent at Ser324, Ser325, and Ser330.12 Phosphorylation is important for increasing the probability of receptor internalization and secondary messenger activation. On a side note mono-ubiquitination occurs at Lys327, Lys331 or Lys333.13 Glycosylation of human born CXCR4 only appears to occur at Asn11 and seems to serve no unique function other than stabilizing CXCL12 binding (lack of glycosylation reduces binding efficiency).1

Sulfation, which takes place primarily at Tyr21 and does not appear to occur on two other potential sites (Tyr7 and Tyr12),15 may the most interesting modification regarding CXCL12 binding probability and functionality.16 When CXCL12 binds to CXCR4 there is a specific site interaction between sulfated Tyr21 on CXCR4 and Arg47 on CXCL12.15 One of the reasons that sulfation appears important is that one study demonstrated that while highly metastatic NPC cells and non-metastatic NPC cells expressed similar levels of CXCR4, both via mRNA and protein, only high levels of sulfinated CXCR4 resulted in high metastatic potential.17

While there are a number of tyrosine sulfation pathways, with regards to CXCR4 one of the more prominent interactions involves the action of the latent membrane protein 1 (LMP1). While LMP1 concentration changes are not universal to CXCR4 activity increases, LMP1 interacts with EGF receptors, which is thought to be one of the early steps in inducing Tyrosylprotein sulfotransferase-1 (TPST-1) dependent tyrosine sulfation of CXCR4.15 However, there is the lingering question of whether sulfation is the chicken or the egg, is it a chief agent in how CXCR4 activation influences the potency of cancer or is it a result of that activation?

CXCR4 activation also significantly increases the overall expression of matrix metalloproteinases (MMP), especially MMP-2, MMP-3, MMP-7 and MMP-9.18,19 One of the major triggers for this action could involve the activated CXCR4 guiding Bone marrow-derived cells (BMDCs) to their pre-metastatic niche, which then triggers BMDCs to initiate the release various metastatic positive elements including various MMPs most notably MMP-7 and MMP-9.20,21 CXCR4 is also involved in the homing of cells into the endosteal HSC,22 which facilitates the expression of SUMO-specific protease 1 that regulates MMP-9 as well.23

As stated above one of the key steps in metastasis is the proteolytic degradation of the extracellular matrix (ECM) in which various MMPs are critical agents. Initially MMPs were thought to be degenerative proteases that were limited to cleaving matrix components, but that role has expanded to include the release of growth factors and other bioactive peptides localized at cleaved extracellular matrices.24-26 While there are up to 26 known MMPs (MMP-1, MMP-2, MMP-3, …) only a few have demonstrated significant roles in both cancer growth and cancer metastasis. Of these select few MMPs that play a prominent role in cancer, MMP-3 and MMP-7 appear to be the most important.

MMP-7, (a.k.a. matrilysin) is the smallest MMP and is commonly expressed in epithelial tumor cells instead of interstitial cells27 and has numerous substrates in the ECM namely collagen fibers, laminin, gelatin, proteoglycan and elastin, etc.28,29 MMP-7 is commonly over-expressed in various types of cancer including, but not limited to non-small cell lung, pancreatic, oral squamous cell carcinoma, colorectal, prostate, stomach and papillary thyroid carcinoma.28,30-34 In addition to its ECM degradation role, MMP-7 can also breakdown cell surface proteins, which aids cancer cell proliferation through the regulation of apoptosis and angiogenesis as well as help evade immune system detection.34-36

Furthermore, as mentioned above, MMP-7 is thought to increase expression of MMP-2 and MMP-9 to aid in ECM degradation and other pro-cancer actions.37,38 Finally not surprisingly MMP-7 levels increase in response to decreased blood glucose levels for this increase is tied to a low quality or deteriorating principal environment for the tumor, which should trigger elements responsible for assisting metastasis like MMP-7. However, while MMP-7 appears to be the most active MMP in most cancers, its activation may only be a downstream event caused by MMP-3.

An early action taken by a member of the MMP family typically involves MMP-3 cleaving decorin, releasing growth factor-beta and cleaving transforming growth-factor-alpha (TGF-a), which activates the MAP-kinase pathway.39 This activation can later activate MMP-7, which as previously mentioned leads to the activation of MMP-2 and MMP-9.40 In addition to activating other MMPs like -2, -7 and -9, MMP-3 can also promote genomic instability and epithelial–mesenchymal transition (EMT) through the activation of Rac1b, which stimulates both the production and release of intercellular mitochondrial superoxide.41,42 MMP-3 appears to be the dominant expression route for Rac1b.41

Due to the important role MMPs play in inducing both metastasis and possible anti-apoptosis protection, a number of researchers have thought of MMP inhibition as a promising treatment option. However, clinical trials investigating the viability of MMP inhibitors, commonly known as tissue inhibitors of metalloproteinases or TIMPs, have not proven successful.43 One of the major theories behind this failure is that during tumor development MMPs have different roles depending on tumor progression and the other molecules present in the tumor microenvironment. Some information has demonstrated anti-tumor effects for certain MMPs, most notably MMP-3, MMP-8, MMP-9, MMP-12, and a newer MMP, MMP-26, which may be a natural protectorate MMP.43-47

Clearly this dual behavior makes targeting MMPs directly difficult for therapeutic reasons, as demonstrated clinically, thus it could be more important to focus on important MMP triggers like CXCR4, which appear to activate MMPs during a time when their interaction with the tumor microenvironment will produce a net negative for the patient.

CXCR4 also can activate the P110-beta isoform of PI3K resulting in the eventual synthesis of phosphatidylinositol (3,4,5)-triphosphate, which leads to the phosphorylation of protein kinase B/Akt and mTOR pathways most notably activation of p70S6K and 4E binding protein 1.7,48,49 Not surprisingly mTOR inhibitor, rapamycin, reduces the extent of p70S6K and 4E binding protein 1 activation in a CXCL12/CXCR4 environment.7,19,50 Furthermore CXCR4 also activates elements in the Src family of protein tyrosine kinases, which aid the activation of focal adhesion elements like Crk, paxillin, and tyrosine kinase/Pyk2.51

For a long time CXCR4 was thought to be a unique target for CXCL12 until CXCR7 was identified, potentially complicating the role of CXCR4. Similar to CXCR4, CXCR7 is expressed at a much higher rate in malignant cancer cells versus normal cells and binds CXCL12 with high affinity.10,52 However, despite the significant similarities between CXCR4 and CXCR7, CXCR7 does not appear to play a meaningful role in cancer development or metastasis.53,54 The role of CXCR7 appears to involve the migration of primordial germ cells or interneurons.55 Its increased expression simply may be the result of dramatically increased levels of CXCL12 in the localized environment. Interestingly enough CXCR7 may prove to be a possible therapeutic element as an indirect natural CXCL12 competitive inhibitor of sorts for every CXCL12 molecule that binds to CXCR7 is no longer available to bind to CXCR4.

Earlier it was mentioned that CXCR4 might have a relationship in tumor growth and/or angiogenesis. If true, then this result is complicated because cancer growth at established tumor sites is more rapid in the absence of CXCR4 rather than its presence.53 Therefore, it may be that while CXCR4 assists growth immediately after invasion, its continued presence becomes detrimental for the tumor because it helps induce metastasis, thereby diverting resources like recruited and differentiated endothelial cells or progenitors from the original tumor towards elements that will be involved in the metastasis or even the attraction of metastatic elements already in the bloodstream.

CXCR4 also appears to interact with another potential important factor in cancer metastasis, macrophage migration inhibitory factor (MIF). MIF is a pro-inflammatory cytokine that plays an important role in inflammation and immune response and is expressed at a higher than normal rate during numerous cancer stages like cell proliferation, angiogenesis and anti-tumor immune interaction.56-58 High MIF concentrations have also been associated with poor outcomes in lymphoma, melanoma and colon cancer.59,60 CXCR4 interacts with MIF through the formation of a MIF receptor complex with CD74, which further enhances MIF-stimulated AKT activation.61

There is some thought that when MIF lacks its traditional activation pathway it requires caspase-1 activity for proper secretion.62 Also Golgi-associated protein p115 may be essential for the transport of MIF from the perinuclear ring to the plasma membrane and then out of the cell.63 In addition to aiding metastasis, MIF is also thought to apply some level of apoptosis resistance to cancer cells, favoring those with androgen-dependency over those with androgen-independence, but that resistance may be tied to CXCR4 interaction.64

With CXCR4 having its “fingerprints” over a number of pro-cancer processes, fortunately an additional element that makes it an attractive therapeutic target is its natural role in the body. In non-cancerous tissue CXCR4 is expressed on hematopoietic cells like CD34+ HSC, B-lymphocytes, neutrophils, monocytes, macrophages, and microglia, etc.65 CXCR4 or CXCL12 knockouts in mice result in impaired hematopoiesis through reduced hematopoietic stem cell (HSC) trafficking, which results in heart and brain defects as well as vascularization commonly producing embryonic death;66 in adults CXCR4 is important in HSC homing for the bone marrow microenvironment and lymphocyte trafficking.65 However, most of the time CXCR4 expression in normal cells is low, unless the body has been recently injured. Therefore, treatments that limit CXCL12/CXCR4 pathway activation should result in limited negative side effects for healthy non-injured individuals.

Another potential benefit from CXCR4 inhibition could involve reducing the probability of chemotherapy agent resistance, including Docetaxel (DTX) resistance. Some research suggests that the CXCL12-CXCR4 pathway interacts with p21-activated kinase 4 (PAK4)-induced LIM domain kinase 1 (LIMK1) via phosphorylation to reduce the ability of DTX to destabilize microtubules, which typically results in cell cycle arrest during the G2/M phase.67 Basically CXCR4 activation provides additional protection against cell death for tumors when exposed to DTX. This result suggests that LIMK1 could have a role similar to microtubule-associated protein (MAP) depending on whether or not it is phosphorylated. Therefore, this chemotherapy resistant pathway has two principal inhibition targets in CXCR4 or PAK4 to negatively influence prospective chemo resistance.

Existing potential therapies involving CXCR4 have focused largely on inhibiting the binding capacity of CXCR4 most notably either through the use of AMD3100, a specific CXCR4 antagonist, or synthetic peptide TM4.14,68,69 AD3100 (a.k.a. (Plerixafor) is a small molecule with two cyclam rings connected by a phenylene linker that have nitrogens on each ring that have charge-charge interactions with carboxylate groups on CXCR4, which inhibits CXCL12 binding.70-72

Plerixafor is most commonly used as a pre-treatment element for chemotherapy where, as mentioned, CXCR4 disruption reduces the probability of hematopoietic stem cells homing to bone marrow, thus it increases their circulation in the blood stream allowing for their collection for transplantation after chemotherapy regimens.73,74 Plerixafor has also proven promising as an anti-cancer treatment via its ability to reduce cancer cell chemotherapy resistance by either neutralizing the CXCL12-CXCR4 pathway or reducing the physical attachment of various micro-environment critical cells, similar to what is expected for a CXCR4 inhibitor.

An interesting side effect in plerixafor treatment is that surface expression of CXCR4 increases both in vitro and in vivo.65 One possible explanation for this outcome could be that principal signals that induce CXCR4 expression continue while plerixafor prevents CXCL12 from binding CXCR4; CXCL12 binding leads to internalization and activation of secondary pathways. When there is no CXCL12 binding there is no CXCR4 internalization, but the pathways governing CXCR4 expression towards the cell surface continue, thus explaining the overall increase in CXCR4 expression. If this tendency is accurate then long-term treatment with plerixafor alone may not be beneficial because the increased surface expression will substitute for the CXCR4 “removed” by plerixafor interaction. Basically plerixafor works well alone in the short-term, but may not work well alone in the long-term, which may be the same fate of all substrate based CXCR4 inhibitors.

Apart from preventing metastasis, treating the primary tumor is also an important task, especially when surgical options are unavailable. One promising potential therapeutic agent that can influence both primary tumors and metastasis is salinomycin (SAL), which has demonstrated effective ability to kill cancer via a perceived mixture of apoptotic and autophagic cell death in breast, prostrate, brain, blood, liver, pancreatic and lung cancers with no immediate lethal toxicity.75-77 Initially it was reported that SAL was toxic to certain neuronal cells (dorsal root ganglion in mice) at 1 uM, but this toxicity was neutralized when paired with factors that inhibited mitochondrial Na+/K+ exchangers with no resultant change in cancer cell cytotoxicity.78,79

One of the chief advantages of SAL in treating cancer is that it uses a different methodology apart from more common chemotherapy drugs like Doxorubicin, Cisplatin, Gemcitabine, Temozolamide, Tratsuzumab, Imatinib, etc.75,80-82 SAL has a preference for targeting cancer stem cells (CSCs), which reduces the probability of cancer reoccurrence after its primary removal.75 CSCs are important to address in treatment because they are commonly thought of as another element responsible for driving the core of cancer metastasis after responding to various signal triggers as well as driving cancer recurrence after the primary tumor is eliminated due to their ability to more frequently resist anti-cancer therapies. Thus, addressing CSCs, either directly or indirectly, is a critical part to addressing both cancer itself as well as its metastasis.

Another interesting behavioral aspect of SAL is amplified effectiveness under hypoxia or starvation conditions. This result makes sense on two different levels: first, it is thought that a means in which SAL triggers cell death is through damage to the mitochondria, in part to being a potassium ionophore, promoting hyperpolarization in the mitochondria, which decreases ATP availability and triggers caspase-3, 8 and 9, a consequence worsened by starvation conditions.76,83 Second, its effectiveness against CSCs is enhanced by the reaction of the tumor to hypoxia. In hypoxia the primary tumor will begin to focus an effort to metastasize due to the negative environment that currently exists; one step in this process requires the recruitment and creation of CSCs which reduce resource availability for the primary tumor, yet those CSCs are more effectively eliminated by SAL versus the cells that comprise the primary tumor.

The ability of SAL to “cooperative” with other anti-cancer drugs directly is questionable for most of the benefit from co-therapy between SAL and given drug x appears indirect.84 This result is somewhat interesting because there is some evidence to suggest that SAL can also function as an efflux pump inhibitor, which is commonly operated by a p-glycoprotein;85-87 efflux pumps increase the ability of cancer cells to remove chemotherapy agents before the inducement of cell death, so inhibiting them would increase tumor susceptibility to these chemotherapy agents. However, Metformin (METF), which is though to lower circulating insulin levels and stimulate AMPK-mediated suppression of mTOR, along with having some anti-cancer properties in thyroid, prostate, gastric, breast and glioblastoma,88-90 seems to have some form of direct enhancing cooperative relationship with SAL.84

This combination activity results in the “unspecific” inhibition of EGFR and HER2/HER3 leading to reduced concentrations of AKT and ERK1/2 via an unknown mechanism.84 However, it seems appropriate to suggest that based on SAL activity when acting alone that this “inhibition” is born from a reduction in available receptors due to cancer cell or associated cell death.

Another mechanism for inducing cancer death that includes SAL interaction is autophagy. In its most basic form autophagy involves the “self-digestion” of intracellular elements via the vacuolar lysosomal degradation pathway to recycle cytoplasmic constituents.91 Autophagy is typically used to prevent the accumulation of damaged proteins and organelles, largely born from cell damage due to outside agents; for cancer it would be anti-cancer drugs. This process also reduces the production potential of reactive oxygen species (ROS) that negatively impact cell survival.

There is reason to believe that SAL can interfere with autophagy in cancer cells by inhibiting lysosomal activity driven by cathepsins.85 Interestingly enough this activity occurs without impacting the lysosomal compartment.85 This aspect of SAL interaction is not surprising due to structural similarities with both nigericin and monensin, which have similar behavior as anti-porters themselves, but the lack of change in pH of the lysosomes from SAL treatment belies a different pathway.

Also the behavior of SAL runs contrast to ATG7 expression where ATG7 acts as a protectorate of sorts ensuring the proper functionality of autophagy. For breast cancer cells and more than likely other forms of cancer, aldehyde dehydrogenase 1 positive cells (ALDH+) promote autophagy.85,92 Thus, SAL directly works against ALDH as well as competes to “thwart” ATG7 autophagy protection. Therefore, ATG7 in some instances is able to neutralize the dual ability of SAL to kill cancer cells via induction of apoptosis while inhibiting autophagy inhibition. Therefore, inhibiting the activity of ATG7 may provide a useful co-therapy with SAL to significantly neutralize the ability of cancer cells to build resistance to SAL-related apoptotic activity.

Another popular method of action for SAL against cancerous agents is thought to be its interaction with Wnt signaling and its relation to b-catenin. The interaction between Wnt and b-catenin begins when Wnt binds to frizzled (Fzd) receptor and then that complex binds to lipoprotein receptor-related protein 5 or 6 (LRP5/6) co-receptors leading to a ternary complex that typically exists at the cell surface.93 The presence of this complex can trigger phosphorylation of either LRP leading to the recruitment of axin, which then undergoes endocytosis.93 The end result of this entire process is the breakdown or inactivation of the Adenomatous polyposis coli (APC)-Axin complex, which is responsible for b-catenin elimination.

This processes is important because b-catenin accumulation leads to its nuclear translocation and can even increase expression of Wnt genes via those tumors located at the invasive front, which have more interaction with growth factors and cytokines including hepatocyte growth factor.94 This interaction may even create a positive feedback loop of sorts.94,95 This nuclear translocation of b-catenin is thought to play some role in tumor cells experiencing cell-cycle arrest and EMTs via the loss of E-cadherin expression creating some form of cancer stem cell, with increased migration/metastasis potential.96,97

SAL interferes with the Wnt pathway by degrading the LRP6 protein and possibly LRP5 protein, which obviously reduces the probability that they form a complex with Wnt and are later phosphorylated activating the complex.85 LRP protein importance is further supported by a level of suppression in breast cancer tumor growth after treatment with a LRP antagonist, Mesoderm development (Mesd).98,99

However, SAL is not a cure-all when it comes to this supposed pro-cancer pathway, for Wnt and its associated complex is not the only significant destruction inhibition interaction experienced by b-catenin. Expression of platelet-derived growth factors (PDGF) can induce the tyrosine phosphorylation of p68 via c-Abl kinase.100 After phosphorylation p68 can bind b-catenin and inhibit GSK3b mediated phosphorylation reducing the probability that it is eliminated, thereby increasing the probability of b-catenin nuclear location.100 It is also thought that EGF and TGF-b can induce p68 phosphorylation via receptor tyrosine kinases.100,101

Another possible strategy to deal with LRP protein complex interaction involves the inhibition of vacuolar H+-adenosine triphosphatase using an agent like archazolid.102 LRP6 phosphorylation and internalization appears to require V-ATPase. The general role of V-ATPase is transport of both intracellular and extracellular organelles near the plasma membrane. Not surprisingly it also pumps protons leading to the acidification of vesicles, which promotes endocytosis.103

Another element in cancer development that has garnered attention for metastasis is the role of carcinoma-associated fibroblasts (CAFs). Tumor invasion is heavily influenced by the tumor microenvironment, especially the types of non-tumor cells. Various types of fibroblast recruitment lead to the production of soluble factors and extra-cellular matrix (ECM) remodeling usually through actin changes and cell migration born from MMPs, Rho targeted via ubiquitination and SUMO pathways104 as well as global DNA hypomethylation and recruitment of mesenchymal stromal cells; these changes increase the viability of future invasion.105-108

The cancer stroma is typically populated by various concentrations of fibroblastic cell groups that make up CAFs and are commonly divided into myofibroblast (MFs) and non-myofibroblast populations (non-MFs).105 MF populations have received much more attention than non-MF populations more than likely due to the diversity of the non-MF populations. It is thought that CAFs differ significantly from normal fibroblasts and myoblasts, but there is little information regarding the extent of these differences.105,109

CAFs are heavily involved in various pro-cancer pathways like tumor necrosis factor alpha (TNFa), IL-1 and IL-6,105,110,111 which lead to promoting invasion, immune suppression and angiogenesis through the secretion of SDF-1, TGF-b, hepatocyte growth factor (HGF), PDGFs, or vascular endothelial growth factors (VEGFs) principally driven by FSP-1- or PDGF receptor alpha-positive stromal fibroblasts.112-116

Not surprisingly if CAFs are thought to play a role in all of these pro-cancer processes, targeting them would prove useful for developing effective therapies. A number of proposals have been made regarding PDGF receptor inhibitors, SUMO inhibitors, Met receptor inhibitors or HGF inhibitors; however, on its face it is difficult to envision how to effectively target the “right” CAFs due to the widely diverse population of cells within the stroma. Interestingly enough some possibly contradictory research could prove some insight.

As mentioned above CAFs in the stroma are typically defined as either MF or non-MF, but both of these groups can be activated and/or transformed as well. One particular group to question is activated non-transformed MFs, which express alpha-smooth muscle actin (a-SMA). There are some that believe that these cells have “anti-cancer” activity instead of “pro-cancer” activity. Support for this mindset comes from studies of early and late stages of pancreatic cancer outcomes, clinical correlation between high a-SMA levels and improved survival on a general level, and studies of resected tumors.117-120 Also there is some question to whether or not a-SMA positive MF cells increase hyaluronic acid concentration.121 The anti-cancer attributes of MFs appear to stem from aiding both innate and adaptive immune response via increased fibrosis.117

Whether or not these MFs are pro-cancer or anti-cancer elements is important to deduce because anti-cancer therapies tend to kill indiscriminately around the principal tumor and its microenvironment, including a-SMA positive MFs. If these particular MFs are anti-cancer then these drugs are inherently less effective because while they are killing cancerous elements they are also killing anti-cancer elements.

The final possible important element to CAFs and their role in cancer is their ability to produce exosomes. For example in breast cancer CAFs secrete Cd81+ exosomes that can induce the planar cell polarity (PCP) signaling pathway targeting Wnt and influencing the polarity of carcinoma cells.122 Internalization of these exosomes also promotes Wnt11-PCP induction via autocrine through Frizzled receptor signaling leading to increased probability of pulmonary metastases.112 Targeting these exosomes may be a valid therapeutic strategy for reducing cancer potency.

As mentioned above directly targeting CAFs via therapies may be difficult, but one potential candidate could be TNF receptor associated factor 6 (TRAF6). At least for squamous cell carcinoma (SCC), TRAF6 plays a role in enabling nuclear factor kappa beta (NF-kB) signaling to activate a number of downstream pathways for CAFs, like Akt, Src-family kinases, IKK, IL-1beta and p38 and can regulate the formation of Cdc42-dependent F-actin microspikes.105,107,123 While the role of Cdc-42 is exactly unclear, TNFa plays a large role in promoting invasion in SCC and TRAF6 plays a significant role in producing sufficient TNFa concentration. The reduction of either one of these pathways significantly reduces cancer invasion, possibly due to the K63 ubiquitin ligase activation associated with TRAF6.124

The final issue when addressing cancer metastasis is developing a strategy to promote delivery of the anti-cancer agents to increase the probability of positive action, especially through ensuring proximity action. A reason behind this strategy is that some agents, like the rather useful SAL, demonstrate low quality aqueous solubility, which restricts their ability to be injected through a more standard IV strategy.125 Not surprisingly nanoparticles have become the most attractive vessel for transporting anti-cancer agents to cancer sites.

Overall nanoparticles are advantageous due to their low to non-immunogenic activity reducing complications and increasing their lifespan in the bloodstream, their natural and generally safe biodegradability and biocompatibility and their general design flexibility for producing the right type of particle for the given job. For example some nanoparticle structures use polypeptides with elastin and hydrophilic properties in effort to produce immune-tolerant elements. These elements are commonly referenced with the acronym, iTEP.126 However, nanoparticles need a form of “navigation” system to reach the appropriate target. The two most common targeting strategies are the use of antibodies or the use of aptamers.

Antibody targeting in some respects is the “old reliable” while aptamer targeting is somewhat new. Aptamers are comprised either of oligonucleic acid (DNA or RNA) or a peptide that are able to bind a specific target molecule. The major advantages of aptamers are their molecular specificity, their lack of immunogenicity, and their low molecular weights. These two latter advantages along with ease of production have further increased the popularity of aptamers versus antibodies regarding therapeutic targeting strategies including those dealing with cancer. A number of aptamers have already been developed for use in cancer treatment.127,128

Regardless of navigation methodology, the drug delivery vessel must have the right navigation point. One molecule that has drawn interest for potential cancer targeting ability is hyaluronic acid (HA). HA typically binds to CD44, a receptor commonly over-expressed on numerous types of tumors.129 Furthermore HA is frequently broken down by tumor cells by hyaluronidases (Hyals), which is widely thought to experience concentration increases in various cancers including prostate, bladder, colorectal, brain and breast due to the presence of increased low weight HA fragments found in these tumors versus normal cells.130-133

The general process of HA catabolism involves binding to CD44 resulting in its breakdown into smaller elements by Hyal-2 while still on the cell surface forming what is known as a caveolae. This caveolae eventually becomes an endosome that fuses with lysosomes resulting in the further degradation of HA fragments into tetrasaccharides by Hyal-1.134,135 Based on this process one could theorize that a self-assembled nanoparticle comprised of HA would serve as an effective means of drug delivery to the tumor site both tracking and through its degradation, a belief that has been supported with early empirical results.129

In addition to HA, it is widely thought that cluster of differentiation 133 (CD133) is a positive stem cell marker for both normal and cancerous tissue and is thought to be a critical agent in identifying CSCs. For example it is common for CD133+ cancer cells to form mammospheres that can initiate tumor growth in non-tumor cells. Due to the importance of CD133 expressing cells, an RNA aptamer (A15) has already been developed that binds to CD133 for use as a “tracking” marker of sorts and some groups have already explored the idea of using A15 as a drug delivery targeting agent.136

However, it must be noted that while CD133 expressing cells appear to be the most important in the CSC pool, tumors do produce CSCs that express other surface receptors while not expressing CD133. For example in osteosarcoma, CD133, CD117 and Stro-1 are all considered to be legitimate CSC markers.48 Additionally there is some evidence to support the idea that CSCs can convert to non-CSCs and back again.137 Therefore, while targeting CD133 is clearly an appropriate strategy for treating CSCs, it may not be the only targeting strategy necessary to eliminate CSCs.

The type of nanoparticle is only part of the issue involving drug delivery. Another important element is whether or not the principal drug should have other elements encapsulated with it to increase efficacy. For example SAL delivery involves a charged hydrophobic drug trapped inside a hydrophobic core of micelle-like nanoparticle; these interacting charges can increase destabilization potential, leading to ineffective drug application, which has been seen in past studies.125,126 Therefore, this charge interaction needs to be neutralized.

An early candidate for cooperation with SAL stability was N,N-dimethyloctadecylamine (DMOA) due to its similar hydrophobic nature, yet positive charge which is obviously counter to the negative charge of SAL. Unfortunately DMOA proved too toxic for this role.126 Fortunately it has a less toxic analogue in N,N-dimethylhexylamine. However, this reduced toxicity comes at the price of reduced hydrophobic strength due to a shorter hydrocarbon chain.126 Thus, researchers have added alpha-tocopherol as a second hydrophobic agent to enhance internal hydrophobicity to increase stability, which appears to work well.126

In the end while metastasis is still a process with a number of question marks associated with its occurrence and action there does appear to be certain elements that have important roles in its successful occurrence and function regardless of these question marks. First, it is quite clear that any therapy will have to involve some form of drug cocktail to cover multiple metastasis pathways including treatment of the principal tumor via either drugs or surgery. With this strategy in mind one interesting combination would involve the use of SAL in HA nanoparticles, some form of CXCR4 inhibitor, something like Plerixafor should be sufficient when not applied by itself, and a standard chemotherapy drug like Docetaxel.

Another possible addition to this cocktail could be an anti-angiogenesis drug. In recent treatment history anti-angiogenesis drugs have had a negative history of being useful anti-cancer agents despite the sound theoretical reasoning that reducing growth resources should reduce cancer growth potential. The failure of anti-angiogenesis drugs more than likely occurred due to the induced hypoxia environment increasing rates of metastasis. However, this increased metastasis may be a benefit when the anti-angiogenesis drug is used in combination with a CXCR4 inhibitor and/or SAL, which could speed cancer death by eliminating the metastatic elements versus attempting to eliminate the principal tumor. Of course this combination and the possible positive outcome is only theoretical, without appropriate empirical evidence the addition of an anti-angiogenesis agent may not provide a benefit, similar to how it functions currently.

While promising gains have been made in recent years in immunotherapy-based techniques to combat cancer, it is important to acknowledge that overall there is no magic bullet, but the above potential cocktail should be able to overlap the important negative cancerous element of both primary tumor elimination through multiple destruction pathways and metastasis neutralization via elimination of CSCs as well as the major pathways the drive the preparation and activation of metastasis itself. This method alone or in combination with a proven effective immunotherapy technique could provide a legitimate anti-cancer therapy for various stages of cancer development.

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