The Complexities of Cancer

There are a collection of papers in Nature Genetics discussing the data collection efforts around various cancers. In summary it states:

The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile.

 Simply viewed we have many layers of data for a variety of cancers. We have pathways that are disturbed, we have BRAF or BRCA changes, we have miRNA interference, we have lncRNA or methylation changes, as well as translocations, SNPs and the like. How do we record all of this and how do we relate this to management of cancers?

There are many paths connecting the various layers. The following are some of the questions they pose:

• What is the spectrum of nucleotide- and dinucleotide-level changes associated with
  different carcinogenic etiologies (for example, tobacco, pathogens or inflammation)
  operating in different parts of the body?
• Will integration of additional data sources, including additional tumor types from TCGA
  and other projects, increase the power of analysis in useful ways?
• How can characterization based on molecular changes complement pathological
  analysis for classification of cancers into tumor lineages with potentially different
  clinical management?
• Can molecular profiles effectively categorize cancers for therapeutic decision-making?
• Are there predictive expression-based signatures for genomic events that transcend
  tissues, reflecting pathways disrupted by the alterations?

The collection of papers is interesting. However it does point to the ever growing complexity of the cancers we study. What appeared as just a process understanding paths is but one of many layers of complexity.

Health Care and Sob Stories

In a recent piece in The New Yorker a physician who also is a writer bemoans the fact that anyone is opposed to the ACA[1]. He starts off with the obligatory sob story of some poor unemployed person who no longer has insurance and gets ill, at lease this person appears to have a biopsy on some "pre-malignant" disorder. Then the poor guy gets the bills. Surprise.

He then states concerning the roll-out of the ACA:

How this will unfold, though, depends on where you live. Governors and legislatures in about half the states—from California to New York, Minnesota to Maryland—are working faithfully to implement the law with as few glitches as possible. In the other half—Indiana to Texas, Utah to South Carolina—they are working equally faithfully to obstruct its implementation. Still fundamentally in dispute is whether we as a society have a duty to protect people like Paul Sullivan. Not only do conservatives not think so; they seem to see providing that protection as a threat to America itself.

That is the way the law was written by the Democrats. One should not blame those who did not even vote for the law. Secondly, and this is the first sob story part of his piece, if someone loses their job, they still have home and auto insurance. No auto insurance no car registration, no driving. No home insurance and some may default on their mortgage and get the home repossessed. So why let health insurance lapse. Because people assume they will be taken care of on someone else’s dime. It does not always work that way. So find a job, any job, and get two or three to survive. Some of us have been there.

Then he bemoans:

Obstructionism has taken three forms. The first is a refusal by some states to accept federal funds to expand their Medicaid programs. Under the law, the funds cover a hundred per cent of state costs for three years and no less than ninety per cent thereafter. Every calculation shows substantial savings for state budgets and millions more people covered. Nonetheless, twenty-five states are turning down the assistance. The second is a refusal to operate a state health exchange that would provide individuals with insurance options. In effect, conservatives are choosing to make Washington set up the insurance market, and then complaining about a government takeover. The third form of obstructionism is outright sabotage. Conservative groups are campaigning to persuade young people, in particular, that going without insurance is “better for you”—advice that no responsible parent would ever give to a child. Congress has also tied up funding for the Web site, making delays and snags that much more inevitable.

The state exchanges will also entail Medicaid expansion. Why? After all the Feds are paying. Well first where do the Feds get the money, simply from us. Second, and this is critical, the Fed support is but for a short while. Then the States must pay. That is excessive. Especially since in some states they are doubling or tripling the Medicaid roles. Take New Jersey, there will almost be a tripling of the roles. Now it is not as if they are not getting care, just go to any ER. But now it gets loaded onto private insurance fees. Taken out of corporate and individual coffers. But when the size triples, it will be all out of the remaining taxpayers pockets, along with the sizeable subsidies. Imaging getting a subsidy even if your income is just shy of $100,000!

And he continues:

Some states are going further, passing measures to make it difficult for people to enroll. The health-care-reform act enables local health centers and other organizations to provide “navigators” to help those who have difficulties enrolling, because they are ill, or disabled, or simply overwhelmed by the choices. Medicare has a virtually identical program to help senior citizens sort through their coverage options. No one has had a problem with Medicare navigators. But more than a dozen states have passed measures subjecting health-exchange navigators to strict requirements: licensing exams, heavy licensing fees, insurance bonds.

Is there any concern in the above statement? Should states just allow anyone to “assist” people in selecting how to spend money on 18% of the economy? The navigator program is open to massive fraud and corruption. The navigators need de minimus training and can put themselves forth as experts and who knows what they will do. We regulate attorneys and accountants and even hair dressers. People will be making tremendous personal and financial decisions on getting insurance. We regulate those who purvey home and auto and life insurance. But this writer seems to consider it some evil to regulate the purveyors under the ACA. Why? Do we trust Government agents any more than others? Just look at the IRS. Argument ended. As for the Medicare program, first we paid for it, second we keep paying for it, third, there is no navigator, there is one program, and fourth it delimits my choice of physicians.

So what is wrong with the ACA? I started this blog in late 2008 recognizing two things. First that the economy was in a mess and not a single academic economist had a clue. A few admitted it but most such as the gnome from the South kept mouthing off as to what should be done. The classic case is the Romer curve, predictions that were not even close, even now! And that person is still teaching on the state dole. Second, was the issue of Health Care? I complained about Hillary Care in the early 90s and when I saw train wreck number two approaching I again was concerned.

In my opinion Health Care should be as follows:

1. Universal coverage. Everyone needs to have it.

2. Commercially available. Insurance entities should market it nationally.

3. Provide catastrophic coverage only by mandate. You get terminal cancer, a stroke, massive MI, you are covered. You have a cold, it is your dime. You can always buy more insurance, but the law must not mandate some full package. That includes birth control.

4. Individual purchases and after tax dollars. That is correct, just like your home and auto insurance.

5. Government subsidies for the lower incomes. That means poor folks. Poor because they cannot find a job. Not poor because they just like hanging out at mom’s through their 20s and 30s.

6. Penalties for lifestyle risks. Smoke and you [pay more, Obese and you pay more. Drugs and you pay more.

7. No Government control. The Government can require it, as a tax if you will, but they get no information, provide no regulations, and demand no specific performance.

Simple. As we have shown this can be done today with a lower expenditure than we have now for everyone.

The author ends with:

This kind of obstructionism has been seen before. After the Supreme Court’s ruling in Brown v. Board of Education, in 1954, Virginia shut down schools in Charlottesville, Norfolk, and Warren County rather than accept black children in white schools. When the courts forced the schools to open, the governor followed a number of other Southern states in instituting hurdles such as “pupil placement” reviews, “freedom of choice” plans that provided nothing of the sort, and incessant legal delays. While in some states meaningful progress occurred rapidly, in others it took many years. We face a similar situation with health-care reform.

I guess every Democrat needs to bring in racism, it seems to be part of the Party rant. No one’s rights are in dispute here. All have a right to buy health care. No one is denied health care because of sex, race, and religion. No group is being barred from hospitals. This in my opinion is just a classic cheap shot. Making this the same as racism is akin to calling a person a Nazi. It is both out of place and destroys the logic of the argument, if ever there was any. It now seems almost obligatory to rant in this manner. Frankly it dilutes whatever argument one may have.

The problem is that we need health care reform, we need universal health care but the Government as controller is the worst of a bad set of options. The regulations resulting from the Law are minion. They are confusing, some contradictory, and a great financial and unnecessary burden. Is this segregation? Hardly. It is the people speaking out against something jammed down their throats.

It would be nice if some of these academics and physicians had a modicum of financial acumen. Just a little bit.

---

[1] http://www.newyorker.com/talk/comment/2013/10/07/131007taco_talk_gawande

What Do You Mean by Blue?

I have from time to time had to deal with the epistemological issue of; what do you mean by blue? It seems that in the small but combative world of daylily fans there is the debate as to whether or not one can grow a blue daylily.

Now it eventually begs the question of: what do you mean by blue? I have written on this issue but alas the doubters remain. I have just read a brilliant paper on the Costa Rican river called the Sky Blue River, and it is a brilliant paper. It seems that there are two rivers in the country that when they meet the pH changes just enough and the molecular content of each river changes by the same so that the result is a brilliant blue river.

The paper by Castellon et al is superbly well done and complete. Simply the molecules from one river combine with those of a second and form an almost uniform molecular size molecule at about 566 nm and thus reflect the light back at a very narrow wavelength, the brilliant blue color.

For any of you who are interested in a wonderful explanation of a natural phenomenon this paper should become a classic!

Castellon, E., et al, Scattering of Light by Colloidal Aluminosilicate Particles Produces the Unusual Sky Blue Color of Rio Celeste, PLOS, September 2013, V 8, N 9.

The Draft and the Generals

The Draft has been around for a while, on again and off again. Recently Generals who have “retired” from various branches of the Military, the Army especially, has been out and about advocating the Universal Draft.

Let us deal with a few facts.

Costs:

One of the Generals, one who seems to have let his own people run amok, says we should draft everyone, for two to three years of Universal Service. Let’s take a look at the costs. Now the Census shows the following age groups[1]:

Age	Number	Percent Total Population
15 to 19 years	22,040,343	7.1
20 to 24 years	21,585,999	7.0
25 to 29 years	21,101,849	6.8
30 to 34 years	19,962,099	6.5
Total	84,690,290	27.4

So let us begin. Do we draft a group? Say we draft anyone 20 to 24 years of age for three years. That is 7% of the population and some 22 million people. That is a rather big Army but let us assume our Generals have thought through this process, after all they are the one running our Wars and also the NSA. They are real smart, are they not?

So we have 22 million taken from colleges, jobs, startup companies, Medical School and the like, we take them for three years, and we send them to where? Well, most would never make the Marines, they have standards, the Navy has just about 300 ships, and at most a third are active at a time, so the Navy really does not need them, the Air Force is using drones, so well that does not require much, the Coast Guard is not in DoD so we eliminate the, thus they all must go into the Army. To manage them we need thousands of more Generals, and thus West Point is happy. But let us look at the costs. A prisoner costs $100K to $150K per year to maintain. 

Let is assume we treat the Army grunts the same, say $100K per year in food, uniforms, housing, health care, benefits etc. Thus we must spend $2.2 Trillion annually for the crowd. Yes, bottom line, with no other stuff, not even bullets, it adds $2.2 Trillion. Perhaps these Generals did not learn math at West Point. As we know, no good Army General would be unable to find tanks, mortars and the like to train these folks on, thus easily doubling the amount! Make it a round added $5 Trillion!

Loss of Opportunity

Thus we take the best and brightest out of their education process and have them do what? Send them to what war? Peel potatoes. The Army, when loaded with people, spends a great deal of time peeling potatoes and sweeping parade grounds, it is “hurry up and wait”. But what of the people? We take them from colleges, graduate schools, Medical Schools, and send them where? To the Army? Why? Because some General believes we should have everyone “serve”. What does he think the entrepreneur is doing? He or she is creating new businesses, new technologies, and new opportunities, often despite our Government. Serving is an interesting idea but it appears that these generals just want more bodies to push around. Think of all the start-up companies that will never happen and the loss of any chance to a China or other aggressive country.

Fighting Enemies has changed

Fighting our enemies, yes we have enemies, have changed or should be changing. We have few enemies who are “countries”. Not that it could not change, but at the present time we most likely will not go to war with China or Russia, frankly it would be devastating and there is little cause. Secondly or enemies are groups with belief systems alien to ours. They are not amassed in large armies that blend with the populace and to fight them we need alternative means which are pari passu with theirs. Namely we need intelligence networks and covert operations. We need the folks at the bar in Istanbul or at the market in Islamabad. We have to have flows of information from the mechanic in Bangkok or the baker in Mumbai. Then to join the enemy we need covert forces who do not announce themselves and a Government who takes no “credit” for the neutralization of the problems. The tanks and Carriers have at best a tertiary role. Thus it begs the question of what the good Generals want to do with all these people.

Thus when one listens to these Generals we need only ask; how much does it costs, what do we risk as a loss, and how are we dealing with our real enemies? The simple answer is that in no case do we need to draft 22 million people. Thus to paraphrase McArthur, “Generals should just fade away” and “keep quiet”.

---

[1]http://factfinder2.census.gov/faces/tableservices/jsf/pages/productview.xhtml?pid=DEC_10_SF2_SF2DP1&prodType=table

Academics and Clean Offices

Frances Woolley again raises a compelling academic issue, clean offices. As she opens her post with the morally provoking dictum:

It happens at universities across the country. Professors do it. Administrative staff do it. Some sneak onto campus on evenings or weekends, and quietly do it when no one is around. Others are bold enough to do it during regular office hours. I'm talking about cleaning. Dusting. Vacuuming. Sweeping. And, for the truly bold: Painting. Unblocking drains. Retrieving and repairing discarded furniture.  

Now the above little guy was as close to a cleaner of my office at MIT that I could remember. Got him a beaker, do not worry, I released him in the park down the street.  But back in the 60s at MIT my office was in Building 20, the old Radiation Lab buildings from WW II. Wooden, loaded with asbestos, riddled with mice, and I do not think anyone cleaned anything anytime. My desk and chairs were left over from WW II as well, undoubtedly having some historic value. The green leather cover with grey handles and legs and a grey linoleum top metal desk, and if one placed their lunch in the drawers the fellow above or his relatives would find it before lunch and take their share.

The walls were unpainted since 1944 and the windows in Winter were as windy as the Grand Canyon in January. Snow would blow in and accumulate on the ledges and the pigeons would on a sunny day sit there and make a racket when one was trying to assist some student.

But the building had character, or at least that is what we told ourselves, how lucky and honored we were to have been housed in such an historic site. I only later found it to be in error, there just was no room in the building with the AC in the summer time.

So as usual with Frances, you are not alone in having the burden of self reliance, but perhaps you have not yet had the opportunity to meet my many friends shown above. Remember, things can only get worse!

Eat Your Broccoli!

In a recent paper by Traka et al the authors state:

These findings suggest that consuming broccoli interacts with GSTM1 genotype to result in complex changes to signalling pathways associated with inflammation and carcinogenesis in the prostate. We propose that these changes may be mediated through the chemical interaction of isothiocyanates with signalling peptides in the plasma. This study provides, for the first time, experimental evidence obtained in humans to support observational studies that diets rich in cruciferous vegetables may reduce the risk of prostate cancer and other chronic disease.

As NCBI states:

Cytosolic and membrane-bound forms of glutathione S-transferase are encoded by two distinct supergene families. At present, eight distinct classes of the soluble cytoplasmic mammalian glutathione S-transferases have been identified: alpha, kappa, mu, omega, pi, sigma, theta and zeta. This gene encodes a glutathione S-transferase that belongs to the mu class. The mu class of enzymes functions in the detoxification of electrophilic compounds, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress, by conjugation with glutathione. The genes encoding the mu class of enzymes are organized in a gene cluster on chromosome 1p13.3 and are known to be highly polymorphic. These genetic variations can change an individual's susceptibility to carcinogens and toxins as well as affect the toxicity and efficacy of certain drugs. Null mutations of this class mu gene have been linked with an increase in a number of cancers, likely due to an increased susceptibility to environmental toxins and carcinogens. 

 GSTM1 is a significant factor in many cancers, especially melanoma. They conclude:

First, we demonstrate that routine prostate needle biopsies can be used for global gene expression analyses in addition to histological assessment, and that it is possible to monitor changes in  expression with time. It is notable that men within both dietary arms of the study had significant changes in the androgen receptor pathway.

 It is possible that these changes in androgen signalling are associated with aging and independent of diets, or they may have been induced by a common component of both the broccoli-rich and pea-rich diet. 

To our knowledge there is no data on the rate of change on androgen signalling in men of this age with HGPIN. This observation suggests further study is warranted. Analysis of the rate of change of gene expression of men diagnosed with either HGPIN or localized prostate cancer through sequential biopsies may provide reliable biomarkers to measure the likelihood of both carcinogenesis and progression to aggressive cancer, and complement
histological examination of needle biopsies and measurement of plasma PSA levels. 

Secondly, stratification of global gene expression profiles by genotype has been informative, and this approach could be extended to other genes to dissect patterns of gene expression in prostate or other tissues.

 Lastly, it is conceivable that other dietary phytochemicals, such as polyphenolic derivatives, could also chemically interact with signalling peptides in the plasma, in a similar manner to the suggested mechanism of action of isothiocyanates.

This is an interesting study especially from the perspective of following the gene trail as well as understanding the detailed chemistry related to its control. We have examined HGPIN in some detail and it has been argued elsewhere that it is a necessary precursor of PCa. However we have also noted that in certain men with HGPIN, after an high density number of cores in a prostate biopsy, 24 or more, that the HGPIN regresses to the point that none can be observed on subsequent exams.

This paper may be of use not only in understanding the nature of phytogenic control but also for remission.

Reference

Traka, M., et al, Broccoli Consumption Interacts with GSTM1 to Perturb Oncogenic Signalling Pathways in the Prostate, PLOS, July 2008, Volume 3, Issue 7

NCBI, http://www.ncbi.nlm.nih.gov/gene/2944

BRAF, MEK, PI3K and Melanoma

Pathway analysis has become a significant element in developing therapeutics for various cancers. Melanoma was first attacked using the BRAF V600 mutation as a target and then the MEK change was added. However as is seen in many cancers other mutations then occur making the initial therapeutic no longer functional. The pathways for melanoma are shown below. 

In a recent paper by Villanueva et al the authors have demonstrated that a tri-partite treatment has efficacy in melanoma.

They state:

Although BRAF and MEK inhibitors have proven clinical benefits in melanoma, most patients develop resistance. We report a de novo MEK2- Q60P mutation and BRAF gain in a melanoma from a patient who progressed on the MEK inhibitor trametinib and did not respond to the BRAF inhibitor dabrafenib.

We also identified the same MEK2-Q60P mutation along with BRAF amplification in a xenograft tumor derived from a second melanoma patient resistant to the combination of dabrafenib and trametinib. Melanoma cells chronically exposed to trametinib acquired concurrent MEK2-Q60P mutation and BRAF-V600E amplification, which conferred resistance to MEK and BRAF inhibitors. The resistant cells had sustained MAPK activation and persistent phosphorylation of S6K.

A triple combination of dabrafenib, trametinib, and the PI3K/mTOR inhibitor GSK2126458 led to sustained tumor growth inhibition. Hence, concurrent genetic events that sustain MAPK signaling can underlie resistance to both BRAF and MEK inhibitors, requiring novel therapeutic strategies to overcome it.

This is an excellent example of a triple therapeutic attack on a cancer. The problem is that the malignant cells seem always to change again so in effect one must continually measure the cell and add a new element to the treatment. It would be useful if one better understood the natural evolution, if such an assumption is viable.

The authors conclude:

Combination therapy with BRAF and MEK inhibitors appears to be more effective than single-agent approaches; however, this combination could have limited activity in resistant tumors, particularly in the context of concurrent resistance mechanisms that hyperactivate the MAPK pathway. Our studies suggest that this combination is likely to be more effective if used as first-line therapy before resistance emerges. Moreover, effective therapies are sorely needed for patients who progress on BRAF/MEK inhibitors.

Targeting the MAPK pathway downstream of MEK at the level of ERK, S6K, or RSK is a potential approach to overcome resistance. We have demonstrated that a triple combination strategy using BRAF, MEK, and PI3K/mTOR inhibitors led to sustained tumor growth control, with no overt signs of toxicity. This type of strategy will need to be further refined and evaluated. Various issues that could be explored include alternative dose scheduling, drug sequencing, drug combinations comprising specific inhibitors of downstream targets, and efficacy in tumors bearing other mechanisms of BRAF- and/or MEK-inhibitor resistance or other tumor types.

Alternative combination strategies, such as the one we tested, warrant preclinical and clinical investigation as potential approaches to treat patients refractory to BRAF and MEK inhibitors.    

The opportunity exhibited by this approach is significant. However it raises several questions.

1. Is there a “natural” and predictable progression of melanoma mutations which can then be therapeutically addressed? Namely, can one anticipate future changes and perhaps deal with them early?

2. How does one know what the full complements of changes are in a single patient? We can extract part of a localized tumor and from that sample and determine but what of the cells that lodged in the brain for example. We know that cells which cross the blood brain barrier exhibit differing surface markers and these may very well be reflective of further mutations. One may then seek to target these as well, which is a significant challenge.

3. Back to the old stem cell problem, namely if there are stem cells in melanoma then do we target them and if so how do we identify them? Are the cells we target merely subservient to the stem cell which avoids being targeted?

4. Does this approach mandate a therapeutic strategy which is truly patient specific? Namely do we now genetically deal with each patient separately or are their reasonably large classes?

There are substantial issues but the results in this paper a quite significant and promising.

References 

Villaneuva, J., et al, Concurrent MEK2 Mutation and BRAF Amplification Confer Resistance to BRAF and MEK Inhibitors in Melanoma, Cell Reports 4, 1–10, September 26, 2013.  

Cancer Cell Movement through the Blood

The movement of cancer cells from the initial site of development and to distant sites is a complex problem. We have previously provided a high level model for this process but it makes significant assumptions of the movement parameters which may not necessarily be reflective of the prime biochemical processes actually involved[1]. In a recent paper by Chen et al the authors have modeled the movement from the blood stream into distant organs.

The metastatic process is a complex concatenation of loss of cell localization and cell survival and proliferation in new environments. Generally as cells mature into specific cell types they become localized to their environment, such as in melanocytes and the E cadherin binding[2]. Cells also work within their own environment via communications with the extra cellular matrices[3].

The authors state:

We demonstrate tight endothelial cell–cell junctions, basement membrane deposition and physiological values of vessel permeability. Employing our assay, we demonstrate impaired endothelial barrier function and increased extravasation efficiency with inflammatory cytokine stimulation, as well as positive correlations between the metastatic potentials of MDA-MB-231, HT-1080, MCF-10A and their extravasation capabilities. High resolution time-lapse microscopy reveals the highly dynamic nature of extravasation events, beginning with thin tumor cell protrusions across the endothelium followed by extrusion of the remainder of the cell body through the formation of small ( 1 mm) openings in the endothelial barrier which grows in size ( 8 mm) to allow for nuclear transmigration. No disruption to endothelial cell–cell junctions is discernible at 60 X, or by changes in local barrier function after completion of transmigration. Tumor transendothelial migration efficiency is significantly higher in trapped cells compared to non-trapped adhered cells, and in cell clusters versus single tumor cells.

Specifically the investigators have developed a mechanical model of the vasculature, one they can manipulate for analytical purposes, and then they demonstrate the movement of the malignant cells across the interface into a quasi-cellular environment.

As Chu states:

Now researchers at MIT have developed a microfluidic device that mimics the flow of cancer cells through a system of blood vessels. Using high-resolution time-lapse imaging, the researchers captured the moments as a cancer cell squeezes its way through a blood vessel wall into the surrounding extracellular matrix.

She continues:

As tumor cells make their way through the circulatory system, some “arrest,” or pause at a particular location, adhering to a blood vessel’s wall — the first stage of extravasation. Scientists have thought that this cell arrest occurs in one of two ways: A cell may send out sticky projections that grab onto the vessel lining, or it may be too big to pass through, literally becoming trapped within the vessel. To investigate which possibility is more likely, the researchers grew a network of tiny blood vessels from a solution of human umbilical-cord endothelial cells. They injected a solution containing vascular cells into a small microfluidic device containing a reservoir of hydrogel, along with growth factors normally present in the developing circulatory system. Within days, an intricate system of microvessels took shape, with each about one millimeter long and 10 to 100 microns in diameter — dimensions similar to the body’s small capillaries. The group then pumped tumor cells through the vascular network, using a line of breast cancer cells known to be particularly invasive. Using high-resolution confocal microscopy, the team watched as tumor cells flowed through the miniature circulatory system. They observed that the majority of cells that arrested along a vessel did so due to entrapment — that is, they simply became stuck.

The observations are unfortunately in vitro and in a constructed environment and lack much of the biochemical elements that often make up for the transport. Although this is interesting in principle it fails to substantiate all of the elements which make up an in vivo process.

Then she concludes:

In addition to observing the extravasation of single tumor cells, the group also looked at the behavior of cell clusters — two or more cancer cells that accumulate in a blood vessel. From their observations, the researchers found that almost 70 percent of cell clusters broke through a blood barrier, compared with less than 10 percent of single cells. But some cells that make it out of the circulatory system may still fail to metastasize. To see whether a cell’s ability to extravasate correlates with its metastatic potential, the group compared the efficiency of extravasation of different cancer cell lines. The lines included breast cancer cells, cells from fibrosarcoma (a cancer of the connective tissue), and a line of nonmetastatic cancer cells. Sure enough, the team observed that the most metastatic cells (fibrosarcoma cells) were also the most likely to extravasate, compared with breast cancer and nonmetastatic cells — a finding suggesting that targeting drugs to prevent extravasation may slow cancer metastasis.

The problem is that the cancer cells move in and out. There is a continual flow and at the same time they have the problem of mutating as well.

 

Observations

This is an interesting and strongly visual result. However, there are several observations:

Mutations: Cancer cells are continually mutating. Mutations results oftentimes in new surface receptors due to the changes in the internal proteins. The cell surface receptors may respond differently to the passage through such a cellular membrane. Thus this model may be reflective of itself but not of reality.                                                                                     

Localization: One of the most intriguing things about cancers is the localization of the metastases. Why, for example, do we so often see prostate cancer go to the bone, melanoma to the brain, across the blood brain barrier, and the same with so many other cancers. There is a predisposition to transfer at specific sites. How does this approach deal with such localization effects?

Stem Cells: Stem cells are a potential significant factor in understanding metastasis. One question is; do stem cells move as easily as others or more so? Or, are stem cells just active wherever they are and their products are carried through the blood stream to sites where they can continue cellular proliferation, and possibly induce a new set of stem cells there?

In and Out Flows: One of the questions one must ask when looking at cancer cells in the blood, as has been done recently, is if the cell is coming or going? Namely is the cell going from a source site, a primary, to a remote or metastatic site, or from an already metastatic site to another new one? The tagging of such cells would be important. The understanding of the genetic changes would also be of critical importance.

Biochemical Drivers: The nature of cell surface markers, receptors and the like, often dominate how the cells behaves, interacts with the ECM, and can move to the blood system and exit from it as well. We have argued that the cancer cell just flows and diffuses in the blood system and that there is no growth. That is just gross speculation but it is open to debate. Moreover the interaction of the cell with the cell way, and the localization effects of the cell way by organ specificity may be an attractive basis for organ specific metastasis. Or possibly not. But, having all these elements at play in vivo is better than in vitro.

Immune System: Then also is the impact of the immune system as the cells flow through the vessels. The cells are in a massive amount of immune system interactions, and how does this impact the cells?

These are but a few of the unanswered questions elicited by this paper. The simulation is well worth looking at the paper, but taking its results as fact is stretching it a bit too far.

References

Chen, M., et al, Mechanisms of tumor cell extravasation in an in vitro microvascular network platform, Integ Bio, 2013, http://pubs.rsc.org/en/content/pdf/article/2013/ib/c3ib40149a

Chu, J., Watching tumors burst through a blood vessel, MIT News,  http://web.mit.edu/newsoffice/2013/watching-tumors-burst-through-a-blood-vessel-0920.html

---

[1] http://www.telmarc.com/Documents/White%20Papers/93%20Cancer%20Cellular%20Dynamics.pdf

[2] http://www.telmarc.com/Documents/Books/Melanoma%20Genomics%2007.pdf

[3] http://www.telmarc.com/Documents/White%20Papers/88%20Extracellular%20Matrix%2002.pdf