Tumorigenesis: Actions to initiate the cancer state.


The Cell Recognition Factor theory of cancer maintains that detachment of a cell from its neighbors is necessary for most cancers to arise. After that, a malfunction or replenishment of the telomere, or a reversion to stem cell, is necessary to permit the growth of cancer cells. The immune system then comes into play in keeping cancer cells in check or in promoting their elimination. A daughter cell has three additional hurdles to overcome on its road to cancer. It must eliminate the threat of apoptosis; eliminate telomere degradation; and, prevent itself from ending up in an inhospitable environment away from resources.

I. Stem cell (immortal)
. a. Detach from neighbors
. b. Escape from Immune Surveillance
II. Daughter cell (specialized, mortal)
. a. Detach from neighbors
. b. Escape from Immune Surveillance
. c. Prevent Apoptosis
. d. Stop Degradation of the Telomere
. e. Prevent displacement into the environment (for example, epithelial cells
sloughing off into the GI tract)


Detachment refers to the loss of cell recognition factors (CRF's). If it remains attached, it means that the cell will continue to function in its original capacity. Detachments are usually the result of environmental factors that denature the adhesive molecules on their membranes but can result from genetic or epigenetic changes that alter the correct CRF expression for that cell type. Detachment is necessary because while the cell is attached, the genome is frozen in a particular stage-specific state. It is only through detachment that the genome is free to engage in reprogramming. Unfortunately, in an adult, the reprogramming that occurs creates a cell looking for stimuli that are no longer in play (those of the embryonic environment).

Why does a cell revert to such an early time period in development? The reason is that the adult cell is the end stage of the process, and any earlier cell type is just embryonic.

At an embryonic period, most cells are migratory and malleable; capable of taking on the characteristics of whatever adult cell type was required for that area of the developing organism that they happened to be in. However, they can only do this if the other cells in the area have not yet reached the adult stage. Once the adult specification is set, no embryonic cell has the mechanism to change into that adult cell type. The options are to die as a result of apoptosis or immune surveillance.

Apoptosis is that process which results in the death of the cell when certain conditions are right. The cell undergoing apoptosis self-destructs based on its own determination or on the orders of an immune cell. Apoptosis is not seen extensively in embryonic tissue for two reasons. First, the degradation of cells could create an environment that may interfere with development. Second, embryonic cells can easily reprogram themselves according to where they happen to be. If they lose contact with their neighbors, they can reprogram instead of self-destructing. While the embryonic state is in play, the right CRF's are available. It is only when the adult state is reached that cells could end up in a limbo state whenever they lose contact with neighbors and begin to express CRF's that are no longer expressed by any of the neighboring cells. [I developed the CRF theory based on the work of a female researcher in the '60's or '70's who took cancer cells and reverted them to normal by putting them in an embryonic environment.]

Immune Surveillance Avoidance means that immune cells are not getting close enough to the cell to initiate killing functions, or that immune cells are dysfunctional. This would partly explain the high prevalence of epithelial cell cancers. Immune cells typically respond to deeper invasions that break through the barrier imposed by epithelial cells. If an immune cell were to get too close to the exterior (or the inside of the gut), it would very likely respond with an unnecessary attack for it would very likely encounter antigens that would trigger it into action. The closer it gets to an exterior area (GI tract, alveoli, skin), the more likely it is to encounter foreign antigens. Once the embryonic state is triggered, the cells avoid attack by constantly changing antigenic expression much as is accomplished by parasites.

Telomere Degradation is that normal process that determines the number of cell divisions that a cell will undertake in its lifetime. The Telomere of a daughter cell sheds some of its substance with every division and when it has shed most or all of its components, it triggers Apoptosis. When a daughter cell does not degrade its telomere, it becomes an immortal cell like the stem cell. Full degradation brings on apoptosis but apoptosis can occur without the full degradation of the telomere.

Displacement is the physical movement of the cell into an area where it will die from lack of resources or from an attack by pathogens. Cancer will not take place unless the cell can remain within the tissues of the organism.

Much work has been done on oncogenes (tumor promoters) and mutations in tumor suppressors as causes of cancer. These theories are not incompatible with the CRF theory. It is only after the cell loses contact and activates a different part of its genome that mutated genes begin to express themselves and perhaps contribute to a more malignant cancer state. Oncogenes are merely facilitators of the embryonic state.

One must be aware that the cause of cancer is the reactivation of the embryonic genomic program and that, I believe, begins with loss of contact. Why should loss of contact result in such changes? Mechanically, it has been shown that permeating the cell are actin fibers that span--like the spokes of a wheel--from each contact point on the cell membrane across the cell to the nucleus--the hub--and on to other contact points on the other side of the cell. When cells lose contact, these fibers probably lose tension. The loss of tension may be a simple mechanism that starts the process of genomic reprogramming by loosening the physical constraints on the nucleus.

As I've pointed out, the cell that loses contact with its neighbors will seek to re-establish contact in the only way open to it--it will start to express other CRF's that it once used in it's development from embryonic cell to adult. Because detachment is almost always necessary for the cancer state, it would seem appropriate to re-connect the cancer cell with the CRF it is seeking. These CRF's may take the form of adhesive (adherans/cadherins*) molecules but they may also be receptors looking for environmental clues. If you've seen videos of very early embryonic cell movements, you become very aware that the choreography that takes place shows very little physical contact between cells. It has been frequently demonstrated that cells react positively or negatively to chemical gradients. If we can produce these chemical attractants in quantity, we can direct metastatic cells to an area where their development can be further directed or where they can be corralled into a kind of killing zone. Also, as it is possible to put cancer cells in an embryo and have them revert to normalcy, why not put embryo or just embryonic CRF's into a cancerous mass? I envision having nano technology producing inert cell-like structures on which CRF's could be placed. These would be infused into an organism where they would attach to cancer cells in order to complete their development. Plastic beads coated with certain substances are already being used to activate neuronal repair.

I would like to re-iterate the evidence for this theory. I will limit my comments to those aspects that relate to CRF's.

The cancers that are most prevalent are those where the cells are exposed to noxious elements: bacteria in the gut, tar in the lungs, UV light on the skin, viruses in the genital areas. These elements may break or denature the CRF's. Brain cells are protected from the environment by a special barrier lacking in other tissues.

Cancers that are rare have extensive CRF's (neurons or circulating white blood cells--the latter use CRF's to tell friend from foe). When brain cancer does occur, it is the supportive cells that turn cancerous, not the neurons.

Bone cancers, where the cells are under additional physical constraints, are not as prone to cancer as epithelial cells. I believe bone is mostly a metastatic site and not a primary site but I may be wrong.

Cells undergoing high replication rates are more prone to cancer than those with lower rates. Cells that are rapidly duplicating (epithelial, blood cell progenitors) expose their CRF's to greater danger from environmental agents.

Agents that constantly break apart cells (and their connections) are known to cause cancers like mesothelioma. The pancreas produces enzymes that could conceivably attack it's own CRF's.

Cancer is a disease of older people because their cells have had more opportunity to be subjected to noxious elements like tobacco tars and UV damage that degrade the CRF's.

Ebryonic Stem Cells were recently shown to immunize mice against colon cancer. The immunity may have come about from any number of molecules that cancer cells and embryonic cells have in common and that are different from normal adult cells. I think the main antigens are the CRF's that cancer cells have in common with those of the embryo. An interesting finding was that IPSC's or artificially produced pluripotential cells did not elicit an immune response. At present, I have no explanation for this other than to say that IPSC's appear not to be the exact equivalent of embryonic stem cells; at least, with regard to the antigenic molecules expressed on their cell membranes or released extracellularly.

Many more factors play a role in the development of the various cancers but the common denominator--the grand initiator--is the loss of self-identity that occurs when a cell loses contact with its neighbors.


*It is interesting to note that adhesive molecules are kept in the lock position with calcium--take away the calcium and the molecules unlock. It is calcium that is recommended in the prevention of cancer of the GI tract.

In a recent op-ed piece in the NY Times, James D. Watson makes several statements on cancer that need to be addressed by this writer.

First, he states that cancer can be beat because we now know the genetics and chemistry of the cancer cell. In line with what I have written so far, the present knowledge on cancer genetics will not lead to a cure. We need to know the steps that the epithelial cells go through from from embryonic stem cells to differentiated cells. Only this will enable us to recreate the embryonic milieu that the cancer cell seeks.

He goes on to say that, "We shall soon know all the genetic changes that underlie the major cancers that plague us." This knowledge will not help us unless it includes CRF's or those cell surface factors that guide cells to their next station in the fully developed organism. [I know I promised to look into possible contenders for these molecules but after reading the only molecular chemistry literature that I could get my hands on, I see only the cadherins/adherins as possible candidates. Although these are indeed promising, I have to reserve judgement until I have more data.]

He talks about targeting a cancer cell's glucose metabolism but a cancer cell is for the most part a normal embryonic cell living at the wrong time (in the adult) and any attacks against it will result in damage to normal adult cells. There are only two ways of curing cancer that I think have any possibility of mass success. The clean way is to reprogram the cell's genome through CRF's expressed on the cell membrane or through other epigenetic means. The dirty way is to target with antibodies all cell surface molecules that are uniquely expressed by cancer cells. This, alone, or in combination with cytotoxic molecules might work.

If there is any chemistry to be done, let it be to characterize the cell surface in its entire tissue/stage specificities and figure out a way to mimic the CRF's of neighboring "cell." I would find a way to create artificial surrogate cells using nanotech.

One final comment I take issue with is his suggestion to President Obama that he must "choose strong new leadership for the [National Cancer] institute from among our nation's best cancer researchers." The best cancer researchers will not get us anywhere unless they pay heed to developmental biology. He also recommends "a seasoned developer of new pharmaceuticals who can radically speed up the pace. . ." He should first suggest a reasonable target for these hypothetical drugs and Big Pharm will take care of the rest but that's if you still believe in the shotgun approach. I don't, not for cancer anyway.

Researchers are still trying to use embryonic stem cells (ES) to cure disease and continue to encounter tumor formation. A recent study did something along the right lines when it co-transplanted bone marrow stem cells (BMSC)along with ES. There were no tumors formed during the 5 weeks of the study. To me, this indicates that the BMSC had started to revert back to ES and these provided the CRF's required by the original ES to prevent them from forming tumors.

What needs to be done is to search for CRF's in embryonic tissues. The main difficulty here is which of the hundreds of molecules on the cell surface are CRF's. I am working on trying to identify candidates for this role. One that caught my eye was the SSEA or stage-specific embryonic antigen because this theory requires that there be stage specificity. A candidate that I focused on back in the 70's when I first came up with the CRF theory were the glycoconjugates simply because they play a role in such phenomena as apoptosis and migration, and there are so many of them but I need to see them characterized as stage-specific.

To recap, these are the requirements for CRF's: stage-specificity, involvement in cell adhesion, involved in a mechanism to reprogram the genome, long-term stability or efficient turnover mechanisms. A problem I've recently grappled with is the possibility that there might exist a one to many arrangement between the CRF and the particular stage of differentiation. It is conceivable that differentiation via CRF's could take place using a minimal number of embryonic and adult CRF's. I think of the four-color map theorem wherein it was proven that no matter how many countries (tissues) to have, only four colors (CRF's) are needed. Of course, because tissues are three dimensional, you would definitely need more than four colors (6?)

With regard to the reprogramming, molecular proof of a genetic mechanism that could support CRF's was recently reported at esciencenews.com on 5/12/08. They wrote that global genetic silencing occurs at the moment of differentiation. Also, the genome remains flexible right up until the end stages. They used microarrays to show genomic expression. I was not able to ascertain exactly how active genes were differentiated from inactive but I assume that some chemical modification of the chromosomes is at play. Once we identify the chemical species of the CRF molecules, we would probably use microarrays to chart the CRF's at each stage of differentiation. Then with the program on hand, we can play gene operator and supply the cancer with the needed CRF's. Initially, we would probably opt to create a ubiquitous adult cell type like connective tissue or capillary cell. The same technology could also be used to ensure that ES or adult stem cells end up as intended in the patient.

How would you go about reprogramming cancer cells back to normalcy? You would first identify the most likely candidate(s) for Cell Recognition Factor(s) and determine how they change during the development of, let's say, a pancreatic cell. From the time of the first egg mass to mature adult cell, what CRF's were being expressed?

Take these and chemically attach them to a carrier that is able to diffuse through tissue. Inject the complex into the blood or lymphatic system. Repeat the cocktail until normalcy is achieved. Once we know the exact sequence that particular CRF's are expressed, we can just inject stage-specific CRF's in a particular sequence.

A difficulty that I'm hoping does not present itself is that of individual variations in CRF's. We may not want to have to design a sequence on an individual basis. It would be much better, at least initially, if one sequence for differentiation of pancreas cells was the same for all individuals.

Essential elements of this theory:

A. With the exception of lymphocytes, cells should not have the capability of existing anywhere in an organism.
B. Apoptosis or Killer cell is activated to eliminate "foreigners" that attempt to exist in an inappropriate location.
C. Cells that lose contact begin expressing earlier CRF's. This encourages Killer Cell targeting. If not killed, cells begin other reprogramming activity.
D. Once a CRF is expressed that is "early" enough, the cell begins acting like early embryo cells and exibit migratory (metastatic) behavior.
E. If the cell is supplied with early CRF's, it could be reprogrammed into a differentiated state.


Note: Cancer cells do communicate which each other but because they are embryonic, they continually seek CFR's that are not there. Even at the most primitive stages, the cancer cell is expecting other signals that are not being provided. Perhaps the womb had CRF's. If I were searching for CRF candidates to use in cancer, I would start with that very earliest of environments.

I'd like to address an issue which is not that well-resolved in my mind. That is, do cancer cells arise from any cell of the body or only from stem cells? I believe that differentiated cells are subject to the Hayflick limit and, as such, will self-destruct (apoptosis) if they are unable to establish contact with the pre-assigned cell neighbors. But stem cells have built-in immortality. (I wish I had a subscription or access to journals so that I can cite the literature for every point I make. Unfortunately, I have to rely on the media to bring me news of new developments) That immortality may be checked by what are called Natural Killer Cells but if a stem cell should lose contact and start to reprogram it's phenotypic expression before NKC's have had a chance to stop them, they will begin to express one CRF after another and thereby avoid detection just like a parasite would do.

Perhaps a little graphics is in order. You are a cell. You reach out with molecules similar to antibodies (I believe) in order to establish contact with your neighbor. You do not make contact and then there is a decision process that's activated. If, after waiting a preordained time, you do not make contact, begin to express some other antibody and check for contact. Now, the exact queue of CRF's that's used by a cell undergoing redevelopment is not known. I believe it may be advantage for the cell to exhibit CRF's that are near its immediate pedigree or near those cells that, earlier in development, had expressed CRF's that were still of the general tissue type in question. "Going back in time" repeats so that at some point, if you express, let's say, an extra early embryonic progenitor to the adult liver cell, you may find yourself no longer expressing liver cells but, rather, an earlier developmental branch that eventually would express mesadermal tissue from an early embryo or blastocyst, even. Trophoblastic cells that differentiated into the placenta seem to express CRF's and other characteristics found in many cancer cells. Indeed, the trophoblast has been called parasitic by some--metastatic by others.

When we figure out the exact program that's executed by the normal developing cell, we would be very close to a cancer cure because we could direct any cell into behaving like the cell that would be least injurious to the patient. For example, if we knew the pathway or programming sequence that the cancerous genome was undergoing , we would be able to provide that cell with the right CRF's that would cause it to develop into something relatively innocuous like connective tissue.

If the cancer is very far progressed, we might then have one cure for all as the necessary clues to take a cell from, let's say, a trophoblast to connective tissue would be the same. Well, here's where I think the promise might be delayed.

The reason is this: for the longest time, we have had to defend against parasites. You can't blame the parasite for it only recognizes the host as a suitable environment in which to live. Now, the parasite is a wily creature indeed. That means that we have to be one step ahead.

Let's imagine what would happen if we only expressed a single unique CRF for any given tissue and everyone else on the planet expressed the same one. In such a scenario, a parasite would have it easy because it need only express that one CRF that would disguise it as a liver cell, let's say. It could then live out the rest of it's lowly existence in someone's liver. To prevent this from happening, the host would, I think, establish a mechanism whereby it's liver CRF was different from that of most other people. If such a case proves to be correct, as I think it will, you can see how the total repertoire of CRF's might be a bit complex. I don't think that an maximum variability is in play but, if it were, I would not be surprised. I just think that to evade parasite you would only need a certain amount under the maximum.

I've addressed this elsewhere, but why is it that a cell needs to know where it is. Why does a stem cell need to know that it just gave rise to a liver daughter cell and that it--the stem cell--still is in the liver? I would submit that a homogeneous arrangement of differentiated cells is much better than a haphazard heterogeneous collection. But why? Well, form follows function for one. A bone cell in the lungs is not conducive to good lung function. Neurons in the blood stream would surely clog things up--you get the idea. In a slightly different vein, you would not want a gastric cell in the brain producing hydrochloric acid or a pancreatic cell in the heart producing digestive enzymes. You would not want skin cells populating the cornea with their light-absorbing melanin. The list goes on for every cell of the body. But what of development? Here again, extremely important, because you do not want your brain any further south than your palate. Every developing cell needs to know where it is in order to produce the final design. Chemotaxic agents play a role but only to establish broad patterns of migration.

This article was recently published in PLOS. This is a great scientific publishing medium that doesn't charge anyone a cent to read their stuff, unlike Science and Nature and the others that hoard their publications at the expense of humanity.

Anyway, the article points out that a boy being treated with stem cells for a rare genetic condition developed tumors of the brain and spinal cord.

These results should come as no surprise for readers of this blog. The cells injected into the nerve tissues were allografts--they were obtained from a source other than the patients own tissues. These clearly will not be at home in another person's body and they will begin to express embryonic Cell Recognition Factors in the hope that they could establish communication.

As we have learned here, a cell must know exactly where it is. Such communication must exist. If it does not, it would mean that A) any manner of invader could easily make its home in another multicellular organism, or B) any tissue of the body could establish a colony at a different tissue or organ. We would have, for instance, lung tissue setting up shop in the brain. Of course, there are mechanisms that prevent many of these migrations (immune surveillance, self-destruct mechanisms) but even with a relatively healthy immune system, a cell that has begun to express different CRF's may escape detection using, unwittingly, the escape mechanisms used by many parasites.

The factors that cause this re-programming of the genome include mutations caused by chemicals or radiation, chronic chemical exposure that alter CRF's, and retroviruses that alter CRF expression.

Please see the first blog entry for a more thorough explanation.

A researcher has found a way to show embryonic development in great detail. He has movies that show hordes of disconnected cells moving to opposite poles of the early embryo. This mass migration shows that cells react to chemical agents that diffuse throughout the tissues and it runs counter to what I've been saying about CRF's.

It should be noted, however, that early on cells need to reproduce rapidly and take positions that are not too specific. This is done so that many tissues can start their development simultaneously. You will still see mass migrations occuring after the formation of the three germ layers but you will also start to see more and more cohesive behavior.