Cancer Initiation: March 2017

Thursday, March 30, 2017

A wave of cancer has (again) hit the sea turtles of Florida

Introduction


   Today we go on a Spring Break trip to the Gumbo Limbo Nature Center in Boca Raton, Florida. I was pleasantly greeted by the wonderful volunteers there, but all is not well. Getting right to the point, we (I) are informed that about 70 percent of green sea turtles (Chelonia mydas ) that come into the facility arrive with varying degrees of fibropapillomatosis. As the link shows, this is the name given to cancerous growths, or tumors that arise on sea turtles. Within the facility, infected turtles are referred to as "FP" infected.

 Welcome to Gumbo Limbo Nature Center  of Boca Raton!
The  exact cause of the tumors is not yet known. The local research center in Boca Raton is Florida Atlantic University, and they have provided a report on FP as long ago as 2001 [1].  It is now regarded to be at the intersection of a few factors. One of them is a herpes virus that is specific to sea turtles [2]. Although a viral vector is known to be driving tumor growth, that is not the whole story. The virus is thought to be ancient, and like many other members of the herpes virus family, it has co-evolved with the sea turtle, so it is species specific. So then, healthy turtles have immune systems that make them resistant to this virus. On the other hand, when infected turtles are discovered and recovered, during the process of rehabilitation, they have found to be immune-suppressed.[1]. Sea turtles have a family of white blood cells that is much like humans, and cell counts of these leukocytes have found them to be below normal.. For the sake of this article, that is the definition of immune-suppressed.


 A plastic model of FP ( with cotton balls representing neoplasms )  on display

 

The Mystery


  So then, the mystery is what causes the immuno-suppression that leads to the turtles inability to defend itself from the virus? Unfortunately, there are many potential causes, and most likely, it is not a single cause but a combination or summation that may in fact be different for each turtle. Known causes of turtle stress are, abnormal weather, ( reptiles are at the mercy of the environment for their temperature regulation ), nutrient runoff, heavy metal accumulation ( mercury, lead, arsenic ) , and pesticides and herbicides.

 This is Jade. notice that there is a melon sized growth on his port stern. Jade is currently awaiting surgery

Turtles as a model system.


 We have previously discussed the interaction between environmental factors such as nutrition and exposure to toxins and the immune system. Because we have many of the same factors here, the case of the sea turtle cancer epidemic is relevant, at least in a research sense, to cancer epidemics in humans.  As a model system, the exact causes of this epidemic could probably be easily found if the proper resources were applied.  Although, the turtles are merely wild life, the lessons learned from solving this problem would be easily translatable to humans. We are really no better at addressing human cancer epidemics than we are addressing wildlife epidemics.


According to their status chart, Gumbo Limbo currently has 3 turtles that are infected with FP. Jade is labeled in the upper right hand corner.

As a close up of the key shows, red dots mean FP ( fibropapilloma ) positive


A close up view of the melon sized tumor on Jade.

 

Discussion


   The story of the green sea turtles plight is actually very relevant to issues facing humans. Viral vectors are also responsible for some  tumors in humans, and we are in most cases, reliant upon our immune systems to protect us. The study of how these causative factors interact to create cancer would ultimately help our understanding of medical issues facing humans.

 Acknowledgments


  Thanks to the volunteers at the Gumbo Limbo Nature Center for their dedication and the time they spent with me to explain their operation, and even take some close up pictures for me.  The most profoundly affected turtles are off limits to the general public.

 

References


[1]Lutz, P. L.; Cray, C.; Sposato, P. L. . Studies of the association between
immunosuppression and fibropapillomatosis within three habitats of Chelonia mydas

(Report). Southwest Fisheries Science Center. [pdf]

[2]Lackovichl et. al Association of herpesvirus with fibropapillomatosis of the green turtle Chelonia  mydas and the loggerhead turtle Caretta caretta in Florida  Diseases of Aquatic Organisms Vol. 37: 89-97, 1999 l  [pdf]


Friday, March 3, 2017

The "False Flag" hypothesis and cancer defense


Introduction

 In the field of psychological operations, or "psyops", a "false flag" operation is one in which a group of government backed  insurgent actors  mount an operation in order to trigger a larger operation in the opposite direction. It turns out, that "false flag" defenses exist in the molecular world too, and may in fact be as ancient as the origin of the species.
  We have previously discussed carbohydrates, or glycosylation in terms of cell-cell recognition, and argue that these systems of carbohydrate "flags" are in fact fossils from a very early phase in the evolution of life. The term "fossils", to my knowledge as first coined by Hal White in relation to nucleotide type co-enzymes that are involved in cellular respiration [1]. I have included a discussion on that hypothesis, that is "rna world" type stuff, because carbohydrate signalling, regulatory RNA and many other "non canonical" concepts are important to studying and understanding cancer progression.

  We have previously described the rattlesnake hypothesis as a system of cancer defense where by a number of protein cell surface antigens are epigenetically suppressed in somatic cells, but are expressed in cancerous cells. As triggering the immune system to distressed cells seems to be their only function, they are merely referred to in literature as cancer - testis antigens ( CTA ) , where the testis is the only other tissue where they are found in large quantity. Cancer and testis is quite a mouthful, so here we say Wingspans antigens.
  Here we describe yet another apparent cancer defense which we are going to call the "false flag" defense. In biology we usually think of bacterial cells as having large amounts of polysaccarides ( chains of sugar molecules ) on their surface , or cell wall. This is also called endotoxin, as it triggers a possibly deadly  ( sepsis ) reaction in humans and a few other mammals such as rabbits.
  The "false flag" hypothesis states that mammals such has humans also have the capability to place polysaccarides on their surface that "look like" pathogens, but the glycosyl-transferases, or enzymes used to construct these surface structures are epigenetically suppressed ( expression is blocked by DNA methylation )  in somatic cells. When the maintenance duplication of DNA methylation patterns fails, as in the case of a cancerous clone of cells, these glycosyl-transferases become expressed, and the resulting cell surface antigens are impacted.

The Forssman antigen in Streptococcus pneomoniae

  The Forssman antigen is a cell surface carbohydrate structure discovered and named for -- Forssman. It was originally discovered as a ABO type antigen on sheep blood cells. The genes for construction of the antigen are actually closely related to ABO blood type antigens. The genes associated with antigens like the Forssman antigens are called glycosyl-transferases, because they  encode amino acid sequences for enzymes which in turn are used to construct carbohydrates. In this sense, the term "glycosyl" refers to a sugar or carbohydrate molecule and "transferase" means "enzyme that moves or constructs". In the case of the Forssman antigen (Fs), the constructed carbohydrate is on the cell surface, or membrane.

Cancer and the Forssman Antigen 

Recently (2014), the Forssman Antigen has been reported to be expressed in ovarian cancer. [3]  The specific glycosyl transferase is known as GBTG1. In the words from Jacob[3]:
The GBGT1 gene encodes the globoside alpha-1,3-N-acetylgalactosaminyltransferase 1. This enzyme catalyzes the last step in the multi-step biosynthesis of the Forssman (Fs) antigen, a pentaglycosyl ceramide of the globo series glycosphingolipids.
Expression  and construction of Fs is interesting because it was previously known as an antigen that causes a spontaneous immunologic reaction in humans. That is, if shee form an l immunological reaction, or agglutinate.  What we presume here is that in cells of the body ( somatic cells ) the expression of GBTG1 is blocked by methylation of the appropriate promoter on the DNA. Thus, in the title to Jacob [3] we see the term "epigenetically regulated". Presumably then, when a clone of cancer cells looses control of its cell cycle, the appropriate DNA methylation is lost on successive generations of cells. The appropriate cancer biology term for this is "global hypomethylation" which translates to "everywhere not enough DNA methylation".

Streptococcus pneumoniae and bacterial defense

 The next important thing to known about Fs is that it is expressed in the cell wall of infectious bacteria, including streptococcus pneumoniae, the infectious agent associated with pneumococcal pneumonia, and meningitis. Since our blood reacts with this antigen, when our immune system is healthy, we are immune to this pathogen, it is a factor when a person becomes immuno-compromised. For the sake of providing some additional background on the immunological status of pneumococcus, I give you Gisch [4]. This is a pretty technical paper, but lets look at an operational term for the sake of our argument.
We here also describe for the first time that the terminal sugar residues in the pnLTA (Forssman disaccharide; α-D-GalpNAc-(1→3)-β-D-GalpNAc-(1→)), responsible for the cross-reactivity with -Forssman antigen antibodies, can be heterogeneous with respect to its degree of phosphorylcholine substitution in both O-6-positions.
What this is saying is that there is a carbohydrate ( disacharride ) which as a particular structure that  causes a reaction with the "anti-Forssman" components of blood, or antibodies. The purpose of this paper it to refine the exact structure of Fs.

The bigger picture

What we want to do now is to combine these two concepts from different areas of research, cancer research and  immunology/biochemistry and come up with a new concept. We see that the Forssman antigen is normally not expressed ( epigenetically repressed ) in tissues such as the ovary, but becomes expressed when that repression fails due to loss of control of the cell cycle. Thus, for the sake of this article, we say that the cancerous cells raise a "false flag". We call it a false flag because the immune system is already primed to launch a counter attack. The cancerous clone of cells looks like an invading infection of pneumococcus. Thus the cancer defense system is in a sense riding piggy back on the bacterial defense system. Its an economy. We might also guess that antibodies to the Forssman antigen would inhibit cancer. This too has been investigated. [5] .( Desselle, 2012)

Summary and Conclusion

Here we introduced the Forssman antigen as a carbohydrate cellular marker that is found in the prokaryot kingdom on streptococcus pneumoniae and found in human cancer cells as a result of loss of promoter methylation. The innate portion of the immune system contains an immunoglobin portion known as complement which is reactive with the Forssman antigen, and thus renders healthy individuals immune to streptococcus pneumoniae. The Forssman antigen was long thought to be absent or inactive in humans, but more recently has been found to be expressed on cancer cells as a result of loss of suppression by promoter methylation  ( epigenetic suppression ) .  The point here is that loss of suppression, presumably as a result of "global hypomethylation" leads to cancer cells which are reactive with the compliment component of the innate immune system, and as such, the immune system is activated against the cancer cells in what we refer to here as a "false flag" defense.

References


[1] White H.B. (1976). Coenzymes as fossils of an earlier metabolic state. Journal of Molecular Evolution,7, 101-104 [Abstract]

[2] Graf, J Glycosylaton of extra-cellular matrix proteins as fossils of an earlier metabolic state, Cancer Initiation, 2015 [here]

[3] Jacob F, Hitchins MP, Fedier A, Brennan K, Nixdorf S, Hacker NF, Ward R, Heinzelmann-Schwarz VA. Expression of GBGT1 is epigenetically regulated by DNA methylation in ovarian cancer cells. BMC Mol Biol. 2014 Oct 7;15:24. [PubMed Central]

[4]  Nicolas Gisch, Thomas Kohler, Artur J. Ulmer, Johannes Müthing,
Thomas Pribyl, Kathleen Fischer, Buko Lindner, Sven Hammerschmidt and Ulrich Zähringer
Structural Reevaluation of Streptococcus pneumoniae Lipoteichoic Acid and New
 Insights into Its Immunostimulatory Potency
May 31, 2013 The Journal of Biological Chemistry 288, 15654-15667. [JBC]


[5] Desselle A, Chaumette T, Gaugler MH, Cochonneau D, Fleurence J, Dubois N, Hulin P, Aubry J, Birkle S, Paris F. Anti-gb3 monoclonal antibody inhibits angiogenesis and tumor development. PLoS One. 2012;7(11):e45423. [PMC free article] [PubMed]