Cancer Initiation: Description of the "Rattlesnake Hypothesis" in developmental biology and cancer defence

Sunday, May 11, 2014

Description of the "Rattlesnake Hypothesis" in developmental biology and cancer defence

doi:10.5072/FK2FT8GQ4T

The Rattlesnake Hypothesis  (RsH)  is an organizing principle which describes organization of gene expression in the developmental biology of higher organisms, and presents an underlying principle which describes natural cancer defenses.
   First must make some notes about the word "hypothesis" in the title and in the concept Rattlesnake hypothesis. In the epistemology of science, hypothesis means something close to "testable conjecture", where testable refers to a controlled laboratory study.  This is not quite what the rattlesnake hypothesis is. In science, it would be more closely related to the word theory which translates to explanation. such as in Darwins's theory of natural selection as a foundation of evolution.
 By way of note, this is not a blog that adheres to the epistemology of science. This is a blog that hopes to contribute to science education. Education has it's own epistemology which is a branch of cognitive science. In the field of cognitive science, the Rattlesnake Hypothesis is more akin to what might be called a  graphic organizer. As is often the case, this description rather awkwardly straddles the epistemologies of science and education, which is often the case in the field of science education.
  The role of the RsH in cancer defense
  We have previously described the suppression of telomerase and the concept of the Hayflick Limit in a previous post. The epigenetic suppression of telomerase can be thought of as a laboratory observable definition of the difference between what might be classified as "germ line" and "stem" cells and what might be described as "somatic" cells, where somatic means "of the body". In broad terms, germ line cells  and stem cells must be "immortal", where as somatic cells are terminally differentiated to their physiologically relative function, and have exited the cell cycle. The fate of somatic cells is presumed to be apoptosis, or programmed cell death at the end of their functional life.
 So, in general terms, two things can go wrong, stem cells can loose control of their cell cycle, and somatic cells can loose suppression of telomerase. In this sense, telomerase is one end of the "Rattlesnake", that is, it is the fangs. If a cell does not have "stem" cell markers and is expressing telomerase, it is a threat to the whole biological system. There must be a marker for the system to throw up warning signs to activate the immune system to destroy the threat. (cancer)
  The role of progressive hypomethylation in cancer progression.
Once checkpoints in the regulation of the cell cycle have been defeated, the process of DNA synthesis becomes compromised. As such, the cell enters into mitosis before the machinery of the S ( synthesis ) phase has completed duplicating DNA and copying promoter methylation markers. Incomplete promoter methylation during duplication can now be thought of as an underlying explanation of the commonly observed phenomenon of "global hypomethylation" associated with cancer stage progression. As a result of global hypomethylation, epigenetically suppressed antigens called cancer testis antigens, (C/T antigens) become expressed. C/T antigens get their name because they are (were originally ) found in two places, cancer and testes. That poses the question "What do cancer and testis have in common?" The RsH proposes an answer to the C/T question, which is that both of these undifferentiated immortal cells pose a threat to the organism since they can be carcinogenic if not properly defended.
  As a note, it has long been noted that cells of the testes (sperm) initiate an autoimmune reaction if their protective encapsulation within the body is breached. The conspicuous location of the testes may be a result of their potential danger in the case of loss of cell cycle control. Also, it is worth while to note that testicular cancer is one of the more common forms of neoplasm.
   The Rattle of the RsH
We have described telomerase as the "fangs" of the rattlesnake, now we are going to go ahead and denote C/T antigens as the "rattle" of the rattlesnake. The purpose of C/T antigens has not been previously proposed, but here we are going to go ahead and say that C/T antigens form a second line of defense against cancer after the Hayflick limit. In other words, we are going to say that if a clone of mitotic cells have breached the Hayflick limit due to loss of suppression of telomerase, global hypomethylation will begin to occur. As it progresses, somaticly suppressed C/T antigens will loose their epigenetic suppression. Since the promoters for C/T antigens are responsive to ubiquitous transcription factors, cells will express these C/T antigens, and as such, such cells will be targeted by the immune system.
Summary
 Cells that are potentially cancerous must be, in some way immortal. In about 90% of fully progressed cancers, telomerase is expressed. Likewise the immune system has always been known to target cancer cells. Here we propose that there is an "dead mans switch" in each cell such that if cancer/testes antigens are not continually suppressed at each mitotic generation, an immunological attack will be mounted against the cell. In most cases, potential neoplasms are destroyed by the immune system. In some cases, cancerous cells develop ways to suppress immunological attack, or merely overwhelm the immune system by brute force. In any case, the rattlesnake hypothesis provides an organizing principle by which each form of cancer can be further described in terms of it's mitotic and immunologic state.
  That is each clone of cells can be described, and possibly quantified in terms of it's immortality potential  ( telomerase, fangs ) , and it's immunological potential ( Cancer testis antigens, rattle ). Together they describe both  ends of the cancer rattlesnake.

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