Cancer Initiation: Towards a better terminology for somatically repressed antigens

Thursday, March 12, 2015

Towards a better terminology for somatically repressed antigens

To this point I have been using the term "Cancer/Testis antigens"  (CTA) to refer to genes which are behind promoters that respond to ubiquitous transcription factors, and yet are completely repressed in somatic cells. These antigens seem to have no other function than to mark stem and germ line cells ( testis, placenta), and then become cryptic ( behind methylated promoters ) essentially forever, in the life of a somatic cell.
  The exception, of course, is the abnormal somatic cell, one that has lost control of its cell cycle, has begun to loose methylation of promoters ( global hypomethylation in oncology terms ). These cryptic antigens re-emerge, and signal the immune system. We seemingly have defined an important function. So then, we look to see what current reviews [1] say about these reclusive coyotes.

Rather than go back to primary, or first observations of these repressed antigens, which I believe I have already done,  I am going to start from a relatively modern  (2011),  highly regarded ( I found it first on Google under the operative keywords ) review paper. The purpose is to demonstrate, that although extensively studied, their biological role has not been clearly stated. According to Frattaa [1].
Most of these CTA are expressed during spermatogenesis, but their function is still largely unknown. Epigenetic events, particularly DNA methylation, appear to be the primary mechanism regulating CTA expression in both normal and transformed cells, as well as in cancer stem cells. (Fratta et. al.)
While Frattaa et. al. go on to produce a comprehensive and useful article on what is known, it remains descriptive rather than insightful.
    Here it is, the promised insight. In order for a species to be immortal, germ line cells must be imortal. That is, they express telomerase ( human Telomere Reverse Transcriptase , hTERT ) because they must. If germ line cells ( sperm ) are subject to the Hayflick limit, that is a limited number of cell divisions as allowed by progressively shortening telomeres, then the species is no more. I have referred to this overall systems biology relationship between somatically repressed antigens and telomerase as the Rattlesnake Hypothesis
  The cells of the testis must be enclosed in a immunologically privileged compartment. If, the barrier of that compartment is breached, an immunological reaction occurs. This has long been observed. Once the cells germline and stem cell mission is complete, The telomerase, as well as the CTA are repressed for the length of the somatic cells life time.
   Sort of. As it turns out, many of our systems need continuous supplies of new cells to function. The blood supply is a good example. The bone marrow, or core of our bones provides the hematopoetic ( blood producing ) stem cells a place to work, that is divide. As it turns out, it appears that these osteoid ( bony ) compartments also seem to be immunologically protected from the immune system. That was in fact the point of the first post in this blog. Don't you wish you hadn't missed that one?

 So there it is, from here in our cumbersome old Cancer/Testis/Placenta/etc antigens are to be called either  somatically repressed antigens ( SRA ) or Wingspans antigens in appreciation for this explanation.

[1]  Elisabetta Frattaa, Sandra Corala,  Alessia Covrea,    Giulia Parisia,  Francesca Colizzia,    Riccardo Daniellia,     Hugues Jean Marie Nicolaya,     Luca Sigalottia, Michele Maioa,
The biology of  cancer testis antigens: Putative function, regulation and therapeutic potential
 Molecular Oncology Volume 5, Issue 2, April 2011, Pages 164–182 [Full Text]

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