Cancer Initiation: An emerging role for cancer/testis antigens in cancer progression and innate defences

Thursday, May 29, 2014

An emerging role for cancer/testis antigens in cancer progression and innate defences


Overview
The family of cancer/testis antigens ( CTA ) represents a class of several families of surface antigens that are expressed on the surface of cancer cells, testis cells, and only in very limited quantities, some somatic tissues. Here we propose a developmental and cancer defense function of these mostly epigenetically suppressed antigens. Cancer/testis antigens are a significant component of the Rattlesnake hypothesis ( alternatively, Wingspans rattlesnake ) model for cancer detection and immunological defense by the host organism. The emergence of CT antigens on the surface carcinogenic clones of cells is regarded by the host immune system as a warning ( rattle ) of a progression of global hypomethylation , in turn a sign that a cell cycle checkpoint has been lost and the cell (or colony)  has lost control of it's division process and is carcinogenic.
   CT antigens are currently a portion of the  "stem cell model" for carcinogenisis.[1]. It is summarized as follows( also from Costa):

Cancer stem cells were first identified in acute myeloid leukemia when surface markers were used to distinguish the stem cell population from the remaining cells with limited proliferative potential [5]. In solid tumors, cancer stem cells have been identified in breast cancer [6, 7], glioblastomas [8], lung cancer [9], ovarian cancer [4], prostate cancer [3], and epithelial gastric cancer [10]. Based on these observations, a cancer stem cell model has been proposed, and it is based on the concept that the great majority of the tumor cells have a limited proliferative potential, but a small cell population—the cancer stem cells—are able to self-renew and proliferate, maintaining the tumor cell mass. In this model, cancer is a disease of deregulated self-renewal of normal stem cells. Thus, in the cancer stem cell model, tumor recurrences and even metastases may occur due to residual cells—probably chemotherapy-resistant—that are able to expand to form secondary tumors [11]      ( Costa et. al. [1] )
The cancer stem cell model as it stands ( stood in 2006, and remains without significant change ) does not tie together loss of a checkpoint with immune system cancer defences. Costa does recognize the potential importance of CT antigens.
  To date, nearly 40 distinct CTAs have been identified based on immunogenic properties [41], expression profiles [42], and by bioinformatic methods [43]. However, little is known about their specific functions, and their functional connection with stem cell biology and cancer is widely unexplored. In this regard, it was recently reported that some CTAs such as N-RAGE, NY-ESO, MAGE-1, and SSX are expressed in human mesenchymal stem cells of the bone marrow, suggesting that CTA expression may not only be a hallmark of gametogenesis but also a stem cell marker [28] (Fig. 1).
We see the statement " little is known about their specific functions, ...", where as in fact under the  Rattlesnake hypothesis, their specific function is to tell the immune system that global hypomethylation is under way in a cell, or clone of cells, and to activate the immune system.  CTAs are a critical component of the hosts defense against cancer. They are a "dead mans switch" in case that a sells methylation "fidelity" has been lost and the cell is careening out of control.

It is also recognized that there is a significant difference between mesenchymal stem cells ( MSC) in that they do not stimulate an immune response where as cancer cells do.  It is evident then that there is some type of "fidelity" involved in normal mesenchymal cells that is lost in cancer cells.  The  following is also from Costa and describes experimental differences betwen MSCs and cancer cells with respect to interaction with cytolytic T  lymphocytes ( CTLs).
It is also possible that MSCs differ from cancer cells and escape recognition by therapeutically infused CTA-specific CTLs. This is supported by the fact that MSCs are not immunostimulatory in vitro when cultured with allogeneic lymphocytes [53, 54]. Furthermore, MSCs can escape lysis by allogeneic cytotoxic CD8+ T cells (CTLs). After transplantation of fully HLA-mismatched MSCs into an immunocompetent fetus, the cells persisted for a long term [55]. The transplanted MSCs did not induce any immune response in the child, again indicating that MSCs have immunoevasive properties



CTAs and the Germ Line Cells
  It has long been known that the cells of the testis generate an immune reaction, not only in foreign hosts, but in the hosts own immunologically environment. As such, the testes must be
compartmentalized in an immunologically privileged area. If the containment of the testicular area is broken, an immune reaction occurs, presumably mediated by cytolytic T cells. The concept of immunologic privilege is one that has been consistently overlooked, particularly given the prevalence of testicular and prostate cancer incidence. The prostate is an organ that must function in contact with cells of the testes, and as such, we might guess ( hypothesize ) that the prostate exists within the immunologically privileged area associated with the testes.

Research history
  C/T antigens were first identified by Van Der Bruggen [3]  ( Boon corresponding author ) and their first characterization noted that when expressed, they attracted the defensive and destructive attention of cytotoxic T lymphocytes( CTLs );
  The behaviorial observations are as follows in  Van Der Bruggen [3]:
 For human tumors, autologous mixed cultures of tumor cells and lymphocytes can generate CTLs that lyse tumor cells(4). These anti-tumor CTLs do not lyse targets of natural killer cells and autologous control cells such as fibroblasts or EBV-transformed B lymphocytes. However, it is difficult to evaluate to what extent the antigens recognized on human tumors by autologous CTLs are relevant for tumor rejection.
So we see that even though the property of tumor attack by CTLs , before Van Der Bruggen,  ( their reference 4 ), and families of specific signaling antigens ( CT antigens ) were identified from 1991 on, researchers have still not described their significance and roll in the larger picture of cancer defenses. That is, they have not connected the central components of the Rattlesnake Hypothesis, that is:
  •  telomerase expression status, ( repression is defense 1 - Hayflick )
  •  loss of a component of a checkpoint, and resulting
  •  progressive global hypomethylation,
  •  emergence of CT antigens as the result of progressive loss of suppression on their promoters, and promoters that are responsive to multiple ubiquitous transcription factors such as sp1
  • initiation of tumor specific immune defenses triggered by recognition of CT antigens by cytotoxic T lymphocytes
Implications for cancer therapy
  Cancer therapies that seek to stimulate and take advantage of the immune system are now, as always relegated to "alternative" therapies, or second line, prospects. We can see from the implications of Van Der Bruggen and Boon [3] [4] [5] [6] there was never really any basis for this in research. As such there is much new interest in designing therapies that stimulate and take advantage of the immune systems natural targeting ability for cancer.


The hTERT ( telomerase ) promoter
  The responsiveness of the telomerase promoter has been characterized by Zhao et. al. [7]. Like CT antigens, the expression of hTERT is suppressed in normal somatic cells by promoter hypermethylation. The promoter itself has been shown to be responsive to ( the ubiquitous ) transcription factor sp1 as described by Zhao:
We have previously cloned the hTERC promoter and in this study have identified several transcription factors that modulate the expression of hTERC. We demonstrate that NF-Y binding to the CCAAT region of the hTERC promoter is essential for promoter activity. Sp1 and the retinoblastoma protein (pRb) are activators of the hTERC promoter and Sp3 is a potent repressor. These factors appear to act in a species-specific manner.[7]
So we see that the ubiquitous promoter sp1 activates both telomerase and CT antigens, so that in both cases, expression is completely dependent upon the promoter methyation state. Thus, in the pathological case of global hypomethyation, both genes will become, at some point expressed, and presumably, the CT antigens are "warnings" or "rattles" that a clone of cells has defeated it's Hayflick limit defense, and presumably needs help from the immune system.

Therapeutic implications and applications
  Although the role of CT antigens has yet to be integrated into a "big picture" of cancer theory , their potential in relation to cancer detection ( biomarkers ), as well as implications for immune system based therapies has been recognized.[8] [11] [12].  A  logical framework for cancer defenses that actively included Cancer/Testis Antigens would therefore be of value in the therapeutic  and clinical  end of the cancer research spectrum because a logical and evidence based foundation for decision making is even more important in clinical practice than it is in education and basic research.

Conclusion
  There is a gene expression symmetry which exists between telomerase and CT antigens that is dictated by the evidence that both genes exist behind promoters that are responsive to ubiquitous transcription factors, and as such, they must be suppressed epigenetically by promoter hypermethylation in somatic cells.  Complementing this parallel expression profile, is the observation that one ( telomerase, hTERT ) is a significant danger to the host as a result of an immortalized clone of cells ( cancer ) and the other is a group of warning signals to the immune system, specifically cytolytic T cells. Underlying both these complementary functions is what has been called "global hypomethylation", or the observed progressive loss of promoter methylation occurs in a colony of cancer cells, presumably as a result of the loss of a cell cycle check point, and incomplete duplication of methylation patterns on the daughter strand of the duplicated DNA.

See Also:

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


References


[1] Costa F1, Le Blanc K, Brodin B. Concise review: cancer/testis antigens, stem cells, and cancer. Stem Cells. 2007 Mar;25(3):707-11. [PubMed] [Full Text]

[2]Yang F, Zhou X, Miao X, Zhang T, Hang X, Tie R, Liu N, Tian F, Wang F, Yuan J.
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[3] van der Bruggen P, Traversari C, Chomez P, Lurquin C, De Plaen E, Van den Eynde B, Knuth A,
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[5]Van den Eynde B, Peeters O, De Backer O, Gaugler B, Lucas S, Boon T. A new family of genes coding for an antigen recognized by autologous cytolytic T lymphocytes on a human melanoma.
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[9] Lim JH1, Kim SP, Gabrielson E, Park YB, Park JW, Kwon TK. Activation of human cancer/testis antigen gene, XAGE-1, in tumor cells is correlated with CpG island hypomethylation. Int J Cancer. 2005 Aug 20;116(2):200-6.[PubMed] [Full Text]

[10] James SR, Cedeno CD, Sharma A, Zhang W, Mohler JL, Odunsi K, Wilson EM, Karpf AR.
DNA methylation and nucleosome occupancy regulate the cancer germline antigen gene MAGEA11.  Epigenetics. 2013 Aug;8(8):849-63. [PubMed Central]

[11] Stacey S Willard and Shahriar Koochekpour  Regulators of gene expression as biomarkers for prostate cancer Am J Cancer Res. 2012; 2(6): 620–657. [PubMed Central]

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