All classes of vertebrates are susceptible to malignant tumors, but the incidence of
the tumors in non-mammalian classes is significantly lower than in mammals. Effron
et al. (1977) studied the rates of neoplasia in wild vertebrates such as mammals, birds,
reptiles and amphibians. Neoplasia was present at necropsy in 2.75% of 3,127
mammals, 1.89% of 5,957 birds, 2.19% of 1,233 reptiles and 0% in 198 necropsies of
amphibians (Effron
et al., 1977). The most frequent malignant tumors in birds and
reptiles are virus-induced sarcoma. However, the most frequent malignant tumors in
mammals are cancers with different etiology (Effron
et al., 1977; Schumberger, 1948).
Laurens (1997) found that spontaneous tumors may develop in inbred and isogeneic
strains of Xenopus laevis, the South African clawed frog, although they are extremely
rare in wild type populations of all amphibians. Cartilaginous fishes such as sharks and
their relatives, have no propensity for malignant tumors, while bonefishes show a little
higher incidence of malignant tumors than sharks (Harshbarger, 1976). We can
conclude from this that our hypothesis about the ascending incidence of malignant tumors on vertebrate evolution scale is plausible. There are several possible factors for
low incidence of malignant tumors in non-mammalian vertebrates as compared to
mammals:
1) The expression of class I and class II molecules, the tissue distribution of the
molecules and the level of polymorphism of class I and class II genes in non-mammals
and mammals are substantially different. In non-mammals, class II genes are more
polymorphic in relation to class I, while class I genes are highly polymorphic in
mammal genome. Tissue distribution of class II molecules in mammals is restricted on
APCs, dendritic cells and B lymphocytes, while non-mammals show the phenomenon
of poor restricted or unrestricted tissue distribution of the molecules (Hughes and Nei,
1993; Lawlor et al., 1990).
2) In all non-mammalian classes of vertebrates class I and class II genes are
intermingled throughout the genome, but lmp and TAP genes are highly evolutionarily
conserved within the class I region. In mammals, class I and class II genes are
clustered on the same chromosome (except equine), but lmp and TAP genes are
conserved within the class II region (Kasahara et al., 1996, 1997; Kaufman and
Wallny, 1996).
3) The transcription of the class II/lmp/TAP genes in mammals is controlled by
the same signals. The absence of class II genes transcription signals down-regulate
antigens processing/presenting machinery and Th1 cells communication with other
cells of the immune system (Chaux et al., 1996; Paul et al., 1998). In non-mammals,
the antigen processing machinery is under the control of class I genes transcription,
because class I/lmp/TAP genes are closely connected on the same chromosomal loci
(Kasahara et al., 1996, 1997; Kaufman and Wallny, 1996).
4) Anti-tumor immunity in non-mammalian vertebrates (except birds)
predominantly depends on the innate immune system, while anti-tumor immunity in
mammals depends on the innate and adoptive immune systems and their
communication (Robert and Cohen, 1999).
5) Specificity in expression and tissue distribution of MHC, lmp and TAP genes
transcription control, as well as communication between native and adoptive immunity
in non-mammalian vertebrates qualifies a substantially different cytokine network
from that in mammals.
6) Malignant cells in fishes, amphibians, reptiles and birds are more susceptible to
apoptosis than mammalian malignant cells (Laurens, 1997).
7) High resistance against carcinogen induced genetic changes is evident in some
experiments with lower vertebrates, leading to a conclusion that DNA from lower
vertebrates shows a high level of resistance to cancerogenesis (Laurens, 1997;
Harshbarger, 1976).
8) The complex and efficient mechanisms of immune reaction control developed
under the evolutionary pressure of high polymorphism of class I genes, autoimmunity
and reproductive effectiveness can be included in mechanisms of anti-tumor immunity
failure in mammals.
9) The mammalian extended cytokine network can be activated/deactivated by the
same or similar factors under different conditions such as pregnancy and malignancy.
A small number of cytokines and a poor cytokine network are characteristics of nonmammalian
vertebrates. For example, cytokines such as IL-10 and TGF-β are unknown in fishes and amphibians, but TGF-β is evident in reptiles and birds
(Paulesu, 1997; Reboul et al., 1999).
10)Th-like cells are detected in reptiles and amphibians (Wei et al., 2001), as well
as Th and/or Th1-like cells in birds (Vandaveer et al., 2001). Mammals though are the
only vertebrates that have an advanced system of immune reaction control based on
Th1 and Th2 cells, and their balanced activity. The absence or fractional presence of
the Th2 model of immune reaction control probably contributes to strong anti-tumor
immunity in non-mammalian vertebrates.
11)The mammalian immune system may be tolerant to cancer cells because they
are very similar to trophoblast cells (reviewed in Bubanovic, 2003a).
12)Sex hormones, steroids and other factors, which are attributes of pregnancy and
malignant processes, can impair the blood-thymus barrier. It could be another
mechanism of acquired thymic tolerance to foreign molecules in pregnancy and
malignancy (Reviewed in Bubanovic, 2003b, c and d).
13)The absence of MHC and costimulatory molecule expression, prostaglandine,
Th2 cytokines, sex hormones, steroids and other factors could be promoters of
extrathymic lymphocytes maturation in antigen-protective manner in mammalians. It
is yet another of the mechanisms that are included in trophoblast and tumor escape
(reviewed in Bubanovic, 2003a, b, c and d).
14)Unlike mammals, the mechanisms of immune reaction control in nonmammalian
vertebrates are essentially independent from the important role of costimulatory
molecules. Actually, co-stimulatory molecules such as CD40, CD80,
CD86 and OX40 were not detected in non-mammalian vertebrates, except CD80 and
CD86-like molecules in birds (O'Regan et al., 1999).
If the mechanisms of anti-tumor immunity in mammals are similar or the same as
the mechanisms of immunoregulation in pregnancy, then mechanisms of anti-tumor
immunity in non-mammalian vertebrates may be very useful in designing new
immunotherapeutic procedures. The model of the cytokine network in non-mammalian
anti-tumor immune response can be useful in modelling the mammalian response.
Furthermore, the model of communication between native and adoptive immune cells
in non-mammalian vertebrates, can also be useful in modelling anti-tumor
immunotherapy in mammals. Non-mammalian cytokines or some other factors might
be a good adjuvant for the current anti-tumor vaccination procedures. Finally,
trophoblast or embryonic cells or their antigens can be used for anti-tumor
immunization. Taking into consideration the fact that anti-tumor immunity failure in
mammals is an immunoreproductive phenomenon could open many new possibilities
for immunotherapy of malignant diseases (reviewed in Bubanovic, 2003a).
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