Similarly to all old and unsubstantiated hypotheses and theories, the hypothesis
about malignant tumors as a phenomenon of reproduction has passed through its own
evolutionary path. In the late seventies and early eighties of the 19th century, the views of Cohnheim (1882) were formed regarding the origin of malignant neoplasms.
According to Cohnheim (1882), malignant tumors develop either from the embryonic
tissue rests that occasionally came to be among definitive tissues of the same
histogenesis. These were not included in the process of building the normal tissues or
from embryonic residues transferred to another place which become heterotopic
objects and therefore are not involved in intratissular relations. These embryonic
residues give rise to neoplastic growth. This "embryonic theory" was tested by
inoculating embryonic cells at all stages into an adult recipient. Results of this
investigation showed that embryonic cells grew for some time and then became
mature tissues. Finally, pathologists found that the mature cells did not look the same
as the malignant cells (Cherezov, 1997).
The so-called "trophoblast thesis" is another idea about the connection between
embryonic and tumor tissue. The "trophoblast thesis" was first put forward in 1902 by
the Scottish embryologist John Beard, and rediscovered about fifty years later by the
controversial Ernst Krebs. His often-quoted statement is that "cancer is trophoblast in
spatial and temporal anomaly, hybridized with, and vascularized by, hostal or somatic
cells and in irreversible and fiercely malignant antithesis to such" (Krebs Jr. et al.,
1950; Krebs Jr, 1993). Today, the Unitarian or "trophoblast thesis" on tumors no
longer has many supporters in the scientific world but the idea has still survived.
Maybe the most persuasive evidence against the "trophoblast thesis" is, in fact, that
malignant tumors are discovered in animals like birds, reptiles and others nonmammalian
classes of vertebrates.
All the hypotheses that have been presented so far are based on the similarities
between tumors and embryonic or trophoblast cells. It is most remarkable that the
similarities are in the antigens phenotype of the cell surface, the endocrine profiles, the
production of oncofetal antigens, the insusceptibility to apoptotic signals, the influence
on the surrounding microenvironmental immune and other cells, etc. Also, the
immunological properties of the two tissues are very similar. Whether or not cancer
originated from a trophoblast, the cells and the immunological events appear to act in
a similar way (reviewed in Bubanovic, 2003a, 2003d).
A modern concept of the connection between malignant tumors and embryonic or
trophoblast tissues has been promoted by Valentin Govallo and Rigdon Lentz
separately. This applies to immunological events in tumor patients and pregnancy
(Govallo, 1983, 1996; Lentz, 1990). In the 1960s, Govallo began his exploration
through studies of parallelism between mother-placenta and host-tumor systems. As a
result of the investigation, Govallo had the idea of using a placental extract to
immunize the patient against "the fetus-like cancer". Unlike most immune therapies
that stimulate the immune system, Govallo's therapy is designed to weaken or
suppress factors within the tumor that "turn off" the normal immune responses of the
host (Govallo, 1983, 1996).
Rigdon Lentz formulated an evolutionary explanation of the similarity between
immunological events in pregnancy and tumor patients. He believed that pregnancy
and cancer are the only two biological conditions in which antigenic tissue is tolerated
by a seemingly intact immune system. Lentz (1990, 1999) suggests that an evolved
mechanism of acquired tolerance to MHC incompatible tissue necessitated by sexual
reproduction consequently provides a mechanism for the tolerance of cancer.
However, many experimental works have shown that trophoblast and cancer cells are associated with an altered expression of MHC class I molecules. Poor prognosis of
malignant disease has been documented in association with HLA loss and there may
be a higher frequency of selective loss of HLA class I specific to metastases in
comparison with the primary lesion (Geertsen et al., 1998). For example, in breast
cancer, the total class I loss was found in >50% of patients, with a further 35%
showing selective losses, whereas only 12% tumor retained full HLA class I
expression (Cabrera et al., 1996). A common reason for decreased class I expression
in mammals tumor cells is the loss of the peptide transporter gene expression (TAP),
as well as the inducible proteasome elements-2 and 7 (lmp-2 and 7). Also, trophoblast
and tumor cells can express unusual forms and numbers of MHC molecules like
HLA-G and HLA-C. These molecules may mediate inhibition of antigen-specific lysis
by cytotoxic T lymphocytes (CTL) and antigen-nonspecific lysis by NK cells (Paul et
al., 1998). For these reasons, Lentz's belief that acquired tolerance to MHC
incompatible tissue provides mechanisms for the immunotolerance of cancers cells is
not valid on the whole.
Immunosuppression is a hallmark of advanced malignancies and successful
pregnancy in humans. Over the past 40 years, many investigators have identified
soluble immunosuppressive factors in blood and trophoblast or cancer tissue in
humans and other mammals. The suppressive factors that are produced by trophoblast,
tumors, and decidual or tumor infiltrating immune cells have also been identified. The
description of immunosuppressive factors in the blood of mammals which either have
cancer or which are pregnant is significant, for only in pregnancy and cancer does a
seemingly normal immune system tolerate proliferative tissues. Because the similarity
between immunological events in pregnancy and malignancy is so significant, the
connection between these processes must be real. The fact that mammals are the only
vertebrates that have a placenta gives us an opportunity to compare anti-tumor
immunity in mammals and other classes of vertebrates. Detection of the anti-tumor
mechanisms in non-mammalian classes of vertebrates can be very usable in efforts to
prove the connection between pregnancy and malignancy (reviewed in Bubanovic,
2003a).
Answers to all your Biology Questions
