| Abstract |
Immunological mechanisms, ie the body's own defense systems, are central
to the defense against malignant cells as well. Cytokines are molecules
produced by the immune system that have been shown in the literature to
have an anti-proliferative effect on both normal cells and cancer cells.
Several clinical and experimental findings suggest that this is also the
case for gynecological cancer. Quite encouraging are the findings that in
certain patient cases, cancer can even be treated with molecules produced
by the immune system: cytokines.
In this thesis, which consists of five parts, I have studied a number of
commercial cytokines in human impact of gynecological cancer cell growth.
The subject of the study is ovarian, uterine trunk and ectopic cancer
cells.
As the cell prepares to divide, it begins to synthesize a new genetic
material, DNA. This dissertation research focuses on the inhibition of
cytokine-induced DNA synthesis in cancer cells, and in particular the
mechanisms by which cytokines inhibit cell proliferation. Cytokines
possible mechanisms of cell growth inhibitory concentration,
intracellularly in programmed cell death (apoptosis), and transcription
factors AP-1 (activating protein 1) and NF-kB (nuclear factor kappaB)
activation. AP-1 and NF-kappaB are proteins that, when bound to DNA,
regulate the function of genes involved in growth and development in many
cells.
The effect of cytokines on the proliferation of cancer cells was studied
with radiolabeled uridine, which, as a "building block" of DNA, applied to
the nuclei of cells the more new DNA was produced in the cell. The effect
of cell growth inhibitory cytokines on the activity of transcription
factors was investigated by so-called EMSA tests (electrophoretic mobility
shift assay). AP-1 was found to be activated in the nucleus under stem
cell culture conditions without cytokine activity in all cell lines. Its
activity was increased by some cell growth inhibitory cytokines in uterine
and ovarian cancer cells. Although a direct relationship between AP-1
activation and growth inhibitory activity cannot be demonstrated in these
tests, it is possible that AP-1 plays an important role in the regulation
of cytokine-induced growth inhibition. This interpretation is supported by
the findings in the literature on the role of AP-1 as a regulator of cell
growth.
The transcription factor NF-kappaB was also found to be continuously
activated in the nucleus in all cell lines. Binding of DNA was increased
by a cell growth inhibitory cytokine, the so-called The effect of TNF-
alpha in ovarian and vulvar cancer cells. Based on the literature,
NF-kappaB is also an important regulator of cell growth, and it is possible
that NF-kappaB is involved in the regulation of TNF-alpha-mediated
inhibition of cell division in cancer cells studied.
According to the literature, several cytokines also cause apoptosis in
malignant cells. It is typical of so-called programmed cell death that in
a dying cell, the DNA is cleaved into short fragments, which can be
detected when colored DNA fragments of different weights travel through
the gel in an electric field. In that study, spontaneous apoptosis was
observed in only one ovarian cancer cell line, which interferon gamma was
able to reduce. According to the literature, NF-kappaB is capable of
inhibiting apoptosis. This phenomenon may well explain the inability of
cell growth inhibitory cytokines to induce apoptosis in the cancer cells
studied.
Very little is known about the growth-regulating effect of cytokines,
especially in ectopic cancer. The function of transcription factors that
regulate cell growth in gynecological cancer cells has also been studied a
little in the past, and therefore this dissertation provides new
information about the biology of these cancers. The project may have
concrete clinical applications in terms of the biology of malignant cell
changes and the treatment of cancer. The role of immunological regulatory
molecules (cytokines) in support of traditional cancer therapies in
gynecological cancer, for example, may be significant in the near future.
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