| Abstract |
Although prognosis of patients with differentiated thyroid cancer is
generally favorable, undifferentiated/anaplastic thyroid cancer is one of
the most aggressive malignancies. The remarkable difference in prognosis
between two types of thyroid cancer indicates that there is a large
biological difference between them. We have been involved in the studies
for exploring new biomarkers to evaluate aggressiveness of thyroid cancer.
These markers are useful not only for predicting prognosis but also for
developing new strategies against aggressive thyroid cancer. We recently
established three different thyroid cancer cell lines, KTC-1, KTC-2 and
KTC-3. KTC-1 cells are derived from a patient with poorly differentiated
thyroid papillary carcinoma. KTC-2 cells are derived from a patient with
anaplastic transformation from papillary thyroid carcinoma. KTC-3 cells
are derived from a patient with primary anaplastic thyroid carcinoma. To
test the hypothesis that overexpression of human epidermal growth factor
receptor (HER) 1 promotes malignant progression in thyroid cancer, the
relationship among expression levels of HER1 and a cognate receptor HER2
and effects of a HER1 tyrosine kinase inhibitor, gefitinib on cell
proliferation, cytokine secretion and the expression level of one of
thyroid differentiation markers, thyroglobulin were investigated using
these three cell lines. Gefitinib inhibited in vitro growth of the thyroid
cancer cells in dose-and time-dependent manners. No significant
correlation was observed between the antitumor effect of gefitinib and
expression level of HER1 or HER2. Gefitinib significantly decreased
secretion of angiogenic cytokines, vascular endothelial growth factor
(VEGF) and interleukin (IL)-8 in KTC-2 cells. In contrast, gefitinib
significantly increased secretion of both angiogenic cytokines in KTC-3
cells. Changes in secretion of IL-6 and parathyroid hormone-related
protein (PTHrP) induced by gefitinib were also different among thyroid
cancer cell lines. Gefitinib did not significantly change the expression
level of thyroglobulin in any thyroid cancer cell lines. These findings
suggest that gefitinib is effective for the treatment of aggressive
thyroid cancer but its influences on cytokine secretion from tumor cells
are different among thyroid cancers. Thrombospondin (TSP)-1 has been
identified as an anti-angiogenic factor. We recently demonstrated that
TSP-1 expression negatively related to extrathyroidal infiltration as well as
angiogenesis in patients with papillary thyroid carcinoma. To elucidate
the relationship between expression levels of p53 and TSP-1 in thyroid
cancer, we studied their expression levels in 75 papillary thyroid
carcinomas. There was an inverse correlation between expression levels of
TSP-1 and p53. Additionally, the effects of TSP-1 and anti-TSP-1 antibody
on invasion were investigated in six thyroid cancer cell lines using the
in vitro invasion assay. Angiogenesis related factors, VEGF, VEGF-C, TSP-1
and TSP-1 receptor (CD36) were expressed at various levels in all cell
lines. Invasion tended to be inhibited by TSP-1 in five of the six cell
lines. These effects inversely related to the expression level of VEGF or
VEGF-C. The effects of anti-TSP-1 antibody on invasion differed among cell
lines. These findings indicate that TSP-1 plays a certain role in invasion
of thyroid cancer cells, and that the effects of TSP-1 and anti-TSP-1
antibody on invasion are different among thyroid cancers.
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