Tumor progression in melanocytic lesions : biological and diagnostic implications
Author: Kanter-Lewensohn, Lena
Date: 1999-06-15
Location: Föreläsningssalen, Radiumhemmet
Time: 13.00
Department: Institutionen för onkologi-patologi / Department of Oncology-Pathology
Abstract
Cutaneous malignant melanoma has an annual incidence of 5% in Sweden,
with about 1500 cases diagnosed yearly. In routine histopathology there
are diagnostic difficulties in the analysis of pigmented lesions. In
spite of useful generalizations and criteria for the diagnosis of
pigmented lesions, there are clinical as well as histological
difficulties. To distinguish melanoma from Spitz nevi proliferation was
assessed using antibodies against Ki-67 (MIB-1) and the anti-apoptotic
protein BcI-2. My results clearly show that benign and dysplastic nevi in
contrast to malignant lesions have a low proliferation. The majority
(96%) of the mm expressed Ki-67 as well as Bcl-2, while this was only
seen in 6% of the Spitz nevi.
IGF-1R is required for the establishment and maintenance of the
transformed phenotype and is also important as an anti-apoptotic
regulator in melanoma cells. By Western blotting and binding analysis I
could confirm IGF-1R expression in 4 several melanoma cell lines. Two
ways of blocking the IGF-1R function were used. For the translocation of
the receptor to the cell surface N-linked glycosylation is essential.
Cell growth arrest and cell death were induced by the N-linked
glycosylation blocker Tunicamycin. A similar effect was obtained by the
[alpha]IR-3 antibody, which blocks the binding domain of IGF-1R. These
treatments resulted in apoptosis. Primary melanoma tissues and tissues
from melanoma metastases, obtained from lymph nodes of patients with
advanced mm, were also found to express the IGF-1R. However, none of
benign nevi used for comparison stained positive. I also noted that there
was an inverse correlation between the expression of IGF-1R. and the
frequency of apoptotic cells, which suggest that IGF-1R. has also an
anti-apoptotic effect in vivo.
Cdk inhibitors may be important in controlling cellular proliferation. To
evaluate other possible mechanisms in IGF-1R. dependent control of
proliferation, the influence of p27 Kip1 and its related cyclins were of
interest as my analyses have revealed an inverse relation between p27
Kip1 and expression of IGF-1R. in melanoma cells. Both Tunicamycin and
[alpha]IR-3 caused substantial redistribution of p27 from cyclin DI to
cyclin E and cyclin A. These effects may underlie the growth-inhibitory
and apoptotic; effect of inhibition of IGF-1R. in melanoma cells.
Previous clinical studies have indicated that the estrogen receptor
blocker, Tamoxifen (TAM) has some favorable effects on the clinical
outcome of mm. There is support from studies on breast cancer that TAM
interferes with the IGF- 1 pathway by increasing the release of
insulin-like growth factor binding proteins (IGFBPs). I showed that TAM
induced cytotoxicity in several nun cell lines, which did not express ER.
I could, however, confirm that TAM did not affect the IGFBPs. Instead, it
seems that TAM inhibits autophosphorylation of the [beta]-subunit of the
IGF- 1 receptor.
This may indicate the role of TAM as an inhibitor of tyrosine kinases and
a potential therapeutical approach for advanced mm.
Issue date: 1999-05-25
Publication year: 1999
ISBN: 91-628-3623-4
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