Br J Ophthalmol 1998;82:961-970 ( August )
Expression patterns of cyclin D1 and related proteins regulating
G1-S phase transition in uveal melanoma and retinoblastoma
S E Coupland,a
N Bechrakis,b
A Schüler,b
I Anagnostopoulos,a
M Hummel,a
N Bornfeld,b
H Steina
a Department of
Pathology, Universitätsklinikum Benjamin Franklin, Freie
Universität, Berlin, Germany, b Department of Ophthalmology,
Universitätsklinikum Benjamin Franklin, Freie Universität, Berlin,
Germany
Correspondence to: Dr S E Coupland, Institut für Pathologie, UKBF, Hindenburgdamm 30, D-12200 Berlin,
Germany.
Accepted for publication 26 February 1998
BACKGROUND/AIMS A
checkpoint mechanism in late G1, whose regulation via loss of
retinoblastoma protein (pRB) or p16, or overexpression of cyclin D1 or
cyclin dependent kinase 4 (CDK4), has been proposed to constitute a
common pathway to malignancy. The aims of this study were (a) to
compare markers of cell cycle G1-S phase transition in an intraocular
tumour with known pRB deficiency (retinoblastoma) and compare it with
one with an apparently functional pRB (uveal melanoma); (b) to
determine if one of these markers may have a role in the pathogenesis
of uveal melanoma; and (c) to determine if there is a difference in
cell cycle marker expression following treatment of uveal melanoma and retinoblastoma.
METHODS90 eyes were
enucleated from 89 patients for retinoblastoma (n=24) or for choroidal
or ciliary body melanoma (n=66). Conventional paraffin sections were
assessed for cell type and degree of differentiation. Additional slides
were investigated applying standard immunohistochemical methods with
antibodies specific for cyclin D1 protein, pRB, p53, p21, p16, BCL-2,
and MIB-1.
RESULTSCyclin D1
protein and pRB were negative in retinoblastoma using the applied
antibodies. In contrast, cyclin D1 protein expression was observed in
65% of uveal melanomas; a positive correlation between cyclin D1 cell
positivity and tumour cell type, location, growth fraction, as well as
with pRB positivity was observed. p53, p21, and p16 could be
demonstrated in both tumours. An inverse relation between p53 and
p21 expression was demonstrated in most choroidal melanomas and in some
retinoblastomas. Apart from a decrease in the growth fractions of the
tumours as determined by MIB-1, a significant difference in the
expression of G1-S phase transition markers in vital areas of uveal
melanoma and retinoblastoma following treatment with radiotherapy
and/or chemotherapy was not observed.
CONCLUSIONRetinoblastomas
and uveal melanomas, two tumours of differing pRB status, differ also
in their immunohistochemical pattern for markers of the G1-S phase
transition of the cell cycle. The results of the present study support
the concept of (a) an autoregulatory loop between pRB and cyclin D1 in
tumours with a functional pRB and the disruption of this loop in the
presence of pRB mutation, as well as (b) a checkpoint mechanism in late
G1, whose regulation via loss of p16 or pRB, or overexpression of
cyclin D1 constitutes a common pathway to malignancy. Further, the
results raise the possibility of cyclin D1 overexpression having a role
in the pathogenesis of uveal melanoma.
Keywords:
cyclin D1;
retinoblastoma
protein;
antigens;
antibodies;
bipolar cells;
uveal melanoma;
retinoblastoma
© 1998 by British Journal of Ophthalmology
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