Thyrotropin May Not Be the Dominant Growth Factor in Benign and Malignant Thyroid Tumors1
Michael Derwahl,
Martina Broecker and
Zaki Kraiem
Department of Medicine, Division of Endocrinology, St. Willehad
Hospital (M.D.), 26382 Wilhelmshaven, Germany; University Clinic of
Internal Medicine, Ruhr-University of Bochum (M.D., M.B.), 44789
Bochum, Germany; and Endocrine Research Unit, Carmel Medical Center,
and Technion Faculty of Medicine (Z.K.), 34362 Haifa, Israel
Address all correspondence and requests for reprints to: Prof. Michael Derwahl, Klinik für Innere Medizin I, St. Willehad Hospital, Ansgaristrasse 12, 26382 Wilhelmshaven, Germany. E-mail:
derwahl.k.m.{at}dgn.de
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Introduction
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TSH, in synergistic action with insulin and/or
insulin-like growth factor I, is still regarded by many researchers to
play the major, if not the exclusive, role in the regulation of thyroid
cell growth. However, this view needs reevaluation because of recent
findings on the diversity of TSH-dependent signaling, including
coupling of the receptor to different G protein-dependent pathways,
cross-talk between different cAMP-dependent and -independent pathways,
and integration of different pathways at the nuclear level. The concept
seems to emerge that TSH may be one of many links within a complex
network of interacting signals that modulates and controls stimulation
of thyroid cell growth and function. This newly emerging concept has
altered our understanding of the pathogenesis of thyroid growth in
disease. We shall attempt to review some of these novel findings as
they relate to benign and malignant human thyroid cell growth.
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TSH and growth of diffuse nontoxic goiter
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In patients with TSH-secreting pituitary adenoma or generalized
thyroid hormone resistance, increased TSH secretion results in an
enlargement of the thyroid gland (1, 2). An increase in goiter size due
to enhanced TSH secretion may also develop in patients with Graves
disease who are overtreated with antithyroid drugs (3). Chronically
elevated, feedback-mediated TSH secretion is also considered to cause
endemic iodine deficiency goiters, although increased serum TSH levels
have not yet been directly demonstrated in this condition.
An indirect hint that points to the relevance of TSH for the regulation
of iodine deficiency goiter comes from therapeutic studies. Not only
does levothyroxine treatment of patients with iodine deficiency goiter
decrease TSH levels by directly inhibiting TSH secretion, but
administration of iodide shows the same, albeit less pronounced, effect
(4). This points to a relative increase in TSH under iodine deficiency
conditions.
At first glance, these clinical examples seem to argue in favor of the
concept that TSH is the major, if not the sole, growth factor of the
thyroid gland. However, this straightforward interpretation neglects
recent findings that point to an intricate complexity of TSH-dependent
and -independent mechanisms within a network of interacting positive
and negative signals (reviewed in Ref. 5). There is no doubt that TSH
is not only involved in the control of differentiated functions,
including expression of thyroid-specific genes and several housekeeping
genes, but that it also regulates the expression of growth factors and
their receptors (reviewed in Refs. 5, 6). This has been
demonstrated, for example, for the expression of epidermal growth
factor (EGF) receptors, which is increased by TSH stimulation (7), and
for insulin-like growth factor I (IGF-I)-dependent signaling (8).
Indeed, TSH promotes the insulin IGF-I signaling system by three
separate mechanisms: TSH enhances the expression of IGF-I messenger
ribonucleic acid (mRNA) (9) and insulin receptor mRNA (10), and
decreases protein levels of different IGF-I-binding proteins (11),
thereby probably raising the availability of free IGF-I (12). Moreover,
exposure to TSH- or cAMP-elevating agents increased the responsiveness
of thyroid cells to stimulation with insulin, IGF-I and IGF-II (10),
and EGF (7).
Accumulated evidence indicates that IGF-I-dependent, TSH-independent
signaling may be of major importance for growth regulation of the human
thyroid gland. This assumption is supported by findings in conditions
not accompanied by increased TSH secretion, such as in acromegaly, in
which high intrathyroidal IGF-I levels may contribute to goiter
development (13), and in part in patients with toxic thyroid adenomas
(see below), whose growth is most likely modulated by IGF-I (14). Thus,
on the one hand, TSH induces the expression of growth factors and their
receptors and may contribute to an increased responsiveness to growth
factor-stimulated tyrosine kinase signaling with consequent
proliferation via pathways other than the cAMP cascade. On the other
hand, as discussed below, growth factor expression may increase
proliferation regardless of the prevailing TSH levels.
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TSH and growth of thyroid nodules and adenomas
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The most striking evidence that thyroid growth may proceed without
support from elevated TSH levels, or in the presence of very low TSH,
comes from patients with nodular goiters whose TSH levels are
suppressed as a consequence of functional autonomy with increased local
production of thyroid hormones and subsequent inhibition of TSH
secretion (15). There is even an inverse relationship between serum TSH
levels and multinodular goiter size (16, 17, 18, 19). Thus, toxic nodular
goiters may function and grow in the absence of significant TSH levels.
Nevertheless, the cAMP signaling cascade may still be highly active at
least in some nodules. This assumption is supported by recent findings
of activating mutations of the cascade in a subset of toxic thyroid
adenomas and hyperfunctioning goiter nodules (20). In these tumors,
mutations in the TSH receptor or the Gs
gene have been
detected that lead to constitutive activation of the TSH
receptor-dependent adenylate cyclase cascade, thus replacing the
stimulatory effect of TSH. There is compelling evidence that these
mutations represent an initial step in the pathogenesis of some, but
not all, toxic adenomas by altering the signaling network of the
affected thyrocytes (21, 22).
These mutations alone, however, are insufficient to generate the tumors
(21). Support for this claim comes from the clinical course of a number
of thyroid diseases, including iodine deficiency goiter, Graves
disease caused by chronic TSH receptor antibody-mediated stimulation
(6, 23), autosomal dominant hyperthyroidism due to TSH receptor gene
mutations with subsequent stimulation of the entire thyroid gland (24),
and the above-mentioned examples of TSH-secreting pituitary adenomas
and thyroid hormone resistance (1, 2). In all of these thyroid
diseases, diffuse goiter develops at first, and nodular transformation
may occur only secondarily and as a late event, often taking years or
even decades (5, 6, 25). Yet, focal nodular growth cannot be explained
solely by TSH receptor gene or Gs
gene mutation, which
should in principle affect all thyrocytes to the same extent, nor can
chronic TSH stimulation per se cause heterogeneous,
i.e. multinodular, growth.
In addition, in vitro evidence argues against the assumption
that activation of the adenylate cyclase cascade is sufficient to cause
nodular transformation. In human thyrocytes held in primary culture,
expression of the Gs
gene mutant under control of a
retroviral vector did not increase the growth of transfected cells,
demonstrating that the sole stimulatory effect of this mutant is too
weak to induce cell proliferation (26). In contrast, transfected FRTL-5
cells expressing a cAMP-stimulating gene underwent neoplastic
transformation when implanted into nude mice (27). The same
investigators, however, when using transgenic mice expressing the same
cAMP-stimulating gene in the thyroid, found hyperthyroidism and thyroid
hyperplasia, but no evidence of neoplasia (28). This discrepancy may
have been due to the use of an immortalized cell line, FRTL-5, which
may have been altered by mutational events (28). Another study using
transgenic mice expressing a cAMP-stimulating gene found hyperthyroid
nodular transformation only as a late event in older animals (29).
The question therefore arises as to which secondary pathogenic
mechanisms are operative that promote cellular growth with consequent
nodule formation. As mentioned above, excessive constitutive synthesis
of IGF-I may be involved in abnormal growth, at least in toxic adenomas
(14). Furthermore, as noted above, TSH stimulates the insulin/IGF-I
signaling system. As activating mutations of the TSH receptor or
Gs
gene mimic and potentiate the effect of TSH, an
enhanced activation of the mitogenic insulin/IGF-I pathway is likely to
occur in toxic adenomas and nodules that harbor such mutations. Thus,
autonomous overactivity of TSH-dependent cascades may represent only
the first step in a sequence of other molecular events. At least in
some nodular goiters and adenomas, additional mechanisms include an
increased expression of EGF receptors (30, 31) and basic fibroblast
growth factor (32), a decreased synthesis of growth inhibitory
transforming growth factor-ß (TGF-ß) (33) and enhanced synthesis of
Ras (34) and Gs
protein (22, 35). Moreover, it has been
shown that constitutive resistance to the growth inhibitory effect of
TGF-ß may not only occur in a subset of normal thyrocytes but may
also be acquired by chronically exposed cells (36). Of particular
relevance, TGF-ß resistance is very frequent in thyrocytes derived
from human nodular goiters (36).
The rarity of toxic adenomas and nodular goiters in regions with
sufficient iodine intake points to an important pathogenetic role of
iodine deficiency in this disease. This is most likely a consequence of
subtle, chronic stimulation of TSH-dependent signaling at the level of
the TSH receptor or enhanced cAMP formation, which is decreased by the
administration of iodine (4, 21). In addition, it has been demonstrated
that different iodine compounds inhibit the signaling of
growth-promoting pathways, e.g. the EGF receptor cascade
(37). However, the physiological concentrations of the iodine compounds
at the unknown site of intracellular action remain elusive. Additional
evidence is required to determine whether the lack of such an
inhibitory effect of iodine compounds may result in a relatively higher
activity of growth-promoting pathways and thus contribute to the higher
prevalence of goiter nodules and adenomas in regions with iodine
deficiency.
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Cross-talk between TSH-dependent and -independent pathways in the
growth and function of benign nodules
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Besides the cAMP-protein kinase A (PKA) pathway, both the
phospholipase C (PLC)-protein kinase C (PKC) and the protein tyrosine
kinase cascades are implicated in the signal transduction pathways that
control human thyroid cell growth and function (38). The complexity of
the interactions of these pathways is particularly well illustrated by
experiments conducted with human thyroid follicles prepared from
colloid nodular tissue (39, 40).
The above studies lead to the following conclusions. EGF, acting via
tyrosine kinase, and activation of PKC inhibit cell function (iodide
uptake, organification, and thyroid hormone secretion) induced by the
TSH-PKA pathway. (39). The TSH-PKA cascade is mitogenic, but much less
so than the PKC and EGF-tyrosine kinase pathways, as judged by
measuring cell growth as well as human thyroid cell
proliferation-associated c-jun and c-fos gene
expression (39, 40). Because PKA inhibits the PKC and EGF-tyrosine
kinase pathways in this (39, 40) and other systems (reviewed in Refs.
41, 42), it is therefore not surprising that the net effect of
combined TSH-PKA and PKC or EGF-tyrosine kinase action regarding cell
proliferation and c-jun, c-fos gene expression
was, albeit still mitogenic, decreased rather than additive compared to
the PKC or EGF-tyrosine kinase cascades alone (39, 40). The above
results are summarized in Table 1
. The
mechanism(s) underlying the antagonistic interactions between TSH-PKA
and PKC or EGF-tyrosine kinase signaling pathways remains to be
determined. Also unknown is whether TSH at high concentration
stimulates the PKC pathway in these cells derived from colloid nodules
as has been demonstrated in normal human thyrocytes (43).
View this table:
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[in a new window]
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Table 1. Interactions of TSH-dependent and -independent
pathways in the control of growth and function of human thyrocytes
derived from benign colloid nodules (39 40 )
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There is a large body of literature dealing with the cross-talk between
Ras and PKA. In some cells, cAMP stimulates the mitogen-activated
protein kinase (MAPK) cascade, whereas in others, cAMP inhibits Ras
signaling through Raf and MAPK (reviewed in Ref. 44). In human
thyrocytes, Ras exhibits a growth stimulatory and partially oncogenic
effect (45, 46). In addition, it has been demonstrated that both Ras
and PKA activity are required for the mitogenic effect of TSH (47),
although TSH down-regulates signaling through Raf and the MAPK cascade
(48, 49). These results indicate that cAMP displays differential
effects on distinct Ras effector pathways in thyroid cells (48). Using
specific Ras mutants, Miller and co-workers recently demonstrated that
rat thyrocytes expressing Ras mutants that are competent to bind to Raf
grew more slowly in the presence than in the absence of TSH, whereas
Ras mutants that bind RalGDS, the Ras-related protein Ral, increased
their growth rate in the presence of TSH (48). These results again
support the concept that TSH-dependent cAMP synthesis is only one
player in a complex growth-regulating signal network.
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TSH-suppressive therapy for treatment of thyroid nodules
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The justification for levothyroxine (L-T4)
administration with the aim of suppressing TSH long enough so as to
decrease the size or arrest the growth of thyroid nodules has been a
highly controversial issue (reviewed in Refs. 50, 51). Most of the
current evidence seems to suggest that thyroid hormone therapy is not
effective in shrinking the majority of thyroid nodules (51).
Furthermore, the high incidence of a spontaneous decrease in nodule
size without any therapy together with the adverse skeletal and cardiac
effects associated with long term L-T4
administration has led most clinical investigators to recommend the
routine use of L-T4 only in selected patients
with thyroid nodules (reviewed in Refs. 50, 51). Indeed, in a recent
comprehensive review of the literature, Gharib and Mazzaferri concluded
that the potential risks of long term L-T4
therapy outweigh the potential benefits in most patients, especially in
postmenopausal women (52).
The clinical experience mentioned above fits in well with the concept
that TSH-dependent signaling is but one link in a complex network of
interacting signals that regulate thyroid growth. Indeed, there are
additional findings that argue against a dominant role of TSH-dependent
signaling in cold benign nodules and nodular goiters. First, it has
been demonstrated that cold thyroid nodules, in contrast to some, but
not all, toxic thyroid adenomas, do not harbor any activating mutations
in the TSH receptor (53). Second, widely varying basal and
TSH-stimulated cAMP levels have been determined in different regions
within single nodular goiters (54). Finally, in nonfunctioning
adenomas, both normal expression and overexpression of
Gs
protein have been reported (35). The clinical
evidence mentioned previously of an inverse relationship between TSH
level and multinodular goiter size is also relevant in this regard. All
of these observations lead to the conclusion that at least a fraction
of all thyroid nodules and tumors grow independently of TSH-induced
signal transduction.
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TSH and growth of thyroid carcinomas
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In some studies, TSH displayed an inhibitory influence on the
growth of thyroid carcinoma cells (55, 56). In contrast, TSH has also
been reported (57) as mitogenic (via PKC stimulation) or devoid of any
effect (58, 59, 60, 61) on the proliferation of thyroid carcinoma cells.
Regarding signal transduction mechanisms, the PKC (57) and EGF-tyrosine
kinase pathways (58, 61, 62) enhanced thyroid carcinoma cell
proliferation, although an antimitogenic effect of EGF has also been
reported (55). Many (56, 58, 59, 62, 63, 64), but not all (57), reports
have noted growth inhibition of thyroid carcinoma cells by the cAMP
pathway, and a recent study (60) indicated a ß-adrenergic receptor-
rather than TSH receptor-mediated pathway of cAMP production and
consequent inhibition of thyroid carcinoma cell proliferation. Some
studies have demonstrated the pivotal role of the PLC-PKC pathway in
the pathogenesis of some thyroid neoplasms (65), and that costimulation
of both the PLC and adenylate cyclase-cAMP pathways promotes malignant
transformation of thyroid follicular cells in transgenic mice (66).
Although our knowledge of TSH-dependent signaling in differentiated
thyroid carcinoma tissue is still fragmentary, it seems that almost all
papillary and follicular carcinomas express TSH receptor mRNA, albeit
at varying levels (67, 68). However, even if functional TSH receptors
are expressed, TSH-dependent signaling may be profoundly disrupted in
thyroid cancer. This has been demonstrated for both the TSH
receptor-Gs
protein-adenylate cyclase cascade as well as
for the TSH receptor-Gq protein-PLC pathway. In the
Gs
-adenylate cyclase cascade, a functional disruption
between the TSH receptor and Gs
(59) or between
Gs
and adenylate cyclase activity may occur (22, 35),
whereas aberrant TSH-stimulated Gq-PLC activity has been
described in thyroid cancers in vivo and in vitro
(65, 69). There is evidence that the interruption of the TSH
receptor-Gq-PLC signaling is due to high protein kinase C
activity, possibly provoked by simultaneous overactivation of growth
factor receptors, such as EGF receptors (69).
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Thyroid hormone treatment of thyroid carcinomas
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Patients with thyroid carcinomas are treated with
L-T4 for two recognized reasons: to avoid
hypothyroidism after surgical and radioiodine treatment and to suppress
alleged TSH-promoted tumor growth. There may be an additional
justification, however, for L-T4 treatment in
these patients. This is because TSH is the most important regulator of
gene expression in normal thyrocytes and presumably also in thyroid
carcinoma cells that are known to maintain, albeit at a variable
degree, expression of thyroid-specific genes (67) and expression of
other cAMP-dependent genes, e.g. the
3-hydroxy-3-methylglutaryl coenzyme A reductase gene (70). Therefore,
even if L-T4 therapy does not affect the growth
of these carcinomas, it seems advisable to maintain a TSH-suppressive
therapy, because suppression of at least some TSH-dependent gene
expression in the tumor cells may also be of benefit for the prognosis
of these tumors.
Thyroid hormone treatment has been shown, although not unanimously, to
result in fewer recurrences and a lower mortality rate (reviewed in
Ref. 71). Controversy continues, however, regarding the optimal dose of
thyroid hormone required to achieve TSH suppression, mainly because
prolonged T4 overreplacement may lead to an increased risk
of osteoporosis and adverse effects on cardiac function even in the
absence of overt hyperthyroid symptoms (reviewed in Refs. 50, 71, 72, 73).
Many investigators have suggested that for low risk thyroid cancer
patients, TSH levels should be held at or just below normal limits (50, 71, 72, 74), whereas others have recommended a high level of TSH
suppression (75).
 |
Intratumoral heterogeneity of growth mechanisms: a phenomenon
independent of TSH
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Almost all studies on thyroid cell lines, monolayer or follicle
cultures, and tissue homogenates assume that all cells of a growing
tissue proliferate homogeneously according to a similar metabolic
pattern. This assumption is most likely to be incorrect. Two points
mentioned above can serve to illustrate this claim. First, both basal
and TSH-dependent adenylate cyclase activities may vary markedly
between different samples taken from the same goiter (54). Second,
resistance to TGF-ß is also variable between cells of a given nodule
(36). Moreover, experimental evidence obtained with thyrocyte cultures
(76), as well as immunohistochemical studies on goiter nodules
(77), demonstrate that thyroid growth proceeds within small
clusters of coordinated cells that replicate by irregularly spaced
growth spurts alternating with quiescent intervals. This growth pattern
cannot solely depend on TSH, but, rather, substantiates the existence
of intercellular regulatory mechanisms.
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Integration of TSH-dependent signaling at the nuclear level and
thyroid growth
|
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The final step in the cAMP signaling cascade is very frequently
the activation of the cAMP-responsive transcription factor CREB
(cAMP-responsive element-binding protein) and CREM (cAMP-responsive
element modulator) that control transcription of cAMP-responsive genes
(78, 79). Activation of CREB and CREM occurs after phosphorylation of
serine residues located in the transcriptional activation domain (80, 81). However, activation of CREB and CREM is not restricted to
phosphorylation by the cAMP-dependent PKA, but may also be mediated by
other protein kinases, e.g. PKC, casein kinase II, or growth
factor-dependent CREB kinase (81, 82). An integration of various
signaling pathways by cAMP-responsive transcription factors may also be
effective in thyroid cells. Indeed, an enhanced phosphorylation of CREB
in response to both TSH as well as 12-O-tetraphorbol
12-myristate 13-acetate-stimulated PKC has been demonstrated in
thyroid cells (83). Further studies on the integration of various
signals by cAMP-responsive transcription factors may answer the
question as to whether in thyroid tumor cells the integration of
different pathways at the nuclear level may be altered.
To understand the role of TSH-dependent signaling at the nuclear level
in the pathogenesis of thyroid nodules and tumors, two other questions
have to be addressed. First, it is still unknown how activation of the
cAMP-dependent pathway enhances insulin receptor and EGF receptor
expression and decreases levels of IGF-binding proteins, as no
cAMP-responsive sequence motifs have been shown in the promoters of
genes that encode these genes (84, 85). One exception is the IGF-I gene
whose expression is stimulated by TSH and in which the cAMP-responsive
sequence in the promoter region of the gene has been described; this is
most likely responsible for its cAMP-dependent transcriptional
regulation (86). Second, the direct effect of cAMP on the cell
cycle-related protein, cyclin, remains to be elucidated. Indeed, cAMP
response elements have been described in the promoters of cyclin D1 and
cyclin A genes (87, 88). In addition, in FRTL-5 cells activation of the
cAMP cascade has been demonstrated to affect the cell cycle in that it
decreases p27kip-1, an inhibitor of cyclin-dependent
kinase-2 that is activated for entry into the S phase of the cell cycle
(89). However, in primary cultures of thyroid epithelial cells the
contrary was found, i.e. a paradoxical accumulation of
p27kip-1 inhibitor during the cAMP-dependent mitogenic
stimulation (90). Finally, there is evidence that other cAMP-dependent,
as yet unknown, signaling pathways that do not result in CREB
phosphorylation may contribute to the control of thyroid gene
expression and modulate thyroid growth (91).
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Conclusions
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This survey has attempted to summarize, with no claim to
comprehensiveness, some of the major strides made toward understanding
the mechanisms that link TSH-dependent and -independent human thyroid
cell growth in neoplastic thyroid disease. A major conclusion is the
demonstration that TSH is but one of many factors in pathological
thyroid growth and, even more relevant, that thyroid tumors may well
evolve in the absence of TSH stimulation. Major gaps still remain, in
particular with regard to thyroid carcinomas. Progress in this field
will probably depend on fresh methodological approaches to overcome the
limitations of sole reliance on cell lines and tissue homogenates.
These issues are of practical clinical importance to enable reaching
valid recommendations with regard to TSH-suppressive therapy using
thyroid hormone. As noted earlier, a subset of thyroid tumors grow
independently of TSH, and others are even inhibited by TSH. This
finding in addition to the adverse effects of long term T4
administration emphasize the necessity of setting proper guidelines to
answer questions such as who should be selected for TSH-suppressive
therapy with T4, for how long, and what should be the
magnitude of TSH suppression.
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Acknowledgments
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We thank Prof. Hugo Studer (Berne, Switzerland) for valuable and
helpful discussions.
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Footnotes
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1 This work was supported by the Charles Krown Research Fund
(Israel), and the Dr. Mildred Scheel Foundation for Cancer
Research (Bonn, Germany). 
Received July 27, 1998.
Revised November 12, 1998.
Accepted November 20, 1998.
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