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GENE EXPRESSION IN NORMAL AND TUMOR THYROID CELLS AND TISSUES
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Carine Maenhaut
Institute of Interdisciplinary Research (IRIBHM), School of Medicine, Free University of Brussels, Campus Erasme, 808 Route de Lennik, 1070 Brussels, Belgium
Jacques E. Dumont
Institute of Interdisciplinary Research (IRIBHM), School of Medicine, Free University of Brussels, Campus Erasme, 808 Route de Lennik, 1070 Brussels, Belgium
Vincent Detours
Institute of Interdisciplinary Research (IRIBHM), School of Medicine, Free University of Brussels, Campus Erasme, 808 Route de Lennik, 1070 Brussels, Belgium
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Editorial 2009
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Dr Maenhaut was the recipient of the Harington-de Visscher Prize at the ETA Meeting 2008.
The Authors declare no conflict of interest related to this work.
Correspondence:
Carine Maenhaut
IRIBHM, Free University of Brussels
Campus Erasme, 808 Route de Lennik
1070 Brussels - Belgium
Phone: +32 2 555 41 37 ; Fax: +32 2 555 46 55
email : cmaenhau@ulb.ac.be
ABSTRACT
Thyroid carcinoma is the most frequent endocrine malignancy. Since a few years, we have defined
in molecular terms the pathways involved in the control of proliferation of normal thyroid cells and
in the perversion of this process in thyroid tumors. We have used the microarray technology to
characterize the fundamental biology of thyroid tumors, to better understand their physiopathology
and to classify them according to their molecular phenotype. We have analyzed hyperfunctioning
autonomous adenomas and papillary thyroid carcinomas and in vitro model systems: human
thyroid cells in primary culture and human thyroid cancer cell lines. Prolonged in vitro stimulation of
the cAMP or the MAPK pathway in normal thyrocytes in primary culture shows a convergence of
gene expression with chronic results of mutagenic events in the corresponding in vivo tumors,
respectively the autonomous adenoma and the papillary carcinoma. Analysis of gene expression in
the primary cultured thyrocytes shows an induction of multiple specific negative feedback proteins
for the cAMP and for the growth factor pathways. Some of these feedbacks do not operate in the
corresponding tumors, suggesting that they constitute pathway-specific tumor suppressor genes.
We also show that thyroid tumor cell lines, often used as models to investigate tumorigenesis,
have evolved into a common, dedifferentiated phenotype. These results raise the very general point that cancer cell lines represent the outcome of an adaptation and evolution in vitro, and
therefore that their use as such as models for human tumors should be considered with caution.
Introduction
Tumors originating from thyroid follicular cells are the most frequent endocrine tumors and
comprise a spectrum of well defined phenotypes with variable rates of growth, differentiation and
biological aggressiveness (1-3). The major ones are the autonomously hyperfunctioning and cold
follicular adenomas, both benign encapsulated tumors, and the malignant carcinomas. These can
be further subdivided in follicular or papillary carcinomas, still partly differentiated, both of which
may evolve in anaplastic carcinoma, totally dedifferentiated. Thyroid carcinogenesis is considered
as a very interesting multi-step process where normal epithelial follicular cells evolve through a
more and more dedifferentiated and aggressive phenotype. The coexistence of the different tumor
types results from the perversion of different mitogenic cascades: constitutive activation of the TSH
receptor/cAMP cascade causes hyperfunctional tumors (4), whereas oncogenic activation of
growth factor pathways (RET/PTC rearrangements, B-Raf mutations) is associated with less
differentiated thyroid papillary carcinomas (5,6). A causal effect of environment has been
demonstrated: irradiation is the cause of “post-Chernobyl” thyroid papillary carcinomas, and iodine
deficiency increases the relative proportion of follicular vs papillary carcinomas (7). While the
differentiated papillary and follicular carcinomas have a relatively good prognosis and can be
treated with I131, the derived, very aggressive, anaplastic carcinomas are generally lethal within six
months and do not respond to any therapy (chemotherapy, I131) (8).
A major public health problem of thyroid tumors is the high frequency of tumors (nodules)
discovered by ultrasound (up to 40 % of the population above the age of 50 years) of which only
5% are cancers (9). Even with modern technologies, such as fine needle aspirate histological
analysis, 20 to 25% of these nodules appear suspect and many therefore are operated, three out
of four unnecessarily. There is thus a need to develop fully reliable diagnostic tools to avoid many unnecessary surgical interventions or dangerous delays, and reliable drugs to treat anaplastic
carcinomas.
Since a few years, we have defined in molecular terms the pathways involved in the control of
proliferation of normal thyroid cells and in the perversion of this process in thyroid tumors. In this
review, we concentrate on the work of our group and do not attempt to review the whole literature
on the subject.
Gene expression in normal thyroid cells
We have first studied normal dog thyroid cells by differential screening: a thyroid cDNA library was
prepared from a methimazole and propylthiouracil treated dog and differentially screened with
probes derived from control or stimulated thyroids. This allowed us to identify 3 new proteins:
C5fw, a novel phosphoprotein, C3vs, and p76RBE (rhophilin 2), a novel activated RhoB binding
protein (10,11). The latter could play a key role between RhoB and potential downstream elements
needed under stimulation of the thyrotropin/cAMP pathway in thyrocytes and responsible for
intracellular motile phenomena such as the endocytosis involved in the thyroid secretory process
(12). Rhophilin 2-deficient mice were generated and their thyroid structure and function analyzed.
Their phenotype was normal, suggesting that rhophilin 2 does not play a unique role in thyroid
physiology (13).
In a second approach, we used filter macroarrays to investigate genes induced by the TSH/cAMP
dependent pathway in dog thyroid cells. The major and most interesting gene was ID3 transcription
factor, identified as an early response protein, downregulated in papillary thyroid carcinomas, and
thus a tumor marker for these carcinomas (14).
The cDNA-AFLP technique is a third approach which allowed us to identify differentially expressed
transcripts in thyrotropin stimulated dog thyroid cells, among which 5 clones encoding known
proteins: thrombospondine-1, TNFR1, RhoE, RalB, and annexin A2. These regulations provide molecular counterparts of in vivo physiological effects of TSH: angiogenesis (decreased
thrombospondin-1), decreased apoptosis (decreased TNFR1) and actin filament disruption,
macropinocytosis and thyroid hormone secretion (decreased RhoE) (15).
Gene expression in thyroid tumors and their in vitro experimental models
New technologies to probe the global gene expression profiles of normal and cancer tissues, such
as microarrays, have recently reached widespread use. Microarray analysis can be used to classify
tumors according to their molecular signatures, and also to indicate the presence of previously
unidentified molecular subtypes. It may also provide invaluable information on the underlying
biology, disease progression, resistance to treatment, and may help identify novel potential drug
targets or individualized therapeutic approaches. We have implemented the biochemical and
bioinformatical tools for this methodology (16,17), in order to define gene expression profiles in
different thyroid tumors and in their in vitro experimental models.
Hyperfunctioning autonomous adenomas
Autonomous thyroid adenomas are monoclonal encapsulated benign tumors that grow, metabolize
iodide, and secrete thyroid hormones independently of the normal thyrotropin (TSH) control
(18,19). They result from the constitutive activation of the TSH/cAMP-dependent mitogenic
cascade, largely through mutations in the TSH receptor (50 to 80%) or in Gsα (8%) (20-24), and
are thus a well-defined example of the results of long-term stimulation by the physiological
TSH/cAMP-dependent pathway. We have defined gene expression profiles of these tumors, and
our data show that several physiological and morphological characteristics of these adenomas can
be explained by their transcriptional program. In particular, our results show 1) a change in the cell
populations of the tumor with a marked decrease in lymphocytes and blood cells and an increase
in endothelial cells. The latter increase would correspond to the establishment of a close relation
between thyrocytes and endothelial cells and is related to increased N-cadherin expression; 2) an
homogeneity of tumor samples, correlating with the clonality of these lesions and their common physiopathological mechanism: the constitutive activation of the TSH/cAMP cascade; 3) a low
proportion of regulated genes consistent with the concept of a minimal deviation tumor: the cells
are intrinsically stimulated, but their functional behavior is normal ; 4) a higher expression of genes
coding for specific functional proteins, consistent with the functional hyperactivity of the tumors; 5)
an increase of phosphodiesterases gene expression which explains the almost normal cAMP
levels measured in these tumors; 6) an overexpression of antiapoptotic genes and
underexpression of proapoptotic genes compatible with their low apoptosis rate; 7) an
overexpression of N-cadherin and downregulation of caveolins which casts doubt about the use of
these expressions as markers for malignancy (25).
Papillary thyroid carcinomas
Thyroid cancers have been the main medical consequence of the Chernobyl accident (26). On the
basis of their pathological features and of the fact that a large proportion of them demonstrate
RET/PTC translocations, these cancers are considered as similar to classical sporadic papillary
carcinomas. We analyzed gene expression in post-Chernobyl cancers, sporadic papillary
carcinomas and autonomous adenomas and showed that, while hyperfunctioning autonomous
adenomas and papillary carcinomas are easily distinguishable on the basis of their gene
expression patterns, post-Chernobyl, radiation-induced, papillary carcinomas have the same
molecular phenotype as sporadic papillary cancers (27). Increasing the number of samples and of
genes analyzed by microarray confirmed that post-Chernobyl and sporadic PTC have similar
overall expression profiles. They both represent the same disease (Figure 1). However, further
studies have shown that subtle expression differences are exploitable to accurately classify these
tumors according to their origin. Part of these expression differences includes genes involved in
the differential response to H2O2 and radiation, and genes involved in homologous recombination.
So, although sporadic and radio-induced PTCs represent the same disease, they are
distinguishable with molecular signatures reflecting specific responses to γ-radiation and H2O2 .
These signatures could reflect the susceptibility profiles of the patients (28).
Figure 1: Global expression profiles of post-Chernobyl and sporadic papillary thyroid cancers. A) hierarchical
clustering on the basis of all genes. B) Multidimensional scaling on the basis of all genes. Post-Chernobyl
tumors are in bold, sporadic tumors in italics.
These data led us subsequently to correlate the molecular phenotype of PTC with their biological
pathology. We combined our dataset with 2 other microarray studies (29,30), to produce a
platform- and study-independent list of PTC-associated genes. Analysis of this list led to several
conclusions: 1) there is a change in cell population with an increased expression of genes involved
in the immune response, reflecting lymphocyte infiltration in the tumor compared to the normal tissue; 2) the JNK pathway is activated by overexpression of its components; 3) the activation of
ERKK1/2 by genetic alterations is supplemented by activation of the EGF but not of the IGF
signaling pathway; 4) there is a downregulation of immediate early genes, as in autonomous
adenomas (25); 5) we observed an overexpression of many proteases and adhesion matrix
proteins in accordance with the important remodelling in PTC, and suggested a probable role of
S100 proteins and annexin A2 in this process; 6) numerous overexpressed genes (cadherins,
claudins, connexins, integrin subunits, proteases) favor the hypothesis of a collective migration
mode of tumor cells (31).
In vitro models of human thyroid tumors
Many differences in gene expression between normal and tumor tissues reflect differences in cell
population rather than changes in the tumor cells themselves. The true differences between normal
and tumor cells have been validated by their reproduction in primary cultures of human thyrocytes.
These cultures contain only thyrocytes and therefore thyrocyte-specific gene expression can be
studied without interference of other cell types. Thyrocytes in primary culture (32) are expected to
be better models than immortalized cell lines that are already well on the way to transformation.
In a first study, we investigated the genes that are modulated by the cAMP signaling pathway in
thyrocytes in vitro treated with their physiological stimulus TSH. These gene expressions were then
compared with the chronically stimulated autonomous adenomas. Human primary cultures of
thyrocytes were treated for different times with TSH to characterize modulations in gene
expression using microarrays. This kinetic study showed a clear difference in expression, early (1.5
and 3 hr) and late (16 to 48 hr) after the onset of TSH stimulation. This suggests a progressive
sequential process leading to a change of cell program. The gene expression profile of the longterm
stimulated cultures resembled autonomous adenomas, but not papillary carcinomas (Figure
2A). The molecular phenotype of the adenomas thus confirms the role of long-term stimulation of
the TSH-cAMP cascade in the pathology. TSH induced a striking upregulation of different
negative feedback modulators of the cAMP cascade. The induction of these proteins demonstrates a remarkable fail-safe control on the system: with these feedbacks, continuous
growth stimulation has little chance to occur. Several of these inductions were downregulated or
non-regulated in the autonomous adenoma, suggesting a loss of negative feedback control in the
tumors. These results suggest that in tumorigenesis, activation of proliferation pathways may be
complemented by suppression of multiple corresponding negative feedbacks, i.e. of specific tumor
suppressors (33). Such inactivations may thus represent a general mechanism in cancer (34).
A similar study was conducted with human thyrocytes treated for different times with epidermal
growth factor and serum (EGF/serum), which stimulate the MAPK cascade, constitutively activated
in PTC (6). Gene expression profiles were obtained by microarrays and compared to the
expression profiles of PTC. Similar to what was observed for TSH-treated thyrocytes, an evolution
from short-term to long-term EGF/serum-treated cells was found, i.e. a program change showing a
distinction between gene expression profiles of short-term and long-term EGF/serum-treated cells.
The pattern of gene expression in long-term EGF/serum stimulated thyrocytes converged to the
pattern of the in vivo PTC (Figure 2B). Overall gene expression profiles of EGF/serum-treated
thyrocytes and PTC were distinct from TSH-treated cells and autonomous adenomas but showed
an overlap in a number of immediate early genes, mostly transcription factors (35). There are thus
commonalities between the initiation steps of even divergent programs.
Thus, prolonged, but not short term, in vitro stimulation of the cAMP or the MAPK pathway in
normal thyrocytes in primary culture shows a convergence of gene expression with chronic results
of mutagenic events in the corresponding in vivo tumors, respectively the autonomous adenoma
and the papillary carcinoma. This shows the adequacy of long-term stimulations of the two
pathways in vitro to mimic to some extent the effect of a chronic stimulation in vivo.
Human thyrocytes in primary cultures present a useful alternative to the two other in vitro models
presently used: the human cancer cell lines which result from a long-term in vitro evolution from the
initial tumor (see below), and transient or permanently oncogene expressing rat cell lines which
present, in addition, the problem of species specificity (36).
Figure 2: A) Hierarchical clustering of the microarray data from five independent human primary thyroid
cultures, labeled A-E, treated with 0.3 mU/ml TSH for 1.5 (1.5hr), 3 (3hr), 16 (16hr), 24 (24hr) and 48 hours
(48hr) or with 10-5 M forskolin for 24 hours (24hr*). In addition, the expression profiles of a pool of
autonomous adenomas (AA) and of papillary tumors (PTC) are shown. Clustering was made based on
considering only differentially expressed genes in the primary thyroid cell cultures selected by SAM (q-value
<0.05). B) Hierarchical clustering of the microarray data from four independent human primary thyroid cell
cultures, labeled A–D, treated with 25 ng/ml EGF and 10% serum for 1.5, 3, 16, 24, and 48 h and of the
microarray data from the averaged papillary thyroid carcinoma (PTC) data from 16 tumors.
Tumor-derived cell lines are extensively used in cancer research as models to elucidate
mechanisms of tumorigenesis, and serve as tools for cancer treatment screenings, implying that
numerous in vivo characteristics of the tumor are still represented in vitro. During the past years, a
number of thyroid tumor cell lines from different pathologic origin have been developed. These
commonly used cell lines were derived from one follicular adenoma (KAK-1), two FTCs (FTC-133
and WRO), three PTCs (B-CPAP, KAT-10, and TPC-1), and two ATCs (8505C and KAT-4). To
investigate whether these thyroid tumor–derived cell lines are representative in vitro models, their
characteristics were investigated using microarrays, expression of differentiation markers, and
karyotyping (37). Gene expression profiling indicated that these cell lines, derived from
differentiated and undifferentiated tumor types, significantly diverged from their original tumor they
are derived from. They have evolved in vitro into similar phenotypes with gene expression profiles
closest to in vivo undifferentiated tumors (Figure 3). Accordingly, the absence of expression of
most thyrocyte-specific genes, including TSHR, NIS, TG, TPO, and ThOX2, their
nonresponsiveness to thyrotropin, as well as their large number of chromosomal abnormalities,
suggest that these cell lines have acquired characteristics of fully dedifferentiated cells. Their
differentiation status was further explored by comparing their gene expression profiles with those of
differentiated cells: human primary cultured thyrocytes treated with TSH, and autonomous
adenomas (33). We found, as might be expected, that the genes that were upregulated in the
differentiated thyrocytes and in the cell lines are more likely involved in proliferation, whereas the
genes upregulated in the primary cultured thyrocytes but downregulated in the cell lines are more
likely involved in differentiation.
Our results thus suggest that the cell lines have evolved into fully dedifferentiated cells. They
represent the outcome of an adaptation and evolution in vitro, which questions the reliability of
these cell lines as models for differentiated tumors. However, they may represent useful models for
undifferentiated cancers, and by their comparison with differentiated cells, can help to define the
genes involved in the differentiation/dedifferentiation process. The use of any cell line as a model
for a cancer therefore requires prior careful and thorough validation for the investigated property.
This work has been generalized to cancers and cancer cell lines of many other tissues (38).
Figure 3: Global gene expression multidimensional scaling of human thyroid tumor cell lines (in
italics) and a panel of PTC (in black) and ATC (in grey). Cell lines and PTCs were hybridized on inhouse–
manufactured slides. Three PTC samples (noted R), already hybridized on homemade
slides, and ATCs were hybridized on Affymetrix slides. Analysis was made based on all the genes
in common between the homemade and the Affymetrix platforms. Comparison of the same PTC
samples between the two platforms showed that their gene expression profiles were highly similar.
Thus, gene expression profiles from all samples can be compared regardless of the platform. The
arrow indicates increased proliferation and dedifferentiation.
Conclusion
Gene expression profiling is a powerful tool to analyze the complexity of cancer biology. It provides
insights into the identification of molecular pathways that may be affected by tumorigenesis and
helps to understand the physiopathology of the tumors, with potentiel therapeutic applications. It
also allows to define signatures of the tumors and to identify new diagnostic markers. We have
analyzed gene expression in human tumor tissues and in model systems, such as human thyroid
cells in primary culture, and human thyroid cancer cell lines. By generating these data, we have
contributed, together with other researchers in the field (39), towards a better understanding of
thyroid cancer biology, although still very incomplete. The combination of this technology with other high throughput techniques aimed to investigate, at RNA level, the miRome, or at DNA level, the
methylome and the genome, will further allow to fully define an integrated molecular phenotype
and genotype of thyroid tumors. |
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Address:
GENE EXPRESSION IN NORMAL AND TUMOR THYROID CELLS AND TISSUES |
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Title: Hot Thyroidology; Abbreviated key title: Hot Thyroidol.; Online ISSN: 2075-2202
Legal Note: © All rights reserved European Thyroid Association 2009
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