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Endocrinology |
Laboratoire de Biopathologie Nerveuse et Musculaire (JE 2053), Institut de Biologie du Développement de Marseille, Université de la Méditerranée, Faculté de Médecine Timone, 13385 Marseille cedex 05 [L. D., W. R., D. F-B.]; Laboratoire d’Histologie et d’Embryologie Moléculaire et Institut National de la Santé et de la Recherche Médicale U433, Faculté de Médecine Lyon RTH-Laennec, 69372 Lyon cedex 08 [J. T., P. C.]; Service de l’Information Médicale, Hôpital de la Timone, 13385 Marseille cedex 05 [J. G.]; and Laboratoire de Génétique et de Physiologie du Développement, Institut de Biologie du Développement de Marseille, 13288 Marseille cedex 09 [G. R.], France
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSPSA-NCAM DetectionStatistical AnalysesRESULTSPSA-NCAM Expression in SMtTW...DISCUSSIONREFERENCES |
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In this rat transplantable pituitary tumor model, PSA-NCAM expression correlated in decreasing order with: (a) invasiveness (P < 0.0001), (b) metastases (P = 0.004), (c) ability to grow under the skin (P = 0.006), and (d) growth rate under the kidney capsule (P < 0.01), but not with hormone secretion (r = 0.207). This model, which is very similar to the human pathology, suggests that PSA-NCAM evaluation is of interest in the diagnosis of malignancy and the prognosis of human pituitary tumors. In addition, the SMtTW tumors could be instrumental in evaluating the effects of new therapeutic agents modulating PSA-NCAM expression.
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSPSA-NCAM DetectionStatistical AnalysesRESULTSPSA-NCAM Expression in SMtTW...DISCUSSIONREFERENCES |
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protein remains debatable (5
, 6)
. No mutations of the p53
suppressor gene have been found in pituitary tumors, including
carcinomas with metastases (7)
. Ras mutation has been
described in only a few carcinomas (8)
. No clear
relationship has been established between invasiveness, malignancy, and
overexpression of hypothalamic hormones, or growth factors.
On the basis of its function and expression in the brain and pituitary,
the
NCAM3
and its polysialylated isoform (PSA-NCAM) may be
of interest in the prognosis of pituitary tumors. NCAM has been
detected in the normal and tumoral pituitary (9
, 10)
. This
membrane glycoprotein of the immunoglobulin superfamily promotes
cell-cell adhesion via a homophilic binding mechanism (11
, 12)
. In mammals, NCAM is the only molecule known to bear long
polymers of 2–8-linked sialic acids
(PSA; Refs. 13
and 14
). The degree of
polysialylation correlates inversely with NCAM-mediated homophilic
binding and thus with attenuated cell-cell adhesion (15
, 16)
. NCAM is expressed in adult tissues, whereas PSA-NCAM is
only highly expressed during the development of the brain
(17)
, kidney (18)
, muscle (19)
,
and pituitary gland (20)
and is not found in mature cells.
In addition, PSA-NCAM is expressed in some aggressive neuroectodermal
tumors, such as neuroblastomas and medulloblastomas, in small cell lung
carcinomas, and in some neuroendocrine tumors (9
, 21
, 22)
.
Thus, PSA-NCAM has been considered as an oncodevelopmental antigen, and
its expression may be related to the invasive and metastatic growth
potential of tumor cells (23)
.
To determine whether PSA-NCAM is involved in the prognosis of pituitary tumors, we investigated its expression in malignant and benign pituitary tumors using a model of spontaneous transplantable tumors in the rat (SMtTW; Ref. 24 ). These tumor lineages, derived from different pituitary tumors and maintained by serial tumor grafts under the kidney capsule and skin, differ in both their growth rate and malignant behavior. They express Pit-1 (25) but differ in their GH/Prl secretion (26, 27, 28) . Their sensitivity to dopamine agonists and to the pituitary adenylate cyclase activating polypeptide varies depending on their expression of the pituitary adenylate cyclase activating polypeptide and the D2 receptor (28 , 29) . Thus, these experimental rat tumors recapitulate the features of human pituitary tumors (28) . The expression of PSA-NCAM in these lineages was studied by Western blotting and immunohistochemistry and quantified by ELISA. Intratumoral concentrations of PSA-NCAM were correlated with clinicobiological parameters, such as growth rate, invasion, metastases, and hormone secretion, and for the first time, we demonstrated a highly significant correlation between PSA-NCAM expression and malignancy in pituitary tumors.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSPSA-NCAM DetectionStatistical AnalysesRESULTSPSA-NCAM Expression in SMtTW...DISCUSSIONREFERENCES |
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Tumor Lineages.
The SMtTW lineages were generated in female inbred rats of the
Wistar/Furth strain. The main characteristics of the strain and the
graft procedure have been presented in detail (24)
.
Briefly, spontaneous primary pituitary tumors were removed by sterile
technique, cut into 2-mm3
(5 mg) pieces, and
slipped under the kidney capsule and skin of the neck. Each lineage was
maintained by serial tumor grafts. Passages are defined as the number
of subsequent transplantations under the kidney capsule. In most cases,
the time interval between two passages was 6 months (3–10 months,
depending on the tumor growth rate).
In this study, we used four different lineages of SMtTW tumors, named SMtTW2, SMtTW3, SMtTW4, and SMtTW10. The main characteristics of each tumor lineage have been established in >80 rats and described in detail (28) . Briefly, tumors of the SMtTW2 lineage show constant characteristics whatever the passage number, exclusively secrete Prl, are benign, and grow slowly. The SMtTW3 lineage secretes mainly Prl, together with a small amount of GH; all of the tumors are benign and grow quickly until the 12th passage, after which the growth rate decreases and a sublineage with a slow growth rate has been distinguished (SMtTW3' sublineage). During the first five passages, tumors of the SMtTW4 lineage are well delimited and do not invade the kidney or grow under the skin, whereas after the sixth passage, they exhibit malignant behavior; these tumors have a Prl phenotype. Finally, the SMtTW10 lineage exhibits a GH/Prl phenotype with a predominant secretion of GH, thereby inducing acromegalic features; its tumoral behavior varies from one animal to another.
Processing of Tumors.
After sacrifice, deep tumors were immediately removed, separated from
the kidney and soft tissues, measured, and weighed. A macroscopic
examination was carefully performed on each tumor. Particular attention
was paid to tumor invasion of neighboring tissues and to metastatic
nodule formation, which was observed in some cases at the upper edge of
the grafted kidney parenchyma, kidney capsule, and/or surrounding soft
tissues. The growth of the graft under the neck skin was also
evaluated. When the graft grew, the tumor was named "neck tumor" to
be differentiated from the kidney tumor. For each tumor, the following
macroscopic features previously described were recorded as present or
absent: invasion, metastases, and neck tumor. Tumors were divided into
pieces and processed for light microscopy and biochemistry. For light
microscopy, tumor fragments were routinely processed as previously
described (28)
. For biochemistry, samples were snap-frozen
in liquid nitrogen and stored at -80°C in the tumor bank until they
were required.
For each lineage, PSA-NCAM expression was studied in at least 10 tumors
taken at different passages (Table 1)
.
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PSA-NCAM Detection |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSPSA-NCAM DetectionStatistical AnalysesRESULTSPSA-NCAM Expression in SMtTW...DISCUSSIONREFERENCES |
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2–8 linked neuraminic acid
characterizing the embryonic form of NCAM (17)
; (b) A
rabbit anti-NCAM polyclonal antibody recognizing the
NH2-terminal domain, a sequence shared by all
NCAM isoforms (30)
; (c) Peroxidase-conjugated goat
antirabbit IgG purchased from Pierce (Beijerland, Netherlands); and (d)
Rabbit antimouse IgM polyclonal antibody purchased from Jackson
(Immunotech, Marseille, France).
Preparation of Protein Extracts.
Protein extracts were prepared from each of the SMtTW tumors. Embryonic
and adult rat brain and adult rat pituitary were used as controls.
Tissues were homogenized at 4°C in 5 mM Hepes (pH 7.4),
0.25 M sucrose containing 10 units/ml of aprotinin, 1
mM 2-macroglobulin, and 0.5 mM
phenylmethylsulfonyl fluoride as protease inhibitors. The homogenates
were centrifuged at 2500 g for 20 min at 4°C, then the
supernatants were centrifuged at 100,000 g for 1 h at
4°C. The pellets were collected and resuspended in 50
mM Tris, 1 mM EDTA (pH
7.4), and the protein concentration was determined using the Bradford
method with BSA as the standard. This extraction procedure allows the
total extraction of membrane-bound protein such as NCAM and its
polysialylated isoform. The protein concentration was adjusted to 10
mg/ml
ELISA.
PSA-NCAM levels were measured in all SMtTW protein extracts using a
previously described double-site ELISA test (31)
. Briefly,
anti-PSA-NCAM antibody was adsorbed onto plastic plates to allow the
immunocapture of PSA-bearing molecules. It was demonstrated that these
molecules are NCAM. The second antibody was directed against an amino
acid sequence shared by all NCAM isoforms. The standard curves were
established using human embryonic brain extracts (17–20 weeks of
gestation) known to be rich in PSA-NCAM. Using a purified sample of
PSA-NCAM, we have previously shown that 1 µg of human embryonic brain
extracts contains 600 pg of PSA-NCAM (31)
. All
measurements were performed at least twice. For each SMtTW tumor, 5
µg of total protein extract were loaded per well. The PSA-NCAM values
are expressed as µg/g. The lowest amount of PSA-NCAM detectable in
our test was 60 µg/g of total protein extract. This value was taken
as the threshold for positivity; PSA-NCAM concentrations below this
value were considered undetectable and given a value of zero in
statistical analyses (32)
.
Immunoblotting.
Immunoblotting was performed on samples from representative SMtTW
tumors and on all controls. Protein extracts were boiled for 3 min in
reducing electrophoresis buffer, then aliquots containing 20 µg of
proteins were resolved on 7% SDS-polyacrylamide gels. The proteins
were transferred at 60 V for 2 h onto nitrocellulose sheets
(Amersham, Les Ulys, France), which were then processed as previously
described for NCAM and PSA-NCAM detection (33)
.
Immunohistochemistry.
For each tumor lineage, three samples were processed for
immunohistochemistry, and serial 5-µm cryostat sections were prepared
from each sample. The first section was stained with H&E, the second
was incubated with anti-PSA monoclonal antibody, and the others were
used as controls (omission of primary antibody or use of an
irrelevant IgM). Immunoperoxidase staining was performed using the
avidin peroxidase complex (ABC Kits, Vector, Burlingame, CA), as
previously described (19)
.
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Statistical Analyses |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSPSA-NCAM DetectionStatistical AnalysesRESULTSPSA-NCAM Expression in SMtTW...DISCUSSIONREFERENCES |
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0.05 was considered as significant. All
data are given as the mean ± SE. |
RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSPSA-NCAM DetectionStatistical AnalysesRESULTSPSA-NCAM Expression in SMtTW...DISCUSSIONREFERENCES |
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SMtTW2 had the lowest growth index (0.5 ± 0.2). SMtTW3 or
SMtTW3' had, respectively, very high (6 ± 2.5) or low (1.2 ± 0.45) growth indices.
SMtTW4 and SMtTW10 both had
a high growth index (2.8 ± 0.9 and 2.3 ± 0.7, respectively; Table 1
). It is worth noting that, whatever
the lineage, tumors began to grow 3–4 months after grafting.
Invasion and Metastases.
On macroscopic examination, all tumors of the
SMtTW2 and SMtTW3 lineages
appeared ovoid and reddish, and they were soft and often hemorrhagic.
These tumors were always well delimited and easily separated from the
kidney (Fig. 1A)
. When grafted under the skin of the neck, they did not
grow.
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and sometimes other tissues, and showed metastatic
nodules. Metastases were found at the upper edge of the kidney on which
the tumor was grafted (Table 1)
. Tumors of the
SMtTW10 lineage were well delimited and did not
invade the kidney, although some were metastatic (Table 2)
. Furthermore, tumors of the SMtTW4 and
SMtTW10 lineages grew if they were grafted under
the skin of the neck. These "neck tumors" were always well
circumscribed and did not invade the skin or the muscle.
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PSA-NCAM Expression in SMtTW Tumors |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSPSA-NCAM DetectionStatistical AnalysesRESULTSPSA-NCAM Expression in SMtTW...DISCUSSIONREFERENCES |
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.
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and
the normal adult pituitary. PSA-NCAM was undetectable in the normal
pituitary and in all tumors of the SMtTW2
lineage, but was always high (410 ± 129 µg/g) in
tumors of the SMtTW4 lineage; however, levels
were lower in tumors of the fourth and fifth passages (47.5 ± 33 µg/g), although the difference did not reach statistical
significance (P = 0.08). Taking together all
tumors of the SMtTW3 lineage
(SMtTW3 and SMtTW3'),
PSA-NCAM levels were low or undetectable (mean, 63 ± 17
µg/g). Interestingly, levels were lower in the
SMtTW3' sublineage (32.1 ± 12
µg/g) than in other SMtTW3 tumors
(99.1 ± 40 µg/g; P = 0.02).
PSA-NCAM values were highly heterogeneous in
SMtTW10 tumors (150 ± 45 µg/g;
Table 2
).
PSA-NCAM levels were significantly related to the tumor lineage
(P = 0.001; Fig. 3
). Significant differences were observed between
SMtTW2 and SMtTW3
(P = 0.008), SMtTW2 and
SMtTW4 (P = 0.001),
SMtTW2 and SMtTW10
(P = 0.02), and SMtTW3
and SMtTW4 (P = 0.005).
There were no significant differences between
SMtTW3 and SMtTW10
(P = 0.5) or SMtTW4 and
SMtTW10 (P = 0.06).
|
. Tumors of the SMtTW3' sublineage
did not express PSA-NCAM, whereas SMtTW3 tumors
showed weak sparse staining (Fig. 4B)
. All tumor cells in
the SMtTW4 lineage strongly expressed PSA-NCAM on
the cell surface (Fig. 4C)
. PSA-NCAM immunoreactivity in the
SMtTW10 lineage was heterogeneous within a given
tumor, with clusters of immunoreactive cells intermingled with negative
cells (Fig. 4D)
.
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0.01). In the SMtTW4 (r = 0.29; P = 0.4) and
SMtTW10 lineages (r = 0.25; P = 0.44), PSA-NCAM values were not
related to tumor growth rate. In the SMtTW3
lineage, the correlation did not reach the threshold for statistical
significance (r = 0.52;
P = 0.06).
High PSA-NCAM levels were seen in tumors exhibiting
malignant features (Fig. 5)
.
Growing s.c. tumors were seen when PSA-NCAM levels were high
(P = 0.006). PSA-NCAM levels were strongly
correlated with invasiveness (P < 0.0001)
and metastases (P = 0.004). In contrast,
PSA-NCAM levels did not correlate with Prl secretion
(r = 0.06) or GH secretion
(r = 0.207).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSPSA-NCAM DetectionStatistical AnalysesRESULTSPSA-NCAM Expression in SMtTW...DISCUSSIONREFERENCES |
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It has been suggested that NCAM and PSA-NCAM play a role in pituitary cell differentiation. In the rat pituitary, as in other neuroectoderm-derived tissues, PSA-NCAM expression is developmentally regulated. In the anterior lobe, PSA-NCAM expression is first detected on embryonic day 15; it is normally first seen in differentiating corticotrophic cells, then extends to the whole anterior lobe. In the adult, only a few corticotrophic and somatotrophic cells are still labeled (20) . However, it is not clear whether there is a direct link between PSA-NCAM expression and secretory maturation of these cells. In our SMtTW tumor model, we demonstrated that PSA-NCAM expression did not correlate with GH and Prl secretion or with the GH/Prl cell phenotype. Thus, PSA-NCAM expression in SMtTW tumors does not reflect the state of differentiation.
Strong widespread expression of PSA-NCAM during anterior lobe development occurs when the primordium separates into cell cords, allowing infiltration of capillaries. This suggests that PSA-NCAM plays a crucial role in the histogenesis of the adenohypophyseal lobe, inducing structural modifications (20) . In the brain, the highest PSA-NCAM levels are observed during critical periods of time that coincide with cluster segregation; at these times, the presence of PSA-NCAM on cells allows them to exhibit the plastic interactions required for motility or to respond to guidance or targeting cues (34 , 35) . During invasion and metastasis, cancer progression mimics changes during development, and thus the same molecules could be involved in cancer and precursor cells (36) . However, the expression of PSA-NCAM by neoplastic cells is rather a part of a separate multistep neoplastic process than dedifferentiation. In the SMtTW tumor model for example, SMtTW4 tumor cells, which expressed PSA-NCAM, are increased in size and contained enlarge nuclei, which is not a feature of developing pituitary cells.
The tumors expressing the highest levels of PSA-NCAM (SMtTW4) invaded the kidney and surrounding tissues and metastasized, whereas the noninvasive and nonmetastatic tumors (SMtTW2 and SMtTW3) expressed NCAM, but only very low or zero levels of PSA-NCAM. A relationship between PSA-NCAM expression and invasion is in keeping with a previous study on human small cell lung carcinomas, which demonstrated that (a) PSA-NCAM modulates both calcium-dependent and calcium-independent cell-cell adhesion, and (b) a PSA-NCAM-expressing cell subline forms more colonies in semisolid media and more intracutaneous metastases in nude mice than does a PSA-NCAM-negative clone (23) . In this regard, those SMtTW tumors expressing high levels of PSA-NCAM (SMtTW4 and SMtTW10) were not only able to grow s.c. in an environment less suitable than the kidney, but could also metastasize.
The metastatic cascade is a multistep process involving the detachment of cells from the primary tumor, invasion, destruction of the basal lamina of the blood vessels, transport into the blood flow, arrest, then migration and growth at the metastatic site. It is likely that PSA-NCAM is involved in these processes by facilitating cell detachment from the primary tumor, migration, and survival in an hostile environment (34 , 35) . Indeed, PSA-NCAM, a highly hydrated and negatively charged polymer, constitutes a coat protecting the cells that express it from detrimental interactions. In this context, the SMtTW10 lineage is of special interest. Although these tumors never invaded the surrounding tissues, some shared with SMtTW4 tumors their metastatic potential and their ability to grow s.c. Thus, their classification as either benign or malignant is difficult, but the expression of PSA-NCAM should contribute to their classification as malignant. Interestingly, in contrast to SMtTW4 tumors in which all of the cells expressed PSA-NCAM, only clusters of SMtTW10 cells were immunoreactive. SMtTW10 tumors are probably polyclonal because they are composed of two populations of secreting cell (GH or Prl; Ref. 28 ), which could possibly allow the cloning of sublines differing in PSA-NCAM expression, as in the case of small cell lung carcinomas (23) .
In addition to invasion and metastasis formation, PSA-NCAM expression correlated, although to a smaller extent, with growth rate. In fact, among the SMtTW3+3' tumors, the SMtTW3' sublineage, which exhibits a slower growth rate, contained lower levels of PSA-NCAM, so it is possible that PSA-NCAM per se might act on cell proliferation. However, the data regarding the effect of PSA-NCAM on tumor growth are conflicting. PSA-NCAM facilitated proliferation in a human neuroblastoma cell line (37) , but had no effect on a human rhabdomyosarcoma cell line TE 6714 . Thus, the involvement of PSA-NCAM in controlling cell proliferation might vary depending on cell phenotypes and/or environmental conditions.
In conclusion, in transplantable rat Prl or Prl/GH tumors, NCAM polysialylation is highly correlated with malignancy and, to a lesser degree, with cell proliferation. The evaluation of PSA-NCAM expression in human pituitary tumors should be of interest. Due to the present lack of reliable pituitary tumor markers, the diagnosis of pituitary carcinoma can presently only be based on the presence of metastases. In addition, the modulation of PSA-NCAM expression on a cell may be relevant for new therapeutic options, including specific cleavage of PSA-NCAM by endoneuraminidase N (38) , immunotherapy, or control of the activity of the polysialyltransferases responsible for PSA biosynthesis (39) . The SMtTW tumor model in an immunocompetent rat is especially suitable for testing some of these new therapeutic options.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by institutional Grants JE2053,
Programme Hospitalier de Recherche Clinique (to D. F-B.), and
Association pour la Recherche Contre le Cancer (to D. F-B. and G. R.). 
2 To whom requests for reprints should be
addressed, at Laboratoire de Biopathologie Nerveuse et Musculaire
(JE2053), Faculté de Médecine de la Timone, 27 Bd Jean
Moulin, 13385 Marseille cedex 05, France. Phone: 33-04-91-32-45-88;
Fax: 33-04-38-49-77-00; E-mail: dfigarel{at}ap-hm.fr
3 The abbreviations used are: NCAM, neural cell
adhesion molecule; PSA-NCAM, polysialylated-NCAM; PSA, polysialic
acid; SMtTW, spontaneous mammotropic transplantable tumor in
Wistar-Furth rats; GH, growth hormone; Prl, prolactin.
4 L. Daniel, P. Durbec, E. Gautherot, E. Rouvier,
G. Rougon, and D. Figarella-Branger, unpublished results.
Received 7/ 8/99. Accepted 10/28/99.
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REFERENCES |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSPSA-NCAM DetectionStatistical AnalysesRESULTSPSA-NCAM Expression in SMtTW...DISCUSSIONREFERENCES |
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chain of Gs and stimulate adenylyl cyclase in human pituitary tumors. Nature (Lond.), 340: 692-696, 1989.
mutations in somatotroph adenomas. J. Clin. Endocrinol. Metab., 83: 1604-1610, 1998.
2–8 linked polysialosyl units in a neural cell adhesion molecule. Biochem. Biophys. Res. Commun., 112: 482-487, 1983.
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