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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 7 2143-2147
Copyright © 1997 by The Endocrine Society

Endocrinological Oncology

Suppression of Tyrosine Kinase Activity Inhibits [3H]Thymidine Uptake in Cultured Human Pituitary Tumor Cells1

T. H. Jones, S. K. Justice and A. Price

University Department of Medicine and Department of Clinical Chemistry, Northern General Hospital, Sheffield, United Kingdom

Address all correspondence and requests for reprints to: Dr. T. H. Jones, University Department of Medicine and Pharmacology, L Floor, Royal Hallamshire Hospital, Glossop Road, Sheffield, United Kingdom S10 2JF.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Tyrosine kinases are involved in the phosphorylation of proteins that regulate cell growth and proliferation. The mitogenic effect of several growth factors requires tyrosine kinase activity of their receptors. The effect of inhibition of tyrosine kinase activity on thymidine uptake into cultured human pituitary adenoma cells was studied using two inhibitors, genestein and methyl-2,3-dihydroxycinnamate (MDHC).

Of 33 pituitary adenomas, 7 incorporated sufficient [3H]thymidine to be investigated in the experiments. Genestein and MDHC both potently inhibited thymidine uptake into these tumors, with a mean inhibition by 74 µmol/L genestein of 61.96 ± 18.96% (±SD inhibition of basal), by 740 µmol/L genestein of 92.65 ± 8.59%, and by 100 µmol/L MDHC of 93.84 ± 3.85%. The 7 pituitary adenomas were all large with suprasellar extension and secreted interleukin-6 in vitro. They included 2 prolactinomas, 1 somatotropinoma, 1 mammosomatropinoma, and 3 clinically nonfunctioning adenomas. Epidermal growth factor stimulated thymidine uptake in 2 of the 3 clinically nonfunctioning adenomas studied, and this stimulation was inhibited by genestein. Both of these tumors released FSH in cell culture and are probably silent gonadotropinomas. The growth stimulatory effect of conditioned medium from human pituitary cell culture on GH3 cells was inhibited by both genestein and MDHC. We conclude that tyrosine kinase activity is crucial for the integrity and growth of pituitary adenomas in culture. Growth factors released by pituitary adenomas potentially may maintain and promote tumor growth by stimulating tyrosine kinase activity.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
TYROSINE kinases phosphorylate intracellular proteins by activating signaling systems, which, in turn, control gene expression, cell growth and proliferation, metabolism, and the integrity of the cytoskeleton (1). Tyrosine kinase activity in the cell either is associated with cell membrane receptors or is entirely cytoplasmic (1). Increased tyrosine kinase activity has been seen in several types of tumor, including breast cancer (2), squamous cell carcinoma (3), and gliomas (4). Tyrosine kinase activity is particularly associated with growth factor receptors, which include epidermal growth factor (EGF), basic fibroblast growth factor, insulin-like growth factor I, platelet-derived growth factor, insulin, and the cytokine, interleukin-6 (IL-6) (5, 6, 7). The mitogenic activity of these growth factors is dependent on the tyrosine kinase activity of their receptors (1, 5, 7, 8). The role of tyrosine kinase activity in human pituitary adenomas has not previously been investigated.

The pathogenesis of pituitary adenomas has not yet been clearly defined. The current hypothesis is that genomic mutation occurs in a single cell, which then undergoes clonal expansion (9, 10). Pituitary adenomas are monoclonal in nature (11), but genomic mutations, such as gsp and ras, have to date only been found in a comparatively small number of pituitary adenomas (12, 13). Pituitary adenomas in culture are known to secrete growth factors, and conditioned medium from the majority of tumors added to cultures of the rat pituitary cell line GH3 stimulates cell growth (14). The exact nature of these particular growth factors has not been established. Growth factors released by the tumor and/or hypothalamic factors may have a role in the promotion of tumor growth leading to clonal expansion (10, 13). Many actions of growth factors, as described above, are mediated by the activation of tyrosine kinases.

We have, therefore, investigated the role of tyrosine kinases in pituitary tumor growth by examining the effects of two tyrosine kinase inhibitors, genestein (4',5,7-trihydroxyisoflavone), a competitive inhibitor of ATP binding, and methyl-2,5-dihydroxycinnamate (MDHC), a competitive inhibitor of substrate binding, on thymidine incorporation into human pituitary adenomas. We have also studied the effect of genestein on human pituitary tumor-conditioned medium-stimulated growth of GH3 cells in culture.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Human pituitary adenomas

Pituitary adenoma tissue excised at routine surgical operations was transported to the laboratory in DMEM with HEPES (Flow Laboratories, Irvine, UK). The tissue was dispersed as previously described (15) using mechanical and enzymatic means, and the cells were plated in 24-well plates at a density of 0.5 million cells/well in Medium 199 with 10% FCS (Northumbrian Biologicals, Cramlington, UK), penicillin (100 U/mL)), streptomycin (100 U/mL), and fungizone (0.25µg/mL)(Bristol-Myers Squibb, Princeton, NJ). After 96 h, the medium was removed and stored at -20 C until assayed, then it was replaced with DMEM D-valine (Flow Laboratories), D-valine with 10% FCS, penicillin, streptomycin, and fungizone as described above for an additional 72 h to inhibit fibroblast growth. The medium was removed and replaced with test substances in DMEM and D-valine with 2% FCS containing [3H]thymidine (Amersham, Aylesbury, UK; 1 µCi/well) for 72 h. The medium was removed, and the cells were rinsed with phosphate-buffered saline. Cell proliferation was stopped by the addition of 10% trichloroacetic acid, and the cells were solubilized overnight with 250 µL NaOH (1 mol/L) added to each well. A 50-µL aliquot of the supernatant was added to 2 mL scintillant (Ultima Gold XR, Packard, Groningen, Netherlands) and counted on a scintillation counter.

GH3 cells and conditioned medium

GH3 rat pituitary tumor cells were cultured in 24-well plates at a density of 200,000 cells/well in medium 199 with 10% FCS, penicillin, streptomycin, and fungizone as described above. The medium was then removed, and the cells were washed with phosphate-buffered saline. Stored conditioned medium from each of the human pituitary adenomas was diluted 1:1 (i.e. by 50%) with medium 199 containing penicillin, streptomycin, and fungizone as described above, with no FCS. The final concentration of FCS was, therefore, 5%.

Each conditioned medium sample was then added to wells in triplicate with and without genestein (74 µmol/L). The cells were incubated for 48 h, then [3H]thymidine, to a concentration of 1 µCi/well, was added for an additional 24 h. Cell proliferation was stopped as described above for the human pituitary adenoma cells, and thymidine incorporation was assessed.

Immunocytochemistry

The tumors of each patient were immunostained by the peroxidase-antiperoxidase method using commercially available antisera, raised in the rabbit, to PRL, GH, TSH, LH, FSH, and ACTH supplied by Biogenesis (Bournemouth, UK). Endogenous peroxidase activity was blocked with hydrogen peroxide. The slides were then treated with the primary antisera, followed by swine antirabbit {gamma}-globulin and then peroxidase-antiperoxidase. The reaction was visualized using diaminobenzidine. Slides of normal human pituitary were used as a positive control. Negative controls used nonreacting serum and phosphate buffer in place of the primary and secondary antisera. The antisera are specific for GH and ACTH. For TSH there is minimal cross-reactivity with FSH, LH, and hCG; for FSH, there is less than 10% cross-reactivity with TSH, LH, and hCG; for LH, there is less than 10% with TSH, FSH, and hCG; and for PRL, there is less than 1% with human GH, TSH, LH, and hCG. Immunogold electron microscopy for GH in tumor 4 was carried out by conjugation of the GH antiserum to 10-nm gold particles (Biocell, Cardiff, UK).

Pituitary hormones

PRL, GH, TSH, LH, and FSH were assayed immunoradiometrically using reagents supplied by North East Thames Radioimmunoassay (London, UK) (16).

IL-6 enzyme-linked immunosorbent assay

Flexible 96-well Costar plates (Costar, High Wycombe, UK) were coated with 50 µL sheep polyclonal antibody to IL-6 (Eurogenetics UK, Hampton, UK) at 2 µg/mL in a 0.05 mol/L sodium carbonate buffer solution, pH 9.6, and incubated at 37 C for 2 h. Nonspecific binding sites were blocked with 5% BSA in Tris-buffered saline (150 µL) overnight at 4 C. Plates were washed three times with Tris-buffered saline and 0.02% Tween-20 between each of the following steps. Samples and standards (diluted in appropriate culture medium) were added and incubated for 2 h at 39 C. After washing, monoclonal antibody to human IL-6 (1 µg/mL; Eurogenetics, UK) was added for 1 h at 37 C. Biotinylated antimouse IgG (Amersham) was added for 30 min, and then streptavidin conjugated to alkaline phosphatase (Amersham) was added at a 1:1000 dilution for an additional 30 min at 37 C. Alkaline buffer solution consisting of 1.5 mol/L 2-amino-2-methyl-1-propranolol (Sigma Chemical Co., Poole, UK), pH 10.3, was added (50 µL to each well), followed by 50 µL phosphatase substrate (Sigma) prepared to 10 mg/mL in distilled water. Plates were incubated at 37 C until fully developed. NaOH (0.1 mol/L; 50 µL) was added to stop the reaction, and absorbance was read at 414 nm on a Dynatech MR500 (Dynatech Laboratories Ltd., Billinghurst, UK). The reaction was then decolorized with 50 µL 4 mol/L HCl/well, and the absorbance was subtracted from the first value to give the absorbance due to the specific enzyme reaction. The detection limit of the assay was 4 U/mL. The coefficient of variation for the assay was 8.3%.

Statistical analyses

Data are expressed as the mean \ SD. Statistical significance was determined by Student’s unpaired t test.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
In a series of 33 pituitary adenomas, 7 incorporated sufficient [3H]thymidine to be studied. These tumors included 2 prolactinomas, 1 GH-secreting adenoma, 1 mixed GH/PRL-secreting adenoma, and 3 clinically nonfunctioning adenomas, of which 2 secreted FSH in cell culture and probably represented silent gonadotropinomas. The clinical data, immunocytochemistry, and in vitro hormone secretion are presented in Table 1Go. All 7 of the pituitary adenomas with high thymidine incorporation secreted IL-6 in culture (Table 1Go). Genestein in all 7 tumors and MDHC in the 5 tumors studied potently inhibited thymidine uptake (Fig. 1Go). Genestein (74 µmol/L) produced 61.9 \ 18.96% (\SD) inhibition, and 740 µmol/L genestein produced 92.65 \ 8.59% inhibition. MDHC (100 µmol/L) produced 93.84 \ 3.85% inhibition. Some cell disruption did occur at the higher doses of genestein (740 µmol/L) and MDHC (100 µmol/L), but cell membranes remained intact, excluding trypan blue at lower doses.


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  		Table 1. Clinical, immunocytochemical, and cell culture data from the seven patients whose pituitary adenomas demonstrated significant [3H]thymidine uptake

 


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  		Figure 1. Effects of genestein and MDHC on [3H]thymidine uptake in cultured human pituitary adenoma cells. The open bars represent basal [3H]thymidine uptake, the hatched bars represent uptake in the presence of genestein, and the dotted bars represent uptake in the presence of MDHC. Data are expressed as the mean ± SD for triplicate wells. For all data with genestein and MDHC: *, P < 0.05; **, P < 0.005 (for inhibition of basal thymidine uptake).

 
Primary pituitary adenoma cell cultures consist of cell types other than the tumor cells, including fibroblasts, macrophages, and normal pituitary cells. These additional cells would have been present in all 33 pituitary adenomas culture, so it would be unlikely that they accumulated sufficient [3H]thymidine to influence any effects on the tumor cells in the seven adenomas with higher [3H]thymidine uptake.

In four of the cultures, sufficient cells were available to study the effect of EGF on thymidine incorporation. EGF (20 ng/mL) stimulated thymidine uptake in two of the adenomas, both of which were silent gonadotropinomas (tumors 2 and 3), and this effect was inhibited in the presence of genestein (Fig. 2Go). EGF had no stimulatory effect in tumors 4 and 6 (a somatotropinoma and a prolactinoma).



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  		Figure 2. Effect of genestein on EGF (20 mg/mL)-stimulated [3H]thymidine uptake in two nonfunctioning pituitary adenoma cell cultures (tumors 2 and 7, respectively). The open bars represent basal [3H]thymidine uptake, the hatched bars represent EGF-stimulated thymidine uptake without genestein, the cross-hatched bars represent uptake with genestein, and the dotted bars represent uptake with EGF and MDHC. Data are expressed as the mean ± SD for triplicate wells. *, P < 0.05; **, P < 0.005 for the inhibitory effect of genestein on EGF-stimulated thymidine uptake. {dagger}{dagger}, P < 0.005 for the stimulatory effect of EGF over basal thymidine uptake.

 
Conditioned medium from 18 hormone-secreting adenomas and 21 nonfunctioning adenomas were examined. This series consisted of additional medium from other pituitary adenoma cultures not included in the 33 tumors studied for [3H]thymidine incorporation. Tumor-conditioned medium from 28 adenomas (11 hormone-secreting and 17 nonfunctioning adenomas) significantly stimulated thymidine incorporation in GH3 cells, whereas 8 had no effect and 3 inhibited uptake (Figs. 3Go and 4Go). In all of the experiments genestein (74 µmol/L) inhibited thymidine uptake to significantly below basal levels, and in the majority of instances the levels of inhibition were comparable with the effect of genestein alone on basal growth.



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  		Figure 3. Effect of conditioned medium from hormone-secreting human pituitary adenomas and the influence of genestein (74 µmol/L) on [3H]thymidine uptake by GH3 rat pituitary tumor cells. The open bars represent [3H]thymidine uptake in the presence of conditioned medium alone, and the hatched bars represent uptake in the presence of conditioned medium and genestein. The numbered tumors represent conditioned medium from adenomas investigated in the primary cell culture study. Data are expressed as the mean ± SD for triplicate wells. *, P < 0.05; **, P < 0.005.

 


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  		Figure 4. Effect of conditioned medium from nonfunctioning human pituitary adenomas and the influence of genestein (74 µmol/L) on [3H]thymidine uptake by GH3 rat pituitary tumor cells. The open bars represent [3H]thymidine uptake in the presence of conditioned medium alone, and the hatched bars represent uptake in the presence of conditioned medium and genestein. The numbered tumors represent conditioned medium from adenomas investigated in the primary cell culture. Data are expressed as the mean ± SD for triplicate wells. *, P < 0.05; **, P < 0.005.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study demonstrates that the suppression of tyrosine kinase activity inhibits thymidine uptake of in vitro cultured human pituitary adenoma cells. Extrapolation of these findings to effects on tumor growth have to be tempered, in that increased thymidine uptake does not necessarily mean that cells are replicating. We have, however, demonstrated that both tyrosine kinase inhibitors used in these experiments inhibit the growth of GH3 cells, as assessed by cell number (our observations). The potent effects of the tyrosine kinase inhibitors imply that tyrosine kinase activity is crucial for the growth of these tumors. It is not clear from this study which specific tyrosine kinases are involved, as both genestein and MDHC, although potent, are not selective for any particular type of enzyme. Selective inhibitors of specific tyrosine kinases are not yet available.

The majority of cultured adenomas secrete growth factors whose stimulatory action on GH3 cell growth can be inhibited by tyrosine kinase inhibition. The nature of these growth factors has not been established. EGF receptors have been identified in some pituitary adenomas (17, 18). In one study EGF receptor messenger ribonucleic acid was found in all types of tumor and was particularly overexpressed in recurrent somatotropinomas and aggressive silent subtype 3 adenomas (17). However, using immunocytochemical techniques, EGF receptors were found to be present only in nonfunctioning adenomas (18). In two of the four pituitary adenomas studied here, EGF-stimulated thymidine uptake, which was inhibited by genistein and MDHC. EGF inhibits the growth of GH3 cells; therefore, it cannot be implicated as the factor in conditioned medium that stimulates GH3 growth. This does not, however, exclude a role for EGF in human pituitary adenoma growth.

IL-6 is synthesized and released by a large number of pituitary adenomas in culture regardless of immunocytochemical classification (15, 19). The IL-6 receptor gene has been shown in one study to be expressed by nonfunctioning and PRL-secreting adenomas (20). The role of IL-6 released by these tumors has not been elucidated, but IL-6 is a growth-promoting cytokine and is known to stimulate the growth of GH3 rat pituitary cells and inhibit normal pituitary cell growth (21). Activation of the IL-6 receptor in other cells induces homodimerization of the receptor-associated protein gp130, which has tyrosine kinase activity (7). Other cytokines are expressed sporadically in pituitary adenomas, and these include IL-1{alpha}, IL-1ß, IL-2, IL-8, and the transforming growth factor-ß family. The data suggest that these particular cytokines may be expressed by other cells, but not the tumor cells (22). Receptors for IL-2 (23) and IL-6 (20) have been identified in some pituitary adenomas. IL-1 is a potent stimulator of IL-6 release from pituitary adenomas, implying that IL-1 receptors are present (24). Cytokines mediate their effects through the intracellular JAK-type tyrosine kinases, which activate transcription factors called STATS (signal transducers and activators of transcription) that couple ligand binding to gene expression (25). We were unable to identify insulin-like growth factor I in the conditioned medium, and in previous work, platelet-derived growth factor was not present in pituitary tumor-conditioned medium. Basic fibroblast growth factor has previously been shown to inhibit growth in a human pituitary tumor cell line (26). It may well be that there are growth factors that have not yet been identified. The study of Webster and colleagues (14) by chromatographic analysis identified two main peaks of growth-promoting activity, in conditioned medium between 2–3 and 11–18 kDa, which stimulated GH3 cell growth. The nature of these peaks has not been elucidated.

The mechanisms by which tyrosine kinases are involved in control cell growth are clearly complex and are subject to regulation by growth factors and possibly hormones. The work presented here demonstrates that tyrosine kinase activity is important for human pituitary tumor cell growth, which may be enhanced by the stimulatory action of growth factors. Which particular tyrosine kinases are important in pituitary adenomas is not clear and will not be determined until specific tyrosine kinase inhibitors are developed. Pituitary adenomas are heterogeneous in nature, and it may be that different growth factors are responsible for stimulatory effects on growth in the various tumor types. From our preliminary work presented here, tyrosine kinases clearly have a key role in controlling the growth of pituitary adenomas. Their activity may be controlled by autocrine or paracrine growth factors or possibly activated by other mechanisms, for example by oncogenic transformation.


   Footnotes
 
1 This work was supported in part by the Northern General Hospital Trust Fund. Back

Received November 19, 1996.

Revised March 20, 1997.

Accepted March 25, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Ullrich A, Schlessinger J. 1990 Signal transduction by receptors with tyrosine kinase activity. Cell. 61:203–212.[CrossRef][Medline]
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  4. Oude Weernink PA, Verheul E, Kerkhof E, Van Veelen CWM, Rijksen G. 1996 Inhibitors of protein tyrosine phosphorylation reduce the proliferation of two human glioma cell lines. Neurosurgery. 38:108–114.[CrossRef][Medline]
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  6. Koch CA, Anderson D, Moran MF, Ellis C, Pawson T. 1991 SH2 and SH3 domains: Elements that control interactions of cytoplasmic signaling proteins. Science. 252:668–674.[Abstract/Free Full Text]
  7. Murakami M, Hibi M, Nakagawa N, et al. 1993 IL-6-induced homodimerization of gp130 and associated activation of a tyrosine kinase. Science. 260:1808–1810.[Abstract/Free Full Text]
  8. Williams LT. 1989 Signal transduction by the platelet-derived growth factor receptor. Science. 243:1564–1570.[Abstract/Free Full Text]
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  11. Herman V, Draznin NZ. Gonsky R, Melmed. 1990 Clonal origin of pituitary adenomas J Clin Endocrinol Metab. 71:1427–1433.[Abstract]
  12. Vallar L, Spada A, Giannattasio G. 1987 Altered Gs and adenylate cyclase activity in human GH-secreting pituitary adenomas. Nature. 330:566–567.[CrossRef][Medline]
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  14. Webster J, Ham J, Bevan JS, ten Horn CD, Scanlon MF. 1991 Preliminary characterization of growth factors secreted by human pituitary tumours. J Clin Endocrinol Metab. 72:687–692.[Abstract]
  15. Jones TH, Daniels M, James RA, et al. 1994 Production of bioactive and immunoreactive interleukin-6 (IL-6) and expression of IL-6 messenger ribonucleic acid by human pituitary adenomas. J Clin Endocrinol Metab. 78:180–187.[Abstract]
  16. Edwards R, Cann PA, Howes IJ, et al. A regional and national immunoassay scheme using matched reagents. Proc of the Symp on Nucl Med and Related Nucleotide Applications in Developing Countries. 1985; 17–30.
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  19. Jones TH, Justice S, Price A, Chapman K. 1991 Interleukin-6 secreting human pituitary adenomas in vitro. J Clin Endocrinol Metab. 73:207–209.[Abstract]
  20. Rezai AR, Rezai A, Martinez-Maza O, Vander-Mayden M, Weiss MH. 1994 Interleukin-6 and interleukin-6 receptor gene expression in pituitary tumours. J Neurooncol. 19:131–135.[CrossRef][Medline]
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