| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
|
FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online July 1, 2002 as doi:10.1096/fj.02-0145fje. |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Laboratory for Psychoneuroimmunology, University Medical Center Utrecht;
* Department of Medical Oncology, University Medical Center Utrecht; and
Department of Psycho- neuropharmacology, Nijmegen Institute of Neuroscience, University of Nijmegen, The Netherlands
3Correspondence: Laboratory for Psychoneuroimmunology, Room KC 03.068.0, UMC Utrecht, Lundlaan 6, 3584 EA Utrecht, The Netherlands. E-mail: c.heijnen{at}wkz.azu.nl
SPECIFIC AIM
Administration of dopamine or dopamine receptor agonists can inhibit the growth of malignant tumors in mice. Patients with schizophrenia, who have a hyperreactive dopaminergic system, are relatively protected from cancer. Finally, it is known that there is great individual variation in the activity of the dopaminergic system. To test the hypothesis that individual differences in reactivity of the dopaminergic system are coupled to individual differences in cancer progression, we analyzed tumor growth and tumor angiogenesis in two types of rats that differ in reactivity of the dopaminergic system.
PRINCIPAL FINDINGS
1. Rats selected for high dopaminergic reactivity develop smaller tumors than rats with low dopaminergic reactivity
To investigate whether natural differences in dopaminergic system reactivity are associated with differences in tumor growth, we used two outbred lines of Wistar rats: APO-SUS (high dopaminergic reactivity) and APO-UNSUS (low dopaminergic reactivity) rats. These rats are present in unselected outbred populations of Wistar rats and display a bimodal variation in response to the dopaminergic agonist apomorphine, the selection criterion for breeding these lines. APO-SUS rats share behavioral, neurochemical, and endocrine characteristics with patients suffering from schizophrenia. We tested the hypothesis that APO-SUS rats would be better protected against the development of tumors than APO-UNSUS rats. Therefore, we implanted rat adenocarcinoma cells (MADB106) in Matrigel subcutaneously (s.c.) and determined tumor weight after 7 days. Tumors from hyperdopaminergic APO-SUS animals were 
35% smaller than tumors from APO-UNSUS animals (P<0.01).
2. Fewer lung metastasis in rats with high dopaminergic reactivity
In a second set of experiments we analyzed the formation of lung metastasis 24 days after intravenous (i.v.) administration of MADB106 cells. Twenty-four days after implantation of the highest number of tumor cells (8x105/animal), 78% of the APO-UNSUS animals had died whereas no APO-SUS animals had died (P<0.01). The experiment was then terminated and the lungs of all animals were examined for the presence of lung metastasis macroscopically. APO-SUS rats developed significantly fewer lung metastases than APO-UNSUS rats. (Fig. 1
) Similarly, after i.v. administration of lower numbers of MADB 106 cells, the number of tumors in the lung was significantly lower in APO-SUS animals than in APO-UNSUS animals (Fig. 1)
.
|
3. Reduced tumor angiogenesis in rats with high dopaminergic activity
Gross examination of MADB106/matrigel implants suggests that the reduced tumor growth in APO-SUS rats was associated with a reduction in blood supply to the tumor compared to APO-UNSUS rats (Fig. 2
A vs. B). Upon histological examination, tumors from APO-SUS rats contained large areas of necrotic cells (Fig. 2C vs. D
) and the number of endothelial cells staining positively for factor VIII appeared to be reduced (Fig. 2E vs. F
). Therefore, as a measure of tumor angiogenesis, we determined hemoglobin content in tumors from APO-SUS and APO-UNSUS rats. Hemoglobin levels were significantly lower in tumors from APO-SUS than from APO-UNSUS rats (APO-SUS: 40.6±7.6; APO-UNSUS: 76.9±13 mg/dl, P<0.05). There was no difference in hemoglobin levels in the peripheral blood. Tumors from APO-SUS rats expressed lower levels of the endothelial cell marker PECAM-1 as determined by Western blot analysis (APO-SUS: 37±18; APO-UNSUS: 69±25 units, P<0.01).
|
4. Angiogenesis in Matrigel containing MADB-106-derived growth factors is lower in APO-SUS rats
It is possible that the reduced vascularization of tumors in APO-SUS was caused by the presence of necrotic tumor cells and/or reduced production of growth factors by the tumor in APO-SUS rats. Therefore, we investigated the angiogenic response in Matrigel implants supplemented with MADB106-conditioned medium as a source of tumor-derived growth factors. The conditioned medium used contained 400 pg/ml VEGF. Matrigel containing 30% MADB106-conditioned medium was implanted s.c. and hemoglobin levels were determined 7 days later. The implants from APO-SUS rats contained significantly less hemoglobin than implants from APO-UNSUS rats (APO-SUS: 11.4±2.6 mg/dl; APO-UNSUS: 33.5±9.1 mg/dl, P<0.05). Thus, in the absence of tumor cells, implants from APO-SUS rats also contained a significantly lower level of hemoglobin, indicating that the decreased angiogenic response in these animals was not secondary to reduced tumor growth factor production or the presence of necrotic cells.
CONCLUSIONS
APO-SUS rats have a hyperreactive dopaminergic system and dopamine is known to inhibit the growth of malignant tumors as well as VEGF-induced angiogenesis. APO-SUS rats are considered a model for some aspects of schizophrenia and patients with schizophrenia appear to be protected from cancer. Therefore, we hypothesized that APO-SUS rats would be protected from tumor growth. Our present results demonstrate that APO-SUS and APO-UNSUS rats show highly significant differences in angiogenic capacity, tumor growth, and metastasis formation (Fig. 3
).
|
The selection criterion for breeding the two lines of Wistar rat was the behavioral response to the dopaminergic receptor agonist apomorphine: APO-SUS rats have a far greater response to apomorphine than APO-UNSUS rats. APO-SUS rats have increased levels of mRNA of tyrosine-hydroxylase in dopaminergic cells in the midbrain, especially the substantia nigra pars compacta, increased expression of mRNA of D1 dopamine receptors in the neostriatum, and more dopamine D2 receptors in the neostriatum. Previous studies have shown that administration of a dopaminergic agonist can inhibit tumor growth in animals. The angiogenic response to VEGF but not to bFGF can be inhibited by administration of dopaminergic agonists. Dopaminergic agonists inhibit signaling through the VEGF receptor. It may well be possible that increased plasma dopamine levels and/or dopamine content in peripheral nerve terminals adjacent to blood vessels and/or increased reactivity of endothelial dopamine receptors are responsible for the lower angiogenic response observed in APO-SUS rats. Future studies are required to assess whether it is a line-specific difference in the dopaminergic activity in the peripheral rather than in the central nervous system that underlies the noted differences in tumor growth and angiogenesis between APO-SUS and APO-UNSUS rats. There is evidence, however, that central dopaminergic activity directly and/or indirectly controls peripheral processes under the control of peripheral dopamine as well. For example, administration of dopamine can control gastric ulceration via an effect on central and peripheral dopamine receptors. Apomorphine susceptibility is negatively correlated with gastric ulceration, suggesting that central dopaminergic reactivity has consequences for processes under the control of peripheral dopamine. Finally, it has been shown that depletion of central dopamine by treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine results in enhanced growth of a s.c. implanted Ehrlich carcinoma in a murine model. These data clearly suggest that central dopaminergic activity has consequences for processes that are under the control of peripheral dopamine as well.
Differences between APO-SUS and APO-UNSUS rats are not limited to the dopaminergic system, but extend to other systems that interact with the dopaminergic system. For example, APO-SUS rats show a large and long-lasting endocrine response to stressors in the release of ACTH and corticosteroids whereas APO-UNSUS rats show small and short-lasting endocrine responses to stress. In line with these differences in the HPA axis, APO-SUS and APO-UNSUS rats differ in susceptibility to autoimmune diseases, parasite infection, and development of periodontitis. The lower susceptibility of APO-SUS rats to autoimmune diseases and their increased IgE production after parasitic infection correlates with a relative increase in production of Th-2 type cytokines. There is evidence that high doses of the Th2 cytokine IL-4 can inhibit angiogenesis. Transgenic IL-4-producing tumors can inhibit growth and angiogenesis in contralaterally implanted tumors that do not produce the cytokine. At lower concentrations, IL-4 has the capacity to induce angiogenesis. Although we do not have evidence for infiltration of immune cells in the MADB106 tumors, it is possible that the Th2-dominated immune system of APO-SUS rats contributes to their reduced tumor growth and angiogenesis.
APO-SUS rats share characteristics with patients who suffer from schizophrenia; some studies show that the incidence of cancer is reduced in these patients. The reduced angiogenic response and the associated reduction in tumor growth or metastasis formation in APO-SUS rats suggest that the APO-SUS rat is a valuable tool in the search after the contribution of genetic and environmental stimuli to the apparent protection of patients with schizophrenia from cancer.
Overall, our results suggest a novel link between hyperreactivity of the dopaminergic system, angiogenesis, and tumor development and may explain part of the host-dependent individual differences in cancer progression. It would be interesting to investigate whether the reactivity of the dopaminergic system in humans diagnosed with cancer can be used to select patients for anti-angiogenic therapy.
FOOTNOTES
1 To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.02-0145fje; to cite this article, use FASEB J. (July 1, 2002) 10.1096/fj.02-0145fje 
2 These authors contributed equally to the study.
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
