Cell Replication and Angiogenesis in Central Nervous System Tumors and Their Relationship with the Expression of Tissue Prolactin and Hyperprolactinemia


This study aimed to assess the effect of intracellular prolactin (ICPRL) and hyperprolactinemia on cell replication, using an immunohistochemical (IHC) technique for Ki-67 and Mcm-2, and angiogenesis, using IHC for endoglin CD-105, in central nervous system (CNS) tumors. This cross-sectional study included 79 cases of surgically excised primary CNS tumors of neuroepithelial origin (41.8% of all cases: 10.2% astrocytomas, 24% glioblastomas and 7.6% oligodendrogliomas) and meningeal origin (58.2% of all cases). Ki-67 and Mcm-2 indexes were calculated as a percentage of marked cells. The medians for Ki-67 and Mcm-2 indexes were significantly lower in meningiomas than in glioblastomas (p < 0.001 for Ki-67 and p < 0.001 for Mcm-2) and oligodendrogliomas (p < 0.001 for Ki-67 and p = 0.02 for Mcm-2). A good correlation was observed between the Ki-67 and Mcm-2 (rS = 0.60) replication markers. There were no significant differences in vascular density between the different histological types. Immunohistochemistry for ICPRL was positive in 45.6% of the tumors. Serum prolactin (PRL) was elevated in 30.6% of the cases. Multiple regression analysis revealed no important correlation of ICPRL and serum PRL on Ki-67 and Mcm-2 indexes or vascular density. The analysis of the combined impact of ICPRL and serum PRL variables revealed a trend towards an increase in microvessel density in tumor tissue and a significant increase in cell replication markers (p = 0.009 for Ki-67 and p = 0.05 for Mcm-2). PRL in tumor tissue may be one of the modulating factors of cell proliferation in the CNS.

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D. M. D. Abech, J. F. S. Pereira-Lima, C. G. S. Leães, R. T. Meurer, L. M. Barbosa-Coutinho, N. P. Ferreira and M. C. Oliveira, "Cell Replication and Angiogenesis in Central Nervous System Tumors and Their Relationship with the Expression of Tissue Prolactin and Hyperprolactinemia," Open Journal of Pathology, Vol. 2 No. 3, 2012, pp. 50-57. doi: 10.4236/ojpathology.2012.23011.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] A. Bachelot and N. Binart, “Reproductive Role of Prolactin,” Reproduction, Vol. 133, No. 2, 2007, pp. 361-369. doi:10.1530/REP-06-0299
[2] V. Goffin, N. Binart, P. Touraine and P. A. Kelly, “Prolactin: The New Biology of an Old Hormone,” Annual Review of Physiology, Vol. 64, 2002, pp. 47-67. doi:10.1146/annurev.physiol.64.081501.131049
[3] N. Ben-Jonathan, J. L. Mershon, D. L. Allen and R. W. Steinmetz, “Extrapituitary Prolactin: Distribution, Regulation, Functions, and Clinical Aspects,” Endocrine Reviews, Vol. 17, No. 6, 1996, pp. 639-669.
[4] J. Harris, P. M. Stanford, S. R. Oakes and C. J. Ormandy, “Prolactin and the Prolactin Receptor: New Targets of an Old Hormone,” Annals of Medicine, Vol. 36, No. 6, 2004, pp. 414-425. doi:10.1080/07853890410033892
[5] C. V. Clevenger, P. A. Furth, S. E. Hankinson and L. A. Schuler, “The Role of Prolactin in Mammary Carcinoma,” Endocrine Reviews, Vol. 24, No. 1, 2003, pp. 1-27. doi:10.1210/er.2001-0036
[6] I. Leav, F. B. Merk, K. F. Lee, M. Loda, M. Mandoki, J. E. McNeal and S. M. Ho, “Prolactin Receptor Expression in the Developing Human Prostate and in Hyperplastic, Dysplastic, and Neoplastic Lesions,” The American Journal of Pathology, Vol. 154, No. 3, 1999, pp. 863-870. doi:10.1016/S0002-9440(10)65333-3
[7] E. Ciccarelli, P. Razzore, D. Gaia, C. Todaro, A. Longo, M. Forni, C. Ghè, F. Camanni, G. Muccioli, G. Faccani and M. M. Lanotte, “Hyperprolactinaemia and Prolactine Binding in Benign Intracranial Tumours,” Journal of Neurosurgical Sciences, Vol. 45, No. 2, 2001, pp. 70-74.
[8] C. G. Soares Leaes, A. P. Filho, J. F. Pereira Lima, C. M. Dallago, R. L. Batista, L. M. Barbosa-Coutinho, N. P. Ferreira and M. da Costa Oliveira, “Hyperprolactinemia and Immunohistochemical Expression of Intracellular Prolactin and Prolactin Receptor in Primary Central Nervous System Tumors and Their Relationship with Cellular Replication,” Brain Tumor Pathology, Vol. 24, No. 2, 2007, pp. 41-46. doi:10.1007/s10014-007-0220-6
[9] N. Ben-Jonathan, K. Liby, M. McFarland and M. Zinger, “Prolactin as an Autocrine/Paracrine Growth Factor in Human Cancer,” Trends in Endocrinology and Metabolism, Vol. 13, No. 6, 2002, pp. 245-250. doi:10.1016/S1043-2760(02)00603-3
[10] B. K. Vonderhaar, “Prolactin in Human Breast Cancer Development,” In: S. P. Ethier, Ed., Endocrine Oncology, Humana Press, Totowa, 2000, pp. 101-120. doi:10.1385/1-59259-223-6:101
[11] S. S. Tworoger, A. H. Eliassen, P. Sluss and S. E. Hankinson, “A Prospective Study of Plasma Prolactin Concentrations and Risk of Premenopausal and Postmenopausal Breast Cancer,” Journal of Clinical Oncology, Vol. 25, No. 12, 2007, pp. 1482-1488. doi:10.1200/JCO.2006.07.6356
[12] S. E. Hankinson, W. C. Willett, D. S. Michaud, J. E. Manson, G. A. Colditz, C. Longcope, B. Rosner and F. E. Speizer, “Plasma Prolactin Levels and Subsequent Risk of Breast Cancer in Postmenopausal Women,” Journal of the National Cancer Institute, Vol. 91, No. 7, 1999, pp. 629-634. doi:10.1093/jnci/91.7.629
[13] M. T. Nevalainen, E. M. Valve, P. M. Ingleton, M. Nurmi, P. M. Martikainen and P. L. Harkonen, “Prolactin and Prolactin Receptors Are Expressed and Functioning in Human Prostate,” The Journal of Clinical Investigation, Vol. 99, No. 4, 1997, pp. 618-627. doi:10.1172/JCI119204
[14] H. Li, T. J. Ahonen, K. Alanen, J. Xie, M. J. LeBaron, T. G. Pretlow, E. L. Ealley, Y. Zhang, M. Nurmi, B. Singh, P. M. Martikainen and M. T. Nevalainen, “Activation of Signal Transducer and Activator of Transcription 5 in Human Prostate Cancer Is Associated with High Histological Grade,” Cancer Research, Vol. 64, No. 14, 2004, pp. 4774-4782. doi:10.1158/0008-5472.CAN-03-3499
[15] W. J. De Vito, W. C. Okulicz, S. Stone and C. Avakian, “Prolactin-Stimulated Mitogenesis of Cultured Astrocytes,” Endocrinology, Vol. 130, No. 5, 1992, pp. 2549-2556. doi:10.1210/en.130.5.2549
[16] E. Jimenez-Hakim, M. El-Azouzi and P. M. Black, “The Effect of Prolactin and Bombesin on the Growth of Meningioma-Derived Cells in Monolayer Culture,” Journal of Neuro-Oncology, Vol. 16, No. 3, 1993, pp. 185-190. doi:10.1007/BF01057032
[17] G. Muccioli, C. Ghè, G. Faccani, M. Lanotte, M. Forni and E. Ciccarelli, “Prolactin Receptors in Human Meningiomas: Characterization and Biological Role,” The Journal of Endocrinology, Vol. 153, No. 3, 1997, pp. 365-371. doi:10.1677/joe.0.1530365
[18] T. Ducret, S. Boudina, B. Sorin, A. M. Vacher, I. Gourdou, D. Liquoro, J. Guerin, L. Bresson-Bepoldin and P. Vacher, “Effects of Prolactin on Intracellular Calcium Concentrations and Cell Proliferation in Human Glioma Cells,” Glia, Vol. 38, No. 3, 2002, pp. 200-214. doi:10.1002/glia.10056
[19] D. N. Louis, H. Ohgaki, O. D. Wiestler, W. K. Cavenee, P. C. Burger, A. Jouvet, B. W. Scheithauer and P. Kleihues, “The 2007 WHO Classification of Tumours of the Central Nervous System,” Acta Neuropathologica, Vol. 114, No. 2, 2007, pp. 97-109. doi:10.1007/s00401-007-0243-4
[20] S. B. Wharton, F. A. Hamilton, W. K. Chan, K. K. Chan and J. R. Anderson, “Proliferation and Cell Death in Oligodendrogliomas,” Neuropathology and Applied Neurobiology, Vol. 24, No. 1, 1998, pp. 21-28.
[21] V. Barresi, S. Cerasoli, E. Vitarelli and G. Tuccari, “Density of Microvessels Positive for CD105 (Endoglin) Is Related to Prognosis in Meningiomas,” Acta Neuropathologica, Vol. 114, No. 2, 2007, pp. 147-156. doi:10.1007/s00401-007-0251-4
[22] M. Pawlikowski, J. Kunert-Radek and M. Radek, “Plurihormonality of Pituitary Adenomas in Light of Immunohistochemical Studies,” Endokrynologia Polska, Vol. 61, No. 1, 2010, pp. 63-66.
[23] P. B. Vermeulen, G. Gasparini, S. B. Fox, C. Colpaert, L. P. Marson, M. Gion, J. A. Beli?n, R. M. de Waal, E. Van Marck, E. Magnani, N. Weidner, A. L. Harris and L. Y. Dirix, “Second International Consensus on the Methodology and Criteria of Evaluation of Angiogenesis Quantification in Solid Human Tumours,” European Journal of Cancer, Vol. 38, No. 12, 2002, pp. 1564-1579. doi:10.1016/S0959-8049(02)00094-1
[24] P. E. McKeever, D. A. Ross, M. S. Strawderman, J. A. Brunberg, H. S. Greenberg and L. Junck, “A Comparison of the Predictive Power for Survival in Gliomas Provided by MIB-1, Bromodeoxyuridine and Proliferating Cell Nuclear Antigen with Histopathologic and Clinical Parameters,” Journal of Neuropathology and Experimental Neurology, Vol. 56, No. 7, 1997, pp. 798-805.
[25] K. Onda, R. L. Davis, M. Shibuya, C. B. Wilson and T. Hoshino, “Correlation between the Bromodeoxyuridine Labeling Index and the MIB-1 and Ki-67 Proliferating Cell Indices in Cerebral Gliomas,” Cancer, Vol. 74, No. 7, 1994, pp. 1921-1926. doi:10.1002/1097-0142(19941001)74:7<1921::AID-CNCR2820740716>3.0.CO;2-9
[26] G. Haddad, O. Al-Mefty and S. Abdulrauf, “Meningiomas,” In: R. H. Winn, Ed., Youmans Neurological Surgery, Elsevier, Philadelphia, 2004, pp. 1099-1128.
[27] M. Lei and B. K. Tye, “Initiating DNA Synthesis: From Recruiting to Activating the MCM Complex,” Journal of Cell Science, Vol. 114, No. 8, 2001, pp. 1447-1454.
[28] I. T. Todorov, B. A. Werness, H. Q. Wang, L. N. Buddharaju, P. D. Todorova, H. K. Slocum, J. S. Brooks and J. A. Huberman, “HsMCM2/BM28: A Novel Proliferation Marker for Human Tumors and Normal Tissues,” Laboratory Investigation, Vol. 78, No. 1, 1998, pp. 73-78.
[29] E. Jouanneau, “Angiogenesis and Gliomas: Current Issues and Development of Surrogate Markers,” Neurosurgery, Vol. 62, No. 1, 2008, pp. 31-52. doi:10.1227/01.NEU.0000311060.65002.4E
[30] A. Lebelt, J. Dzieciol, K. Guzinska-Ustymowicz, D. Lemancewicz, L. Zimnoch and E. Czykier, “Angiogenesis in Gliomas,” Folia Histochemica et Cytobiologica, Vol. 46, No. 1, 2008, pp. 69-72. doi:10.2478/v10042-008-0009-4
[31] R. O. Barnard, “The Development of Malignancy in Oligodendrogliomas,” The Journal of Pathology and Bacteriology, Vol. 96, No. 1, 1968, pp. 113-123. doi:10.1002/path.1700960112
[32] G. C. Netto, C. B. Bleil, A. Hilbig and L. M. Coutinho, “Immunohistochemical Evaluation of the Microvascular Density through the Expression of TGF-Beta (CD 105/Endoglin) and CD 34 Receptors and Expression of the Vascular Endothelial Growth Factor (VEGF) in Oligodendrogliomas,” Neuropathology, Vol. 28, No. 1, 2008, pp. 17-23. doi:10.1111/j.1440-1789.2007.00825.x
[33] R. P. Shah, M. E. Leavens and N. A. Samaan, “Galactorrhea, Amenorrhea, and Hyperprolactinemia as Manifestations of Parasellar Meningioma,” Archives of Internal Medicine, Vol. 140, No. 12, 1980, pp. 1608-1612. doi:10.1001/archinte.1980.00330230054014
[34] J. Kolodny and R. G. Dluhy, “Recurrent Prolactinoma and Meningioma Following Irradiation and Bromocriptine Treatment,” The American Journal of Medicine, Vol. 78, No. 1, 1985, pp. 153-155. doi:10.1016/0002-9343(85)90477-2
[35] K. C. McCowen, J. N. Glickman, P. M. Black, N. T. Zervas, H. G. Lidov and J. R. Garber, “Gangliocytoma Masquerading as a Prolactinoma. Case Report,” Journal of Neurosurgery, Vol. 91, No. 3, 1999, pp. 490-495. doi:10.3171/jns.1999.91.3.0490
[36] I. P. Santosh and V. Rajshekhar, “Galactorrhea as the Sole Presenting Symptom of a Posterior Third Ventricular Epidermoid Cyst,” Surgical Neurology, Vol. 55, No. 1, 2001, pp. 46-49. doi:10.1016/S0090-3019(00)00351-7
[37] I. Fernandez, P. Touraine and V. Goffin, “Prolactin and Human Tumourogenesis,” Journal of Neuroendocrinology, Vol. 22, No. 7, 2010, pp. 771-777.
[38] E. Tallet, V. Rouet, J. B. Jomain, P. A. Kelly, S. Bernichtein and V. Goffin, “Rational Design of Competitive Prolactin/Growth Hormone Receptor Antagonists,” Journal of Mammary Gland Biology and Neoplasia, Vol. 13, No. 1, 2008, pp. 105-117. doi:10.1007/s10911-008-9066-8
[39] M. Llovera, C. Pichard, S. Bernichtein, S. Jeay, P. Touraine, P. A. Kelly and V. Goffin, “Human Prolactin (hPRL) Antagonists Inhibit hPRL-Activated Signaling Pathways Involved in Breast Cancer Cell Proliferation,” Oncogene, Vol. 19, No. 41, 2000, pp. 4695-4705. doi:10.1038/sj.onc.1203846

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