Skip to main content

Advertisement

SpringerLink
Log in

Angiogenesis in Prolactinomas: Regulation and Relationship with Tumour Behaviour

  • Published:
Pituitary Aims and scope Submit manuscript

Abstract

Tumours are dependent on angiogenesis for growth and inhibition of angiogenesis has become a target for antineoplastic therapy. In the pituitary, unlike other tissues, vascularization is lower in adenomas compared to the normal gland. Despite this finding, a relationship between increased vascularity and several aspects of prolactinoma behaviour such as size, invasiveness, surgical outcome and malignancy, has been demonstrated. The process of angiogenesis is the result of a balance of stimulating and inhibiting factors. It is likely that an interaction between gene expression (such as pituitary tumour transforming gene (PTTG) and a novel gene located within the Edpm5 quantitative trait locus), hormonal stimuli including oestrogens, dopamine, 16 kDa fragments of prolactin and proangiogenic and antiangiogenic growth factors (for example, vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF-2), determine the final angiogenic phenotype of prolactinomas, and thus subsequent tumour behaviour. The elucidation of all the factors involved in the regulation of angiogenesis and their interactions might open new possibilities in the treatment of prolactinomas, especially in those cases with resistance or intolerance to dopamine agonists.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Canfield AE, Schor AM. Evidence that tenascin and thrombospondin- 1 modulate sprouting of endothelial cells. J Cell Sci 1995;108:797–809.

    CAS  PubMed  Google Scholar 

  2. Nickoloff BJ, Mitra RS, Varani J, Dixit VM, Polverini PJ. Aberrant production of interleukin-8 and thrombospondin-1 by psoriatic keratinocytes mediates angiogenesis. Am J Pathol 1994;144:820–828.

    CAS  PubMed  Google Scholar 

  3. Sharp PS. The role of growth factors in the development of diabetic retinopathy. Metabolism 1995;44(Suppl 4):72–75.

    Article  CAS  PubMed  Google Scholar 

  4. Colville-Nash PR, Scott DL. Angiogenesis and rheumatoid arthritis: pathogenic and therapeutic implications. Ann Rheum Dis 1992;51:919–925.

    Article  CAS  PubMed  Google Scholar 

  5. Brem SS, Gullino PM, Medina D. Angiogenesis: a marker for neoplastic transformation of mammary papillary hyperplasia. Science 1977;195:880–881.

    Article  CAS  PubMed  Google Scholar 

  6. Folkman J, Shing Y. Angiogenesis. J Biol Chem 1992;267:10931–10934.

    CAS  PubMed  Google Scholar 

  7. Folkman J. Tumour angiogenesis. In: Lea and Febiger (eds.), Cancer Medicine, IV edn, 1993, 153–171.

  8. Gasparini G, Harris AL. Clinical importance of the determination of tumour angiogenesis in breast carcinoma: Much more than a new prognostic tool. J Clin Oncol 1995;13:765–782.

    CAS  PubMed  Google Scholar 

  9. Folkman J. What is the evidence that tumours are angiogenesis dependent? J Natl Cancer Inst 1989;82:4–6.

    Article  Google Scholar 

  10. Weidner N, Carroll PR, Flax J, Blumenfeld W, Folkman J. Tumour angiogenesis correlates with metastasis in invasive prostate carcinoma. Am J Pathol 1993;143:401–409.

    CAS  PubMed  Google Scholar 

  11. Weidner N, Folkman J, Pozza F, Bevilacqua P, Allred EN, Moore DH, Meli S, Gasparini G. Tumour angiogenesis: A new significant and independent prognostic indicator in early-stage breast carcinoma. J Natl Cancer Inst 1992;84:1875–1887.

    Article  CAS  PubMed  Google Scholar 

  12. Maeda K, Chung YS, Takatsuka S, Ogawa Y, Sawada T, Yamashita Y, Onoda N, Kato Y, Nitta A, Arimoto Y. Tumour angiogenesis as a predictor of recurrence in gastric carcinoma. J Clin Oncol 1995;13:477–481.

    CAS  PubMed  Google Scholar 

  13. Bochner BH, Cote RJ, Weidner N, Groshen S, Chen SC, Skinner DG, Nichols PW. Angiogenesis in bladder cancer: relationship between microvessel density and tumour prognosis. J Natl Cancer Inst 1995;87:1603–1612.

    Article  CAS  PubMed  Google Scholar 

  14. Hanahan D, Folkman J: Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996;86:353–364.

    Article  CAS  PubMed  Google Scholar 

  15. Schechter J. Ultrastructural changes in the capillary bed of human pituitary tumours. Am J Pathol 1972;67:109–126.

    CAS  PubMed  Google Scholar 

  16. Jugenburg M, Kovacs K, Stefaneanu L, Scheithauer BW. Vasculature in nontumorous hypophyses, pituitary adenomas and carcinomas: a quantitative morphologic study. Endocr Pathol 1995;6:115–124.

    Article  PubMed  Google Scholar 

  17. Turner HE, Nagy Z, Gatter KC, Esiri MM, Harris AL, Wass JAH. Angiogenesis in pituitary adenomas and the normal pituitary gland. J Clin Endocrinol Metab 2000;85:1159–1162.

    Article  CAS  PubMed  Google Scholar 

  18. Viacava P, Gasperi M, Acerbi G, Manetti L, Cecconi E, Bonadio A, Naccarato AG, Acerbi F, Parenti G, Lupi I, Genovesi M, Martino E. Microvascular density and vascular endothelial growth factor expression in normal pituitary tissue and pituitary adenomas. J Endocrinol Invest 2003;26:23–28.

    CAS  PubMed  Google Scholar 

  19. Brem SS, Gullino PM, Medina D. Angiogenesis as a marker of preneoplastic lesions of the human breast. Cancer 1978;41:239–244.

    Article  CAS  PubMed  Google Scholar 

  20. Smith-McCune KK, Weidner N. Demonstration and characterization of the angiogenic properties of cervical dysplasia. Cancer Res 1994;54:800–804.

    CAS  PubMed  Google Scholar 

  21. Dobbs SP, Hewett PW, Johnson IR, Carmichael J, Murray JC. Angiogenesis is associated with vascular endothelial growth factor expression in cervical intraepithelial neoplasia. Br J Cancer 1997;76:1410–1415.

    CAS  PubMed  Google Scholar 

  22. Jensen HM, Chen I, DeVault MR, Lewis AE. Angiogenesis induced by “normal” human breast tissue: A probable marker for precancer. Science 1982;218:293–295.

    Article  CAS  PubMed  Google Scholar 

  23. Folkman J, Watson K, Ingber D, Hanahan D. Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 1989;339:58–61.

    Article  CAS  PubMed  Google Scholar 

  24. García de la Torre N, Buley I, Wass JAH, Jackson D, Turner HE. Angiogenesis and lymphangiogenesis in parathyroid proliferative lesions. J Clin Endocrinol Metab 2004;89:2890–2896.

    Article  PubMed  CAS  Google Scholar 

  25. Bernini GP, Moretti A, Bonadio AG, Menicagli M, Viacava P, Naccarato AG, Iacconi P, Miccoli P, Salvetti A. Angiogenesis in human normal and pathologic adrenal cortex. J Clin Endocrinol Metab 2002;87:4961–4965.

    Article  CAS  PubMed  Google Scholar 

  26. Turner HE, Moore NR, Byrne JV, Wass JAH. Pituitary, thyroid and adrenal incidentalomas. Endocr Rel Cancer 1998;5:131–150.

    Article  Google Scholar 

  27. Stanfield JP. The blood supply of the human pituitary gland. J Anat 1960;94:257–273.

    CAS  PubMed  Google Scholar 

  28. Terayama N, Terada T, Nakanuma Y. An immunohistochemical study of tumour vessels in metastatic liver cancers and the surrounding liver tissue. Histopathology 1996;29:37–43.

    Article  CAS  PubMed  Google Scholar 

  29. Powell DF, Baker HL, Laws ER. The primary angiographic findings in pituitary adenomas. Radiology 1974;110:589–595.

    CAS  PubMed  Google Scholar 

  30. Yuh WT, Fisher DJ, Nguyen HD, Tali ET, Gao F, Simonson TM, Schlechte JA. Sequential MR enhancement pattern in normal pituitary gland and in pituitary adenoma. AJNR Am J Neuroradiol 1994;15:101–108.

    CAS  PubMed  Google Scholar 

  31. Gorczyca W, Hardy J. Microadenomas of the human pituitary and their vascularization. Neurosurgery 1988;22:1–6.

    Article  CAS  PubMed  Google Scholar 

  32. Schechter J, Goldsmith P, Wilson C, Weiner R. Morphological evidence for the presence of arteries in human prolactinomas. J Clin Endocrinol Metab 1988;67:713–719.

    CAS  PubMed  Google Scholar 

  33. Elias KA, Weiner RI. Direct arterial vascularization of oestrogen-induced prolactin-secreting anterior pituitary tumours. Proc Natl Acad Sci USA 1984;81:4549–4553.

    Article  CAS  PubMed  Google Scholar 

  34. Schechter J, Ahmad N, Elias K, Weiner R. Oestrogen-induced tumours: changes in the vasculature in two strains of rat. Am J Anat 1987;179:315–323.

    Article  CAS  PubMed  Google Scholar 

  35. Delgrange E, Trouillas J, Maiter D, Donckier J, Turniaire J. Sex-related difference in the growth of prolactinomas: A clinical and proliferation marker study. J Clin Endocrinol Metab 1997;82:2102–2107.

    Article  CAS  PubMed  Google Scholar 

  36. Vidal S, Kovacs K, Horvath E, Scheithauer BW, Kuroki T, Lloyd RV. Microvessel density in pituitary adenomas and carcinomas. Virchows Arch 2001;438:595–602.

    Article  CAS  PubMed  Google Scholar 

  37. Turner HE, Nagy Z, Gatter KC, Esiri MM, Harris AL, Wass JAH. Angiogenesis in pituitary adenomas- relationship to endocrine function, treatment and outcome. J Endocrinol 2000;165:475–481.

    Article  CAS  PubMed  Google Scholar 

  38. Turner HE, Nagy Z, Gatter KC, Esiri MM, Wass JAH, Harris AL. Proliferation, bcl-2 expression and angiogenesis in pituitary adenomas: Relationship to tumour behaviour. Br J Cancer 2000;82:1441–1445.

    CAS  PubMed  Google Scholar 

  39. Vidal S, Horvath E, Kovacs K, Lloyd RV, Scheithauer BW. Microvascular structural entropy: A novel approach to assess angiogenesis in pituitary tumours. Endocr Pathol 2003;14:239–247.

    Article  PubMed  Google Scholar 

  40. Turner HE, Nagy Z, Esiri MM, Harris AL, Wass JAH. Role of Matrix Metalloproteinase 9 in pituitary tumour behaviour. J Clin Endocrinol Metab 2000;85:2931–2935.

    Article  CAS  PubMed  Google Scholar 

  41. Linn R, DuPont BR, Knight CB, Plaetke R, Leach RJ. Reassignment of the 92kDa type IV collagenase gene (CLG4B) to human chromosome 20. Cytogenet Cell Genet 1996;72:159–161.

    Article  CAS  PubMed  Google Scholar 

  42. Vu TH, Shipley JM, Bergers G, Berger JE, Helms JA, Hanahan D, Shapiro SD, Senior RM, Werb Z. MMP9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes. Cell 1998;93:411–422.

    Article  CAS  PubMed  Google Scholar 

  43. Turner HE, Nagy Z, Sullivan N, Esiri MM, Wass JAH. Expression analysis of cyclins in pituitary adenomas and the normal pituitary gland. Clin End 2000;53:337–344.

    Article  CAS  Google Scholar 

  44. Ferrara N, Schweigerer L, Neufeld G, Mitchell R, Gospodarowicz D. Pituitary follicular cells produce basic fibroblast growth factor. Proc Natl Acad Sci USA 1987;84:5775–5777.

    Article  Google Scholar 

  45. Ferrara N, Henzel WJ. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun 1989;161:851–858.

    Article  CAS  PubMed  Google Scholar 

  46. Ferrara N, Bunting S. Vascular endothelial growth factor, a specific regulator of angiogenesis. Curr Opin Nephrol Hypertens 1996;5:35–44.

    Article  CAS  PubMed  Google Scholar 

  47. Alon T, Hemo I, Itin A, Pe'er J, Stone J, Keshet E. Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. Nat Med 1995;1:1024–1028.

    Article  CAS  PubMed  Google Scholar 

  48. Jabbour HN, Boddy SC, Lincoln GA. Pattern and localisation of expression of vascular endothelial growth factor and its receptor flt-1 in the ovine pituitary gland: expression is independent of hypothalamic control. Mol Cell Endocrinol 1997;134:91–100.

    Article  CAS  PubMed  Google Scholar 

  49. Vidal S, Oliveira MC, Kovacs K, Scheithauer BW, Lloyd R. Immunolocalization of vascular endothelial growth factor in the GH3 cell line. Cell Tissue Res 2000;300:83–88.

    CAS  PubMed  Google Scholar 

  50. Lohrer P, Gloddek J, Hopfner U, Losa M, Uhl E, Pagotto U, Stalla GK, Renner. Vascular endothelial growth factor production and regulation in rodent and human pituitary tumour cells in vitro. Neuroendocrinology 2001;74:95–105.

    Article  CAS  PubMed  Google Scholar 

  51. Nishikawa R, Cheng SY, Nagashima R, Huang HJ, Cavenee WK, Matsutani M. Expression of vascular endothelial growth factor in human brain tumours. Acta Neuropathol (Berl) 1998;96:453–462.

    Article  CAS  Google Scholar 

  52. Lloyd RV, Scheithauer BW, Kuroki T, Vidal S, Kovacs K, Stefaneanu L. Vascular Endothelial Growth Factor (VEGF) Expression in Human Pituitary Adenomas and Carcinomas. Endocr Pathol 1999;10:229–235.

    Article  CAS  PubMed  Google Scholar 

  53. Vlodavsky I, Folkman J, Sullivan R, Fridman R, Ishai-Michaaeli R, Sasse J, Klagsbrun M. Endothelial cell-derived basic fibroblast growth factor: synthesis and deposition into subendothelial extracellular matrix. Proc Natl Acad Sci USA 1987;84:2292–2296.

    Article  CAS  PubMed  Google Scholar 

  54. Komorowski J, Jankewicz J, Stepien H. Vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and soluble interleukin-2 receptor (sIL-2R) concentrations in peripheral blood as markers of pituitary tumours. Cytobios 2000;101:151–159.

    CAS  PubMed  Google Scholar 

  55. Basu S, Nagy JA, Pal S, Vasile E, Eckelhoefer IA, Bliss VS, Manseau EJ, Dasgupta PS, Dvorak HF, Mukhopadhyay D. The neurotransmitter dopamine inhibits angiogenesis induced by vascular permeability factor/vascular endothelial growth factor. Nat Med 2001;7:569–574.

    Article  CAS  PubMed  Google Scholar 

  56. Stepien H, Grochal M, Zielinski KW, Mucha S, Kunert-Radek J, Kulig A, Stawowy A, Pisarek H. Inhibitory effects of fumagillin and its analogue TNP-470 on the function, morphology and angiogenesis of an oestrogen-induced prolactinoma in Fischer 344 rats. J Endocrinol 1996;150:99–106.

    Article  CAS  PubMed  Google Scholar 

  57. Banerjee SK, Sarkar DK, Weston AP, De A, Campbell DR. Over expression of vascular endothelial growth factor and its receptor during the development of oestrogen-induced rat pituitary tumours may mediate oestrogen-initiated tumour angiogenesis. Carcinogenesis 1997;18:1155–1161.

    Article  CAS  PubMed  Google Scholar 

  58. Banerjee SK, Zoubine MN, Sarkar DK, Weston AP, Shah JH, Campbell DR. 2-Methoxyestradiol blocks oestrogen-induced rat pituitary tumour growth and tumour angiogenesis: possible role of vascular endothelial growth factor. Anticancer Res 2000;20:2641–2645.

    CAS  Google Scholar 

  59. Clapp C, Martial JA, Guzman RC, Rentier-Delure F, Weiner RI. The 16-kilodalton N-terminal fragment of human prolactin is a potent inhibitor of angiogenesis. Endocrinology 1993;133:1292–1299.

    Article  CAS  PubMed  Google Scholar 

  60. D'Angelo G, Martini JF, Iiri T, Fantl WJ, Martial J, Weiner RI. 16K human prolactin inhibits vascular endothelial growth factor-induced activation of Ras in capillary endothelial cells. Mol Endocrinol 1999;13:692–704.

    Article  PubMed  Google Scholar 

  61. Duenas Z, Torner L, Corbacho AM, Ochoa A, Gutierrez-Ospina G, Lopez-Barrera F, Barrios FA, Berger P, Martinez de la Escalera G, Clapp C. Inhibition of rat corneal angiogenesis by 16-kDa prolactin and by endogenous prolactin-like molecules. Invest Ophthalmol Vis Sci 1999;40:2498–2505.

    CAS  PubMed  Google Scholar 

  62. Clapp C, Sears PS, Russell DH, Richards J, Levay-Young BK, Nicoll CS. Biological and immunological characterization of cleaved and 16K forms of rat prolactin. Endocrinology 1988;122:2892–2898.

    Article  CAS  PubMed  Google Scholar 

  63. Zhang X, Horwitz GA, Heaney AP, Nakashima M, Prezant TR, Bronstein MD, Melmed S. Pituitary tumour transforming gene (PTTG) expression in pituitary adenomas. J Clin Endocrinol Metab 1999;84:761–767.

    Article  CAS  PubMed  Google Scholar 

  64. Heaney AP, Horwitz GA, Wang Z, Singson R, Melmed S. Early involvement of oestrogen-induced pituitary tumour transforming gene and fibroblast growth factor expression in prolactinoma pathogenesis. Nat Med 1999;5:1317–1321.

    Article  CAS  PubMed  Google Scholar 

  65. Heaney AP, Fernando M, Melmed S. Functional role of oestrogen in pituitary tumour pathogenesis. J Clin Invest 2002;109:277–283.

    Article  CAS  PubMed  Google Scholar 

  66. Heaney AP, Singson R, McCabe CJ, Nelson V, Nakashima M, Melmed S. Expression of pituitary-tumour transforming gene in colorectal tumours. Lancet 2000;355:716–719.

    Article  CAS  PubMed  Google Scholar 

  67. Ishikawa H, Heaney AP, Yu R, Horwitz GA, Melmed S. Human pituitary tumour-transforming gene induces angiogenesis. J Clin Endocrinol Metab 2001;86:867–874.

    Article  CAS  PubMed  Google Scholar 

  68. McCabe CJ, Boelaert K, Tannahill LA, Heaney AP, Stratford AL, Khaira JS, Hussain S, Sheppard MC, Franklyn JA, Gittoes NJ. Vascular endothelial growth factor, its receptor KDR/Flk-1, and pituitary tumour transforming gene in pituitary tumours. J Clin Endocrinol Metab 2002;87:4238–4244.

    Article  CAS  PubMed  Google Scholar 

  69. Pandey J, Bannout A, Wendell DL. The Edpm5 locus prevents The angiogenic switch in an oestrogen-induced rat pituitary tumour. Carcinogenesis 2004 (electronic publication ahead of print).

Download references

Author information

Authors and Affiliations

  1. Servicio de Endocrinología, Hospital Clínico San Carlos, Profesor Martín Lagos s/n, 28040, Madrid, Spain

    N. Garcia de la Torre

  2. Department of Endocrinology, The Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Headington, Oxford, OX3 7LJ, UK

    H. E. Turner & J. A. H. Wass

Authors
  1. N. Garcia de la Torre
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H. E. Turner
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. A. H. Wass
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J. A. H. Wass.

Rights and permissions

Reprints and permissions

About this article

Cite this article

la Torre, N.G.d., Turner, H.E. & Wass, J.A.H. Angiogenesis in Prolactinomas: Regulation and Relationship with Tumour Behaviour. Pituitary 8, 17–23 (2005). https://doi.org/10.1007/s11102-005-5081-6

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11102-005-5081-6

Key Words

Search

Navigation