Abstract
The prediction of pituitary tumour behaviour, in terms of response to treatment from which can be derived optimal management strategies, is a challenge that has been approached using several different means. Angiogenesis in other tumour types has been shown to be correlated with poor response to treatment and tumour recurrence. The aim of this paper is to assess the role of measurements of cell proliferation and angiogenesis in predicting pituitary tumour behaviour. The proliferative capacity of the tumour was assessed using the Ki-67 labelling index (LI) while bcl-2 expression was used to assess anti-apoptotic pathways. The microvessel density (MVD) was assessed using antibodies to CD31 and factor VIII-related antigen, and with biotinylated ulex europaeus agglutinin I. There was no difference between Ki-67 LI and MVD of functionless tumours that recurred and those that did not, but bcl-2 expression was significantly lower in tumours that subsequently regrew. Macroprolactinomas had significantly higher LI than microprolactinomas and than all other tumours. Cell proliferation and angiogenesis were not related, showing that both processes are under different control mechanisms in pituitary tumours. In contrast there was a positive relationship between markers of angiogenesis and bcl-2 expression in prolactinomas, GH-secreting tumours and non-recurrent functionless tumours with higher levels of bcl-2 expression being found in the more vascular tumours. These findings may suggest that angiogenesis is related to the ability of tumour cells to survive rather than their proliferative activity. © 2000 Cancer Research Campaign
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Abe T, Sanno N, Osamura YR and Matsumoto K (1997) Proliferative potential in pituitary adenomas: measurement by monoclonal antibody MIB-1. Acta Neurochir 139: 613–618
Berardo MD, Elledge RM, de Moor C, Clark GM, Osborne CK and Allred DC (1998) bcl-2 and apoptosis in lymph node positive breast carcinoma. Cancer 82: 1296–1302
Blagosklonny MV, An WG, Romanova LY, Trepel J, Fojo T and Neckers L (1998) p53 inhibits hypoxia-inducible factor-stimulated transcription. J Biol Chem 273: 11995–11998
Bochner BH, Cote RJ, Weidner N, Groshen S, Chen SC and Skinner DG (1995) Angiogenesis in bladder cancer: relationship between microvessel density and tumour prognosis. J Natl Cancer Inst 87: 1603–1612
Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brusselmans K, Dewerchin M, Neeman M, Bono F, Abramovitch R, Maxwell P, Koch CJ, Ratcliffe P, Moons L, Jain RK, Collen D and Keshet E (1998) Role of HIF-1 alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394: 485–489
Charpin C, Garcia S, Bonnier P, Martini F, Andrac L, Horschowski N, Lavaut MN and Allasia C (1998) bcl-2 automated and quantitative immunocytochemical assays in breast carcinomas: correlation with 10-year follow-up. J Clin Oncol 16: 2025–2031
Christofori G, Naik P and Hanahan D (1995) Vascular endothelial growth factor and its receptors, flt-1 and flk-1, are expressed in normal pancreatic islets and throughout islet cell tumorigenesis. Mol Endocrinol 9: 1760–1770
Dameron KM, Volpert OV, Tainsky MA and Bouck N (1994) Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science 265: 1582–1584
Delgrange E, Trouillas J, Maiter D, Donckier J and Turniaire J (1997) Sex-related difference in the growth of prolactinomas: a clinical and proliferation marker study. J Clin Endocrinol Metab 82: 2102–2107
Fan L and Iseki S (1998) Immunohistochemical localization of vascular endothelial growth factor in the endocrine glands of the rat. Arch Histol Cytol 61: 17–28
Fontanini G, Vignati S, Bigini D, Mussi A, Lucchi M, Angeletti CA, Basolo F and Bevilacqua G (1995) Bcl-2 protein: a prognostic factor inversely correlated to p53 in non-small-cell lung cancer. Br J Cancer 71: 1003–1007
Fox SB, Gatter KC, Bicknell R, Going JJ, Stanton P, Cooke TG and Harris AL (1993) Relationship of endothelial cell proliferation to tumor vascularity in human breast cancer. Cancer Res 53: 4161–4163
Fox SB, Leek RD, Weekes MP, Whitehouse RM, Gatter KC and Harris AL (1995) Quantification and prognostic value of breast cancer angiogenesis: Chalkley count and computer image analysis. J Pathol 177: 275–283
Frank RE, Saclarides TJ, Leurgans S, Speziale NJ, Drab EA and Rubin DB (1995) Tumor angiogenesis as a predictor of recurrence and survival in patients with node-negative colon cancer. Ann Surg 222: 695–690
Gasparini G, Weidner N, Bevilacqua P, Maluta S, Palma PD, Caffo O, Barbareschi M, Boracchi P, Marubini E and Pozza F (1994) Tumour microvessel density, p53 expression, tumour size and peritumoural lymphatic vessel invasion are relevant prognostic markers in node-negative breast carcinoma. J Clin Oncol 12: 454–466
Holthofer H, Virtanen I, Kariniemi AL, Hormia M, Linder E and Miettinen A (1982) Ulex europaeus I lectin as a marker for vascular endothelium in human tissues. Lab Invest 47: 60–65
Hockenbery DM (1992) The bcl-2 oncogene and apoptosis. Semin Immunol 4: 413–420
Jin L, Qian X, Kulig E, Sanno N, Scheithauer BW, Kovacs K, Young WF Jr and Lloyd RV (1997) Transforming growth factor-beta, transforming growth factor-beta receptor II, and p27 Kip1 expression in nontumorous and neoplastic human pituitaries. Am J Pathol 151: 509–510
Knosp E, Kitz K and Perneczky A (1989) Proliferation activity in pituitary adenomas: measurement by monoclonal antibody Ki-67. Neurosurgery 25: 927–930
Knowlton K, Mancini M, Creason S, Morales C, Hockenbery D and Anderson BO (1998) Bcl-2 slows in vitro breast cancer growth despite its antiapoptotic effect. J Surg Res 76: 22–26
Landis JR and Koch GC (1977) The measurement of observer agreement for categorical data. Biometrics 33: 159–174
Maeda K, Chung Y-S, Takasuka S, Ogawa Y, Sawada T and Yamashita Y (1995) Tumour angiogenesis as a predictor of recurrence in gastric carcinoma. J Clin Oncol 13: 477–481
Mukai K, Rosai J and Burgdorf WHC (1980) Localisation of factor VIII-related antigen in vascular endothelial cells using an immunoperoxidase method. Am J Surg Pathol 4: 273
Nagy ZS, Esiri MM and Smith AD (1997) Expression of cell division markers in the hippocampus in Alzheimer's disease and other neurodegenerative conditions. Acta Neuropathol 93: 294–300
Nor JE, Christensen J, Mooney DJ and Polverini PJ (1999) Vascular endothelial growth factor (VEGF)-mediated angiogenesis is associated with enhanced endothelial cell survival and induction of Bcl-2 expression. Am J Pathol 154: 375–384
Terris B, Scoazec JY, Rubbia L, Bregeaud L, Pepper MS, Ruszniewski P, Belghiti J, Flejou J and Degott C (1998) Expression of vascular endothelial growth factor in digestive neuroendocrine tumours. Histopathology 32: 133–138
Thapar K, Kovacs K, Scheithauer BW, Stefaneanu L, Horvath E, Pernicone PJ, Murray D and Laws ER (1996 a) Proliferative activity and invasiveness among pituitary adenomas and carcinomas: an analysis using the MIB-1 antibody. Neurosurgery 38: 99–107
Thapar K, Scheithauer BW, Kovacs K, Pernicone PJ and Laws ER Jr (1996 b) p53 expression in pituitary adenomas and carcinomas: correlation with invasiveness and tumor growth fractions. Neurosurgery 38: 763–770; discussion 770–771
Turner HE and Wass JAH (1999) Are markers of proliferation valuable in the histological assessment of pituitary tumours?. Pituitary 1: 147–151
Vartanian RK and Weidner N (1994) Correlation of intratumoural endothelial cell proliferation with microvessel density (tumour angiogenesis) and tumour cell proliferation in breast carcinoma. Am J Pathol 144: 1188–1194
Vermeulen PB, Gasparini G, Fox SB, Toi M, Martin L, McCulloch P, Pezella F, Viale G, Weidner N, Harris AL and Dirix LY (1996) Quantification of angiogenesis in solid human tumours: an international consensus on the methodology and criteria of evaluation. Eur J Cancer 32A: 2474–2484
Vermeulen PB, Dirix LY, Libura J, Vanhoolst IF, Van Marck E and Oosterom AT (1997) Correlation of the fractions of proliferating tumour and endothelial cells in breast and colorectal adenocarcinoma is independent of tumour histiotype and microvessel density. Microvasc Res 54: 88–92
Wang DG, Johnston CF, Atkinson AB, Heaney AP, Mirakhur M and Buchanan KD (1996) Expression of bcl-2 oncoprotein in pituitary tumours: comparison with c-myc. JClinPathol 49: 795–797
Weidner N, Semple JP, Welch WR and Folkman J (1991) Tumour angiogenesis and metastasis: correlation in invasive breast carcinoma. N Engl J Med 324: 1–8
Weidner N, Folkman J, Pozza F, Bevilacqua P, Allred EN, Moore DH, Meli S and Gasparini G (1992) Tumour angiogenesis: a new significant and independent prognostic indicator in early stage breast carcinoma. J Natl Cancer Inst 84: 1875–1887
Weidner N (1996) Intratumoural vascularity as a prognostic factor in cancers of the urogenital tract. Eur J Cancer 32A: 2506–2512
Witt M and Klessen Ch (1987) Galactose and fucose binding sites in anterior pituitary cells of the rat: detection by means of biotinylated lectins. Folia Histochem Cytobiol 25: 115–118
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Turner, H., Nagy, Z., Gatter, K. et al. Proliferation, bcl-2 expression and angiogenesis in pituitary adenomas: relationship to tumour behaviour. Br J Cancer 82, 1441–1445 (2000). https://doi.org/10.1054/bjoc.1999.1074
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1054/bjoc.1999.1074