Skip to main content

Advertisement

SpringerLink
Log in

Enhanced nestin expression and small blood vessels in human pituitary adenomas

  • Published:
Pituitary Aims and scope Submit manuscript

Abstract

The role of angiogenesis in human pituitary tumor progression is questioned. Our aim was to characterize the morphologic changes that occur in the vasculature of pituitary adenomas, in correlation with the expression of nestin, a protein found in endothelial cells of newly formed vessels of developing organs. We also evaluated the relation of angiogenic markers and nestin with Ki-67 index. Immunohistochemical studies were performed on paraffin embedded samples of 47 pituitary adenomas and six normal pituitaries. We determined microvessel density (number of CD31+ or CD34+ vessels per square millimetre), vascular area (cumulative area occupied by vessels), average vessel size, and further classified vessels as small (<100 μm2) or large (>100 μm2). We correlated the above parameters with nestin expression and Ki-67 index. Lower vascular area compared to normal tissue was found in adenomas (p < 0.05). Interestingly, pituitary adenomas had significantly more small vessels than control pituitaries (p < 0.04 for CD31 and CD34). In tumors many capillaries were positive for nestin, while scarce staining was detected in controls, so that nestin positive area was significantly higher in tumors. Furthermore, nestin area correlated positively with the % of small vessels. Ki-67 correlated neither with vascular area nor with nestin expression. In human pituitary tumors there was a predominance of small capillaries in correlation with increased expression of the progenitor marker nestin. We suggest that angiogenesis is an active process in these tumors, in spite of their low total vascular area when compared to normal pituitaries.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186

    Article  CAS  PubMed  Google Scholar 

  2. Folkman J (1990) What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 82:4–6

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. Weidner N, Semple J, Welch W, Folkman J (1991) Tumor angiogenesis and metastasis–correlation in invasive breast carcinoma. N Engl J Med 324:1–8

    Article  CAS  PubMed  Google Scholar 

  5. Weidner N (1996) Intratumoral vascularity as a prognostic factor in cancers of the urogenital tract. Eur J Cancer 32A:2506–2512

    Article  CAS  PubMed  Google Scholar 

  6. Turner HE, Harris AL, Melmed S, Wass JA (2003) Angiogenesis in endocrine tumors. Endocr Rev 24:600–632

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  8. Toi M, Inada K, Suzuki H, Tominaga T (1995) Tumor angiogenesis in breast cancer: its importance as a prognostic indicator and the association with vascular endothelial growth factor expression. Breast Cancer Res Treat 36:193–204

    Article  CAS  PubMed  Google Scholar 

  9. Vermeulen PB, Dirix LY, Van Marck E, Van Oosterom AT (1996) High endothelial cell proliferation index and high microvessel density in vascular hotspots suggest an active angiogenic process in human colorectal adenocarcinomas. Angiogenesis Group. Br J Cancer 74:1506–1507

    Article  CAS  PubMed  Google Scholar 

  10. Mokry J, Ehrmann J, Karbanova J, Cizkova D, Soukup T, Suchanek J, Filip S, Kolar Z (2008) Expression of intermediate filament nestin in blood vessels of neural and non-neural tissues. Acta Medica (Hradec Kralove) 51:173–179

    Google Scholar 

  11. Gautron L, De Smedt V, Laye S (2009) Age-related changes in nestin immunoreactivity in the rat pituitary gland. Neuroendocrinology 90:19–30

    Article  CAS  PubMed  Google Scholar 

  12. Rotondo F, Kovacs K, Horvath E, Bell CD, Lloyd RV, Scheithauer BW (2006) Immunohistochemical expression of nestin in the non-tumorous hypophysis and in pituitary neoplasms. Acta Neuropathol 111:272–277

    Article  CAS  PubMed  Google Scholar 

  13. Molitch ME (2005) Pharmacologic resistance in prolactinoma patients. Pituitary 8:43–52

    Article  CAS  PubMed  Google Scholar 

  14. Cristina C, Diaz-Torga G, Baldi A, Gongora A, Rubinstein M, Low MJ, Becu-Villalobos D (2005) Increased pituitary vascular endothelial growth factor-a in dopaminergic D2 receptor knockout female mice. Endocrinology 146:2952–2962

    Article  CAS  PubMed  Google Scholar 

  15. Cristina C, Diaz-Torga G, Gongora A, Guida MC, Perez-Millan MI, Baldi A, Becu-Villalobos D (2007) Fibroblast growth factor-2 in hyperplastic pituitaries of D2R knockout female mice. Am J Physiol Endocrinol Metab 293:E1341–E1351

    Article  CAS  PubMed  Google Scholar 

  16. Nico B, Benagiano V, Mangieri D, Maruotti N, Vacca A, Ribatti D (2008) Evaluation of microvascular density in tumors: pro and contra. Histol Histopathol 23:601–607

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  18. Di Ieva A, Grizzi F, Gaetani P, Goglia U, Tschabitscher M, Mortini P, Baena R (2008) Euclidean and fractal geometry of microvascular networks in normal and neoplastic pituitary tissue. Neurosurg Rev 31:271–281

    Article  PubMed  Google Scholar 

  19. Schechter J (1972) Ultrastructural changes in the capillary bed of human pituitary tumors. Am J Pathol 67:109–126

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  21. Brem SS, Jensen HM, Gullino PM (1978) Angiogenesis as a marker of preneoplastic lesions of the human breast. Cancer 41:239–244

    Article  CAS  PubMed  Google Scholar 

  22. Poncelet C, Madelenat P, Feldmann G, Walker F, Darai E (2002) Expression of von Willebrand’s factor, CD34, CD31, and vascular endothelial growth factor in uterine leiomyomas. Fertil Steril 78:581–586

    Article  PubMed  Google Scholar 

  23. de la Torre NG, Buley I, Wass JA, Turner HE (2006) Angiogenesis and lymphangiogenesis in thyroid proliferative lesions: relationship to type and tumour behaviour. Endocr Relat Cancer 13:931–944

    Article  PubMed  Google Scholar 

  24. Jasek E, Furgal-Borzych A, Lis GJ, Litwin JA, Rzepecka-Wozniak E, Trela F (2009) Microvessel density and area in pituitary microadenomas. Endocr Pathol 20:221–226

    Article  CAS  PubMed  Google Scholar 

  25. Itoh J, Serizawa A, Kawai K, Ishii Y, Teramoto A, Osamura RY (2003) Vascular networks and endothelial cells in the rat experimental pituitary glands and in the human pituitary adenomas. Microsc Res Tech 60:231–235

    Article  PubMed  Google Scholar 

  26. Cristina C, Perez-Millan MI, Luque G, Dulce RA, Sevlever G, Berner SI, Becu-Villalobos D (2010) VEGF and CD31 association in pituitary adenomas. Endocr Pathol 21:154–160

    Article  CAS  PubMed  Google Scholar 

  27. Luque GM, Perez-Millan MI, Ornstein AM, Cristina C, Becu-Villalobos D (2011) Inhibitory effects of anti-VEGF strategies in experimental dopamine resistant prolactinomas. J Pharmacol Exp Ther 337:766–774

    Google Scholar 

  28. Lendahl U, Zimmerman LB, McKay RD (1990) CNS stem cells express a new class of intermediate filament protein. Cell 60:585–595

    Article  CAS  PubMed  Google Scholar 

  29. Veselska R, Kuglik P, Cejpek P, Svachova H, Neradil J, Loja T, Relichova J (2006) Nestin expression in the cell lines derived from glioblastoma multiforme. BMC Cancer 6:32

    Article  PubMed  Google Scholar 

  30. Gravdal K, Halvorsen OJ, Haukaas SA, Akslen LA (2009) Proliferation of immature tumor vessels is a novel marker of clinical progression in prostate cancer. Cancer Res 69:4708–4715

    Article  CAS  PubMed  Google Scholar 

  31. Mokry J, Cizkova D, Filip S, Ehrmann J, Osterreicher J, Kolar Z, English D (2004) Nestin expression by newly formed human blood vessels. Stem Cells Dev 13:658–664

    Article  CAS  PubMed  Google Scholar 

  32. Klein T, Ling Z, Heimberg H, Madsen OD, Heller RS, Serup P (2003) Nestin is expressed in vascular endothelial cells in the adult human pancreas. J Histochem Cytochem 51:697–706

    Article  CAS  PubMed  Google Scholar 

  33. Sugawara K, Kurihara H, Negishi M, Saito N, Nakazato Y, Sasaki T, Takeuchi T (2002) Nestin as a marker for proliferative endothelium in gliomas. Lab Invest 82:345–351

    Article  CAS  PubMed  Google Scholar 

  34. Teranishi N, Naito Z, Ishiwata T, Tanaka N, Furukawa K, Seya T, Shinji S, Tajiri T (2007) Identification of neovasculature using nestin in colorectal cancer. Int J Oncol 30:593–603

    CAS  PubMed  Google Scholar 

  35. Salehi F, Kovacs K, Cusimano MD, Horvath E, Bell CD, Rotondo F, Scheithauer BW (2008) Immunohistochemical expression of nestin in adenohypophysial vessels during development of pituitary infarction. J Neurosurg 108:118–123

    Article  PubMed  Google Scholar 

  36. Chen J, Hersmus N, Van Duppen V, Caesens P, Denef C, Vankelecom H (2005) The adult pituitary contains a cell population displaying stem/progenitor cell and early embryonic characteristics. Endocrinology 146:3985–3998

    Article  CAS  PubMed  Google Scholar 

  37. Vankelecom H (2007) Stem cells in the postnatal pituitary? Neuroendocrinology 85:110–130

    Article  CAS  PubMed  Google Scholar 

  38. Krylyshkina O, Chen J, Mebis L, Denef C, Vankelecom H (2005) Nestin-immunoreactive cells in rat pituitary are neither hormonal nor typical folliculo-stellate cells. Endocrinology 146:2376–2387

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  40. Vidal S, Horvath E, Kovacs K, Lloyd RV, Scheithauer BW (2003) Microvascular structural entropy: a novel approach to assess angiogenesis in pituitary tumors. Endocr Pathol 14:239–247

    Article  PubMed  Google Scholar 

  41. Pizarro CB, Oliveira MC, Pereira-Lima JF, Leaes CG, Kramer CK, Schuch T, Barbosa-Coutinho LM, Ferreira NP (2009) Evaluation of angiogenesis in 77 pituitary adenomas using endoglin as a marker. Neuropathology 29:40–44

    Article  PubMed  Google Scholar 

  42. Turner HE, Nagy Z, Gatter KC, Esiri MM, Wass JA, Harris AL (2000) Proliferation, bcl-2 expression and angiogenesis in pituitary adenomas: relationship to tumour behaviour. Br J Cancer 82:1441–1445

    Article  CAS  PubMed  Google Scholar 

  43. Niveiro M, Aranda FI, Peiro G, Alenda C, Pico A (2005) Immunohistochemical analysis of tumor angiogenic factors in human pituitary adenomas. Hum Pathol 36:1090–1095

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors acknowledge to the Consejo Nacional de Investigaciones Científicas y Técnicas, the Fundación Agencia Nacional de Promoción Científica y Técnica, and the Fundación Florencio Fiorini for the grants received that supported the work. This work was supported by the Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina (CONICET, grant PIP 640, 2009, to Damasia Becú-Villalobos), Agencia Nacional de Promoción Científica y Técnica, Buenos Aires, Argentina (grant PICT N459, 2010, to Damasia Becú-Villalobos. Agencia Nacional de Promoción Científica y Técnica, Buenos Aires, Argentina grant PICT N1326, 2008 to Carolina Cristina, and Fundación Florencio Fiorini—Academia Nacional de Medicina, Buenos Aires, Argentina 2010 to Carolina Cristina).

Conflict of interest

The authors do not have conflict of interests.

Author information

Authors and Affiliations

  1. Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina

    María Inés Perez-Millan, Guillermina María Luque & Damasia Becu-Villalobos

  2. Universidad Nacional del Noroeste de la Provincia de Buenos Aires (UNNOBA), Roque Sáenz Peña 456, 6000, Junín, Buenos Aires, Argentina

    Carolina Cristina

  3. Servicio de Neurocirugía, Hospital Santa Lucía, Buenos Aires, Argentina

    Silvia Inés Berner

  4. Servicio de Neurocirugía, Clínica Santa Isabel, Buenos Aires, Argentina

    Cristian De Bonis

  5. Departamento de Neuropatología, Instituto FLENI, Buenos Aires, Argentina

    Gustavo Sevlever

Authors
  1. María Inés Perez-Millan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Silvia Inés Berner
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Guillermina María Luque
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Cristian De Bonis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gustavo Sevlever
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Damasia Becu-Villalobos
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Carolina Cristina
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Carolina Cristina.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Perez-Millan, M.I., Berner, S.I., Luque, G.M. et al. Enhanced nestin expression and small blood vessels in human pituitary adenomas. Pituitary 16, 303–310 (2013). https://doi.org/10.1007/s11102-012-0421-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11102-012-0421-9

Keywords

Search

Navigation