title: Changes in the balance between proliferation and apoptosis during the progression of malignancy in thyroid tumours.
abstract: The aim of this study was to gain better insight into molecular changes which reflect disturbances in the balance between proliferation and apoptosis during progression of thyroid malignancy from papillary microcarcinoma (PMC) via clinically manifest papillary carcinoma (PTC) to anaplastic carcinoma (ATC). The apoptosis related molecules (Bcl-2, Bax) and proliferation related marker (PCNA) were analysed immunohistochemically in 120 archival cases comprising PMC (n=34), PTC (n=52) and ATC (n=34). In addition, in situ apoptotic cell death was analysed by the TUNEL method. The average Bcl-2 staining score did not differ between PMC and PTC (p>0.05), but was significantly lower in ATC (p<0.05).The Bax score was higher in PTCs and ATCs than in PMCs (p<0.05). Due to these changes, the Bcl-2/Bax ratio showed a marked decrease from PMC to ATC (p<0.05), while proliferation activity increased significantly from PTC to ATC (p<0.05). Despite high Bax expression, the rate of apoptotic cell death was low in the investigated carcinomas, especially in ATC, i.e. the increase in proliferative activity was not counterbalanced with appropriate cell death. Differences were found in the expression of apoptotic molecules (Bcl-2 and Bax), their ratio (Bcl-2 /Bax) and in the rate of apoptotic cell death and proliferative activity between PMC, PTC and ATC, indicating that disturbances in the balance between apoptosis and proliferation, in favour of the latter, occur gradually during the progression of malignancy in thyroid tumours.
authors.affiliation: Institute for the Application of Nuclear Energy - INEP, University of Belgrade, Zemun - Belgrade, Serbia. dubravka@inep.co.yu
authors.forename: D
authors.initials: D
authors.lastname: Cvejic
authors.forename: S
authors.initials: S
authors.lastname: Selemetjev
authors.forename: S
authors.initials: S
authors.lastname: Savin
authors.forename: I
authors.initials: I
authors.lastname: Paunovic
authors.forename: S
authors.initials: S
authors.lastname: Tatic
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D049109:Cell Proliferation; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000378:metabolism / Q000473:pathology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C494826:BAX protein, human; D018809:Proliferating Cell Nuclear Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein
references.citation: Ann Oncol. 2000 Sep;11(9):1083-9
references.pmid: 11061600
references.citation: Curr Biol. 1993 Jun 1;3(6):391-4
references.pmid: 15335741
references.citation: Cancer. 1978 Jun;41(6):2267-75
references.pmid: 657091
references.citation: Surgery. 2006 Dec;140(6):899-905; discussion 905-6
references.pmid: 17188136
references.citation: Eur J Histochem. 2008 Jul-Sep;52(3):153-62
references.pmid: 18840555
references.citation: Nature. 1991 Jun 6;351(6326):453-6
references.pmid: 2046748
references.citation: Neoplasma. 2001;48(4):299-301
references.pmid: 11712682
references.citation: Biochim Biophys Acta. 2004 Mar 1;1644(2-3):229-49
references.pmid: 14996506
references.citation: Am J Med. 1994 Nov;97(5):418-28
references.pmid: 7977430
references.citation: Eur J Histochem. 2007 Oct-Dec;51(4):291-300
references.pmid: 18162459
references.citation: J Cell Biol. 1994 Jan;124(1-2):1-6
references.pmid: 8294493
references.citation: Adv Anat Pathol. 2006 Mar;13(2):69-75
references.pmid: 16670460
references.citation: Endocr Pathol. 2003 Fall;14(3):183-91
references.pmid: 14586064
references.citation: Cancer. 1997 Feb 1;79(3):564-73
references.pmid: 9028369
references.citation: Crit Rev Oncol Hematol. 1995 Feb;18(2):67-102
references.pmid: 7695829
references.citation: J Pathol. 1994 Apr;172(4):337-42
references.pmid: 8207614
references.citation: Br J Cancer. 1996 Jan;73(2):139-43
references.pmid: 8546897
references.citation: Histopathology. 1998 Jan;32(1):35-42
references.pmid: 9522214
references.citation: Pathol Int. 2005 Nov;55(11):694-702
references.pmid: 16271081
references.citation: Acta Chir Belg. 2005 Nov-Dec;105(6):644-8
references.pmid: 16438077
references.citation: J Cell Mol Med. 2003 Jul-Sep;7(3):249-57
references.pmid: 14594549
references.citation: J Clin Endocrinol Metab. 2006 Jun;91(6):2171-8
references.pmid: 16478817
references.citation: Arch Otolaryngol Head Neck Surg. 1988 Jan;114(1):40-4
references.pmid: 3334817
references.citation: Surg Today. 1999;29(3):204-8
references.pmid: 10192728
references.citation: Endocr Pathol. 1993 Dec;4(4):215-221
references.pmid: 32370456
references.citation: Int J Cancer. 2001 Jun 15;92(6):805-11
references.pmid: 11351299
references.citation: Virchows Arch. 1997 Feb;430(2):125-30
references.pmid: 9083515
references.citation: Exp Oncol. 2004 Dec;26(4):282-6
references.pmid: 15627060
references.citation: Thyroid. 2000 Feb;10(2):117-22
references.pmid: 10718547
references.citation: Eur J Surg Oncol. 2006 Dec;32(10):1144-8
references.pmid: 16872798
references.citation: Pathology. 2008 Aug;40(5):475-80
references.pmid: 18604733
references.citation: Genes Dev. 1999 Aug 1;13(15):1899-911
references.pmid: 10444588
references.citation: J Clin Endocrinol Metab. 1996 Jul;81(7):2726-30
references.pmid: 8675602