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BMC Cancer
Published in: BMC Cancer 1/2011

Open Access 01-12-2011 | Research article

Apoptosis-related deregulation of proteolytic activities and high serum levels of circulating nucleosomes and DNA in blood correlate with breast cancer progression

Authors: Carina Roth, Klaus Pantel, Volkmar Müller, Brigitte Rack, Sabine Kasimir-Bauer, Wolfgang Janni, Heidi Schwarzenbach

Published in: BMC Cancer | Issue 1/2011

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Abstract

Background

As cell-free circulating DNA exists predominantly as mono- and oligonucleosomes, the focus of the current study was to examine the interplay of circulating nucleosomes, DNA, proteases and caspases in blood of patients with benign and malignant breast diseases.

Methods

The concentrations of cell-free DNA and nucleosomes as well as the protease and caspase activities were measured in serum of patients with benign breast disease (n = 20), primary breast cancer (M0, n = 31), metastatic breast cancer (M1, n = 32), and healthy individuals (n = 28) by PicoGreen, Cell Death Detection ELISA, Protease Fluorescent Detection Kit and Caspase-Glo®3/7 Assay, respectively.

Results

Patients with benign and malignant tumors had significantly higher levels of circulating nucleic acids in their blood than healthy individuals (p = 0.001, p = 0.0001), whereas these levels could not discriminate between benign and malignant lesions. Our analyses of all serum samples revealed significant correlations of circulating nucleosome with DNA concentrations (p = 0.001), nucleosome concentrations with caspase activities (p = 0.008), and caspase with protease activities (p = 0.0001). High serum levels of protease and caspase activities associated with advanced tumor stages (p = 0.009). Patients with lymph node-positive breast cancer had significantly higher nucleosome levels in their blood than node-negative patients (p = 0.004). The presence of distant metastases associated with a significant increase in serum nucleosome (p = 0.01) and DNA levels (p = 0.04), and protease activities (p = 0.008).

Conclusion

Our findings demonstrate that high circulating nucleic acid concentrations in blood are no indicators of a malignant breast tumor. However, the observed changes in apoptosis-related deregulation of proteolytic activities along with the elevated serum levels of nucleosomes and DNA in blood are linked to breast cancer progression.
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Literature
1.
Coughlin SS, Ekwueme DU: Breast cancer as a global health concern. Cancer Epidemiol. 2009, 33 (5): 315-318. 10.1016/j.canep.2009.10.003.CrossRefPubMed
2.
Vetto JT, Luoh SW, Naik A: Breast cancer in premenopausal women. Curr Probl Surg. 2009, 46 (12): 944-1004. 10.1067/j.cpsurg.2009.07.002.CrossRefPubMed
3.
Fleischhacker M, Schmidt B: Circulating nucleic acids (CNAs) and cancer--a survey. Biochim Biophys Acta. 2007, 1775 (1): 181-232.PubMed
4.
Stroun M, Lyautey J, Lederrey C, Olson-Sand A, Anker P: About the possible origin and mechanism of circulating DNA apoptosis and active DNA release. Clin Chim Acta. 2001, 313 (1-2): 139-142. 10.1016/S0009-8981(01)00665-9.CrossRefPubMed
5.
Enari M, Sakahira H, Yokoyama H, Okawa K, Iwamatsu A, Nagata S: A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature. 1998, 391 (6662): 43-50. 10.1038/34112.CrossRefPubMed
6.
Choi JJ, Reich CF, Pisetsky DS: The role of macrophages in the in vitro generation of extracellular DNA from apoptotic and necrotic cells. Immunology. 2005, 115 (1): 55-62. 10.1111/j.1365-2567.2005.02130.x.CrossRefPubMedPubMedCentral
7.
Rumore P, Muralidhar B, Lin M, Lai C, Steinman CR: Haemodialysis as a model for studying endogenous plasma DNA: oligonucleosome-like structure and clearance. Clin Exp Immunol. 1992, 90 (1): 56-62. 10.1111/j.1365-2249.1992.tb05831.x.CrossRefPubMedPubMedCentral
8.
Schwarzenbach H, Kemper B, Beeger C, Otterbach F, Kimmig R, Pantel K, S K-B: Evaluation of cell-free tumor DNA in blood and disseminated tumor cells in bone marrow of patients with primary breast cancer. Breast Cancer Res. 2009
9.
Schwarzenbach H, Muller V, Beeger C, Gottberg M, Stahmann N, Pantel K: A critical evaluation of loss of heterozygosity detected in tumor tissues, blood serum and bone marrow plasma from patients with breast cancer. Breast Cancer Res. 2007, 9 (5): R66-10.1186/bcr1772.CrossRefPubMedPubMedCentral
10.
Schwarzenbach H, Muller V, Stahmann N, Pantel K: Detection and characterization of circulating microsatellite-DNA in blood of patients with breast cancer. Ann N Y Acad Sci. 2004, 1022: 25-32. 10.1196/annals.1318.005.CrossRefPubMed
11.
Schwarzenbach H, Pantel K, Kemper B, Beeger C, Otterbach F, Kimmig R, Kasimir-Bauer S: Comparative evaluation of cell-free tumor DNA in blood and disseminated tumor cells in bone marrow of patients with primary breast cancer. Breast Cancer Res. 2009, 11 (5): R71-10.1186/bcr2404.CrossRefPubMedPubMedCentral
12.
Holdenrieder S, Nagel D, Schalhorn A, Heinemann V, Wilkowski R, von Pawel J, Raith H, Feldmann K, Kremer AE, Muller S, et al: Clinical relevance of circulating nucleosomes in cancer. Ann N Y Acad Sci. 2008, 1137: 180-189. 10.1196/annals.1448.012.CrossRefPubMed
13.
Deligezer U, Akisik EE, Akisik EE, Kovancilar M, Bugra D, Erten N, Holdenrieder S, Dalay N: H3K9me3/H4K20me3 Ratio in Circulating Nucleosomes as Potential Biomarker for Colorectal Cancer. Adv Exp Med Biol Ed Gahan P Springer. 2010, 97-104.
14.
Holdenrieder S, Spuler A, Tischinger M, Nagel D, Stieber P: Presence of Nucleosomes in Cerebrospinal Fluid of Glioblastoma Patients - Potential for Therapy Monitoring. Adv Exp Med Biol Ed Gahan P Springer. 2010, 79-84.
15.
Kohles N, Nagel D, Jüngst D, Durner J, Stieber P, Holdenrieder S: The Course of Circulating Nucleosomes in Liver Cancer Patients Undergoing Transarterial Chemoembolization Therapy. Adv Exp Med Biol Ed Gahan P Springer. 2010, 73-78.
16.
Stoetzer OJ, Fersching DMI, Holdenrieder S: Circulating Nucleosomes and DNAse in Breast Cancer Patients During Neoadjuvant Chemotherapy. Adv Exp Med Biol Ed Gahan P Springer. 2010, 85-90.
17.
Kuroi K, Tanaka C, Toi M: Plasma Nucleosome Levels in Node-Negative Breast Cancer Patients. Breast Cancer. 1999, 6 (4): 361-364. 10.1007/BF02966454.CrossRefPubMed
18.
Kuroi K, Tanaka C, Toi M: Clinical significance of plasma nucleosome levels in cancer patients. Int J Oncol. 2001, 19 (1): 143-148.PubMed
19.
Lopez-Otin C, Matrisian LM: Emerging roles of proteases in tumour suppression. Nat Rev Cancer. 2007, 7 (10): 800-808. 10.1038/nrc2228.CrossRefPubMed
20.
Turk B: Targeting proteases: successes, failures and future prospects. Nat Rev Drug Discov. 2006, 5 (9): 785-799. 10.1038/nrd2092.CrossRefPubMed
21.
22.
Vakkala M, Paakko P, Soini Y: Expression of caspases 3, 6 and 8 is increased in parallel with apoptosis and histological aggressiveness of the breast lesion. Br J Cancer. 1999, 81 (4): 592-599. 10.1038/sj.bjc.6690735.CrossRefPubMedPubMedCentral
23.
Deligezer U, Erten N, Akisik EE, Dalay N: Circulating fragmented nucleosomal DNA and caspase-3 mRNA in patients with lymphoma and myeloma. Exp Mol Pathol. 2006, 80 (1): 72-76.CrossRefPubMed
24.
Friedl P, Wolf K: Tube travel: the role of proteases in individual and collective cancer cell invasion. Cancer Res. 2008, 68 (18): 7247-7249. 10.1158/0008-5472.CAN-08-0784.CrossRefPubMed
25.
Aimes RT, Zijlstra A, Hooper JD, Ogbourne SM, Sit ML, Fuchs S, Gotley DC, Quigley JP, Antalis TM: Endothelial cell serine proteases expressed during vascular morphogenesis and angiogenesis. Thromb Haemost. 2003, 89 (3): 561-572.PubMed
26.
Pantel K, Alix-Panabieres C, Riethdorf S: Cancer micrometastases. Nat Rev Clin Oncol. 2009, 6 (6): 339-351. 10.1038/nrclinonc.2009.44.CrossRefPubMed
27.
Pantel K, Brakenhoff RH: Dissecting the metastatic cascade. Nat Rev Cancer. 2004, 4 (6): 448-456. 10.1038/nrc1370.CrossRefPubMed
28.
Schwarzenbach H, Alix-Panabieres C, Muller I, Letang N, Vendrell JP, Rebillard X, Pantel K: Cell-free Tumor DNA in Blood Plasma As a Marker for Circulating Tumor Cells in Prostate Cancer. Clin Cancer Res. 2009, 15 (3): 1032-1038. 10.1158/1078-0432.CCR-08-1910.CrossRefPubMed
29.
Clark IM, Swingler TE, Sampieri CL, Edwards DR: The regulation of matrix metalloproteinases and their inhibitors. Int J Biochem Cell Biol. 2008, 40 (6-7): 1362-1378. 10.1016/j.biocel.2007.12.006.CrossRefPubMed
30.
Hemsen A, Riethdorf L, Brunner N, Berger J, Ebel S, Thomssen C, Janicke F, Pantel K: Comparative evaluation of urokinase-type plasminogen activator receptor expression in primary breast carcinomas and on metastatic tumor cells. Int J Cancer. 2003, 107 (6): 903-909. 10.1002/ijc.11488.CrossRefPubMed
31.
Wu ZS, Wu Q, Yang JH, Wang HQ, Ding XD, Yang F, Xu XC: Prognostic significance of MMP-9 and TIMP-1 serum and tissue expression in breast cancer. Int J Cancer. 2008, 122 (9): 2050-2056. 10.1002/ijc.23337.CrossRefPubMed
32.
Jiang N, Pisetsky DS: The effect of inflammation on the generation of plasma DNA from dead and dying cells in the peritoneum. J Leukoc Biol. 2005, 77 (3): 296-302. 10.1189/jlb.0704411.CrossRefPubMed
33.
Zanetti-Dallenbach RA, Schmid S, Wight E, Holzgreve W, Ladewing A, Hahn S, Zhong XY: Levels of circulating cell-free serum DNA in benign and malignant breast lesions. Int J Biol Markers. 2007, 22 (2): 95-99.PubMed
34.
Schubbert R, Lettmann C, Doerfler W: Ingested foreign (phage M13) DNA survives transiently in the gastrointestinal tract and enters the bloodstream of mice. Mol Gen Genet. 1994, 242 (5): 495-504. 10.1007/BF00285273.CrossRefPubMed
35.
Holdenrieder S, von Pawel J, Dankelmann E, Duell T, Faderl B, Markus A, Siakavara M, Wagner H, Feldmann K, Hoffmann H, et al: Nucleosomes, ProGRP, NSE, CYFRA 21-1, and CEA in monitoring first-line chemotherapy of small cell lung cancer. Clin Cancer Res. 2008, 14 (23): 7813-7821. 10.1158/1078-0432.CCR-08-0678.CrossRefPubMed
36.
Kim MJ, Park BW, Lim JB, Kim HS, Kwak JY, Kim SJ, Park SH, Sohn YM, Moon HJ, Kim EK: Axillary lymph node metastasis: CA-15-3 and carcinoembryonic antigen concentrations in fine-needle aspirates for preoperative diagnosis in patients with breast cancer. Radiology. 2010, 254 (3): 691-697. 10.1148/radiol.09091031.CrossRefPubMed
37.
Zeiwar MM, Zaki SM, Mohammad LA, Zidan AA, El Nagar MR: HER-2 gene amplification, serum nucleosomes, CEA and CA15.3 tumor markers in breast cancer patients. Egypt J Immunol. 2007, 14 (2): 29-41.PubMed
Metadata
Title
Apoptosis-related deregulation of proteolytic activities and high serum levels of circulating nucleosomes and DNA in blood correlate with breast cancer progression
Authors
Carina Roth
Klaus Pantel
Volkmar Müller
Brigitte Rack
Sabine Kasimir-Bauer
Wolfgang Janni
Heidi Schwarzenbach
Publication date
01-12-2011
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2011
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-11-4

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