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BMC Cancer
Published in: BMC Cancer 1/2016

Open Access 01-12-2016 | Research article

Angiogenic cytokines and their influence on circulating tumour cells in sera of patients with the primary diagnosis of breast cancer before treatment

Authors: Theresa Vilsmaier, Brigitte Rack, Wolfgang Janni, Udo Jeschke, Tobias Weissenbacher, SUCCESS Study Group

Published in: BMC Cancer | Issue 1/2016

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Abstract

Background

Circulating tumour cells (CTCs) have been found to be a prognostic marker for reduced disease free survival, breast cancer–specific survival, and overall survival before the start of systemic treatment.

Methods

A total of 200 patients’ sera were included in this study, 100 patients being CTC positive and 100 patients being CTC negative. Matching criteria were histo-pathological grading, lymph node metastasis, hormone receptor status, TNM classification and survived breast cancer patients vs. deceased tumor associated patients. A multi cytokine/chemokine array was used to screen the sera for the angiogenic markers.

Results

Statistical significant correlation was exposed for sFlt1 values in regard to the CTC-Status. CTC negative patients displayed increased sFlt1 expression opposed to CTC positive breast cancer patients. Furthermore, significant enhanced PIGF values were also disclosed in CTC negative patients compared to patients being CTC positive. Analyzing the living patient collective we found significant differences in sFlt1 and PlGF values in regard to CTC negative and CTC positive patients.

Conclusion

Both vascular markers showed enhanced expression in the CTC negative patient collective. To continue, the collective graded G2 showed significantly enhanced sFlt1 expressions amongst patients with no CTCs. Moreover, the patient collective with no lymph node metastasis and CTC negativity indicated statistically significant increased sFlt1 values. A functional interaction of sFlt1 and PlGF was found, suggesting that their overexpression in tumour cells inhibits CTCs entering the peripheral blood. Furthermore, in regard to CTC negativity, sFlt1 and PlGF values may potentially serve as predictive markers.

Trial registration

The TRN of this study is NCT02181101 and the date of registration was the 4th of June 2014. The study was retrospectively registered.
Literature
1.
Organization WH. World Cancer Report 2014. 2014.
2.
Kristensen TB, Knutsson ML, Wehland M, Laursen BE, Grimm D, Warnke E, Magnusson NE. Anti-Vascular Endothelial Growth Factor Therapy in Breast Cancer. Int J Mol Sci. 2014;15(12):23024–41.CrossRefPubMedPubMedCentral
3.
Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, Reuben JM, Doyle GV, Allard WJ, Terstappen LW, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004;351(8):781–91.CrossRefPubMed
4.
Daskalaki A, Agelaki S, Perraki M, Apostolaki S, Xenidis N, Stathopoulos E, Kontopodis E, Hatzidaki D, Mavroudis D, Georgoulias V. Detection of cytokeratin-19 mRNA-positive cells in the peripheral blood and bone marrow of patients with operable breast cancer. Br J Cancer. 2009;101(4):589–97.CrossRefPubMedPubMedCentral
5.
Bidard FC, Vincent-Salomon A, Sigal-Zafrani B, Dieras V, Mathiot C, Mignot L, Thiery JP, Sastre-Garau X, Pierga JY. Prognosis of women with stage IV breast cancer depends on detection of circulating tumor cells rather than disseminated tumor cells. Ann Oncol. 2008;19(3):496–500.CrossRefPubMed
6.
Hayes DF, Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Miller MC, Matera J, Allard WJ, Doyle GV, Terstappen LW. Circulating tumor cells at each follow-up time point during therapy of metastatic breast cancer patients predict progression-free and overall survival. Clin Cancer Res. 2006;12(14 Pt 1):4218–24.CrossRefPubMed
7.
Botteri E, Sandri MT, Bagnardi V, Munzone E, Zorzino L, Rotmensz N, Casadio C, Cassatella MC, Esposito A, Curigliano G, et al. Modeling the relationship between circulating tumour cells number and prognosis of metastatic breast cancer. Breast Cancer Res Treat. 2010;122(1):211–7.CrossRefPubMed
8.
Rack B, Schindlbeck C, Juckstock J, Andergassen U, Hepp P, Zwingers T, Friedl TW, Lorenz R, Tesch H, Fasching PA et al: Circulating tumor cells predict survival in early average-to-high risk breast cancer patients. J Natl Cancer Inst. 2014;106(5):pii: dju066. doi: 10.​1093/​jnci/​dju066.
9.
Nienhuis HH, Gaykema SB, Timmer-Bosscha H, Jalving M, Brouwers AH, Lub-de Hooge MN, van der Vegt B, Overmoyer B, de Vries EG, Schroder CP. Targeting breast cancer through its microenvironment: Current status of preclinical and clinical research in finding relevant targets. Pharmacol Ther. 2015;147:63-79. doi: 10.​1016/​j.​pharmthera.​2014.​11.​004. Epub 2014 Nov 6.
10.
Harper J, Moses MA. Molecular regulation of tumor angiogenesis: mechanisms and therapeutic implications. EXS. 2006;96:223–68.PubMed
11.
Neufeld G, Kessler O. Pro-angiogenic cytokines and their role in tumor angiogenesis. Cancer Metastasis Rev. 2006;25(3):373–85.CrossRefPubMed
12.
Baeriswyl V, Christofori G. The angiogenic switch in carcinogenesis. Semin Cancer Biol. 2009;19(5):329–37.CrossRefPubMed
13.
Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 1996;86(3):353–64.CrossRefPubMed
14.
15.
16.
Ferrara N. The role of VEGF in the regulation of physiological and pathological angiogenesis. EXS. 2005;94:209–31.PubMed
17.
Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev. 2004;25(4):581–611.CrossRefPubMed
18.
Grimm D, Bauer J, Ulbrich C, Westphal K, Wehland M, Infanger M, Aleshcheva G, Pietsch J, Ghardi M, Beck M, et al. Different responsiveness of endothelial cells to vascular endothelial growth factor and basic fibroblast growth factor added to culture media under gravity and simulated microgravity. Tissue Eng A. 2010;16(5):1559–73.CrossRef
19.
Jelkmann W. Pitfalls in the measurement of circulating vascular endothelial growth factor. Clin Chem. 2001;47(4):617–23.PubMed
20.
Vatten LJ, Romundstad PR, Jenum PA, Eskild A. Angiogenic balance in pregnancy and subsequent breast cancer risk and survival: a population study. Cancer Epidemiol Biomarkers Prev. 2009;18(7):2074–8.CrossRefPubMed
21.
Gingery A, Bahe EL, Gilbert JS. Placental ischemia and breast cancer risk after preeclampsia: tying the knot. Expert Rev Anticancer Ther. 2009;9(5):671–81.CrossRefPubMed
22.
Fritz A, Percy C, Jack A, Shanmugaratnam K, Sobin L, Parkin DM, Whelan S. International Classification of Diseases for Oncology 3. Genf: WHO; 2000.
23.
24.
Mitsunaga S, Ikeda M, Shimizu S, Ohno I, Furuse J, Inagaki M, Higashi S, Kato H, Terao K, Ochiai A. Serum levels of IL-6 and IL-1beta can predict the efficacy of gemcitabine in patients with advanced pancreatic cancer. Br J Cancer. 2013;108(10):2063–9.CrossRefPubMedPubMedCentral
25.
Breitbart W, Rosenfeld B, Tobias K, Pessin H, Ku GY, Yuan J, Wolchok J. Depression, cytokines, and pancreatic cancer. Psycho-Oncology. 2014;23(3):339–45.CrossRefPubMed
26.
Verrax J, Defresne F, Lair F, Vandermeulen G, Rath G, Dessy C, Preat V, Feron O. Delivery of soluble VEGF receptor 1 (sFlt1) by gene electrotransfer as a new antiangiogenic cancer therapy. Mol Pharm. 2011;8(3):701–8.CrossRefPubMed
27.
Shibuya M. Vascular endothelial growth factor and its receptor system: physiological functions in angiogenesis and pathological roles in various diseases. J Biochem. 2013;153(1):13–9.CrossRefPubMed
28.
Bazan-Peregrino M, Sainson RC, Carlisle RC, Thoma C, Waters RA, Arvanitis C, Harris AL, Hernandez-Alcoceba R, Seymour LW. Combining virotherapy and angiotherapy for the treatment of breast cancer. Cancer Gene Ther. 2013;20(8):461–8.CrossRefPubMed
29.
Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, Ferrara N. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature. 1993;362(6423):841–4.CrossRefPubMed
30.
Rudge JS, Thurston G, Davis S, Papadopoulos N, Gale N, Wiegand SJ, Yancopoulos GD. VEGF trap as a novel antiangiogenic treatment currently in clinical trials for cancer and eye diseases, and VelociGene- based discovery of the next generation of angiogenesis targets. Cold Spring Harb Symp Quant Biol. 2005;70:411–8.CrossRefPubMed
31.
Kong HL, Hecht D, Song W, Kovesdi I, Hackett NR, Yayon A, Crystal RG. Regional suppression of tumor growth by in vivo transfer of a cDNA encoding a secreted form of the extracellular domain of the flt-1 vascular endothelial growth factor receptor. Hum Gene Ther. 1998;9(6):823–33.CrossRefPubMed
32.
Bodempudi V, Ohlfest JR, Terai K, Zamora EA, Vogel RI, Gupta K, Hebbel RP, Dudek AZ. Blood outgrowth endothelial cell-based systemic delivery of antiangiogenic gene therapy for solid tumors. Cancer Gene Ther. 2010;17(12):855–63.CrossRefPubMedPubMedCentral
33.
Schmitz V, Kornek M, Hilbert T, Dzienisowicz C, Raskopf E, Rabe C, Sauerbruch T, Qian C, Caselmann WH. Treatment of metastatic colorectal carcinomas by systemic inhibition of vascular endothelial growth factor signaling in mice. World J Gastroenterol. 2005;11(28):4332–6.CrossRefPubMedPubMedCentral
34.
Dewerchin M, Carmeliet P. Placental growth factor in cancer. Expert Opin Ther Targets. 2014;18(11):1339–54.CrossRefPubMed
35.
Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, Libermann TA, Morgan JP, Sellke FW, Stillman IE, et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest. 2003;111(5):649–58.CrossRefPubMedPubMedCentral
36.
Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, Schisterman EF, Thadhani R, Sachs BP, Epstein FH, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med. 2004;350(7):672–83.CrossRefPubMed
37.
Tjoa ML, Levine RJ, Karumanchi SA. Angiogenic factors and preeclampsia. Front Biosci. 2007;12:2395–402.CrossRefPubMed
38.
Remy S, Govarts E, Bruckers L, Paulussen M, Wens B, Hond ED, Nelen V, Baeyens W, van Larebeke N, Loots I, et al. Expression of the sFLT1 gene in cord blood cells is associated to maternal arsenic exposure and decreased birth weight. PLoS One. 2014;9(3):e92677.CrossRefPubMedPubMedCentral
39.
Odorisio T, Schietroma C, Zaccaria ML, Cianfarani F, Tiveron C, Tatangelo L, Failla CM, Zambruno G. Mice overexpressing placenta growth factor exhibit increased vascularization and vessel permeability. J Cell Sci. 2002;115(Pt 12):2559–67.PubMed
40.
Fischer C, Jonckx B, Mazzone M, Zacchigna S, Loges S, Pattarini L, Chorianopoulos E, Liesenborghs L, Koch M, De Mol M, et al. Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell. 2007;131(3):463–75.CrossRefPubMed
41.
Van de Veire S, Stalmans I, Heindryckx F, Oura H, Tijeras-Raballand A, Schmidt T, Loges S, Albrecht I, Jonckx B, Vinckier S, et al. Further pharmacological and genetic evidence for the efficacy of PlGF inhibition in cancer and eye disease. Cell. 2010;141(1):178–90.CrossRefPubMed
42.
Schomber T, Kopfstein L, Djonov V, Albrecht I, Baeriswyl V, Strittmatter K, Christofori G. Placental growth factor-1 attenuates vascular endothelial growth factor-A-dependent tumor angiogenesis during beta cell carcinogenesis. Cancer Res. 2007;67(22):10840–8.CrossRefPubMed
43.
Eriksson A, Cao R, Pawliuk R, Berg SM, Tsang M, Zhou D, Fleet C, Tritsaris K, Dissing S, Leboulch P, et al. Placenta growth factor-1 antagonizes VEGF-induced angiogenesis and tumor growth by the formation of functionally inactive PlGF-1/VEGF heterodimers. Cancer Cell. 2002;1(1):99–108.CrossRefPubMed
44.
Xu L, Cochran DM, Tong RT, Winkler F, Kashiwagi S, Jain RK, Fukumura D. Placenta growth factor overexpression inhibits tumor growth, angiogenesis, and metastasis by depleting vascular endothelial growth factor homodimers in orthotopic mouse models. Cancer Res. 2006;66(8):3971–7.CrossRefPubMed
45.
Hedlund EM, Hosaka K, Zhong Z, Cao R, Cao Y. Malignant cell-derived PlGF promotes normalization and remodeling of the tumor vasculature. Proc Natl Acad Sci U S A. 2009;106(41):17505–10.CrossRefPubMedPubMedCentral
46.
Bjorndahl M, Cao R, Eriksson A, Cao Y. Blockage of VEGF-induced angiogenesis by preventing VEGF secretion. Circ Res. 2004;94(11):1443–50.CrossRefPubMed
47.
Hedlund EM, Yang X, Zhang Y, Yang Y, Shibuya M, Zhong W, Sun B, Liu Y, Hosaka K, Cao Y. Tumor cell-derived placental growth factor sensitizes antiangiogenic and antitumor effects of anti-VEGF drugs. Proc Natl Acad Sci U S A. 2013;110(2):654–9.CrossRefPubMed
48.
Cao Y, Linden P, Shima D, Browne F, Folkman J. In vivo angiogenic activity and hypoxia induction of heterodimers of placenta growth factor/vascular endothelial growth factor. J Clin Invest. 1996;98(11):2507–11.CrossRefPubMedPubMedCentral
49.
Cao Y, Chen H, Zhou L, Chiang MK, Anand-Apte B, Weatherbee JA, Wang Y, Fang F, Flanagan JG, Tsang ML. Heterodimers of placenta growth factor/vascular endothelial growth factor. Endothelial activity, tumor cell expression, and high affinity binding to Flk-1/KDR. J Biol Chem. 1996;271(6):3154–62.CrossRefPubMed
50.
Angelucci C, Lama G, Iacopino F, Maglione D, Sica G. Effect of placenta growth factor-1 on proliferation and release of nitric oxide, cyclic AMP and cyclic GMP in human epithelial cells expressing the FLT-1 receptor. Growth Factors. 2001;19(3):193–206.CrossRefPubMed
Metadata
Title
Angiogenic cytokines and their influence on circulating tumour cells in sera of patients with the primary diagnosis of breast cancer before treatment
Authors
Theresa Vilsmaier
Brigitte Rack
Wolfgang Janni
Udo Jeschke
Tobias Weissenbacher
SUCCESS Study Group
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2016
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-016-2612-7

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