Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2016

Open Access 01-12-2016 | Research article

CXCR4-SDF-1 interaction potentially mediates trafficking of circulating tumor cells in primary breast cancer

Authors: M. Mego, D. Cholujova, G. Minarik, T. Sedlackova, P. Gronesova, M. Karaba, J. Benca, S. Cingelova, Z. Cierna, D. Manasova, D. Pindak, J. Sufliarsky, M. Cristofanilli, J. M. Reuben, J. Mardiak

Published in: BMC Cancer | Issue 1/2016

Login to get access

Abstract

Background

Cytokines are involved in cancer invasion and metastasis. Circulating tumor cells (CTCs) play key role in tumor dissemination and are an independent survival predictor in breast cancer patients. The aim of this study was to assess correlation between CTCs and plasma cytokines in primary breast cancer (PBC) patients.

Methods

This study included 147 chemotherapy naïve PBC patients. Peripheral blood mononuclear cells (PBMC) were depleted of hematopoetic cells using RossetteSep™ negative selection kit. RNA extracted from CD45-depleted PBMC was interrogated for expression of EMT (Twist1, Snail1, Slug, Zeb1) and epithelial (Ck19) gene transcripts by qRT-PCR. The concentrations of 51 plasma cytokines were measured using multiplex bead arrays.

Results

CTCs were detected in 25.2 % patients. CTCs exhibiting only epithelial markers (CTC_EP) and only EMT markers (CTC_EMT) were present evenly in 11.6 % patients, while CTCs co-expressing both markers were detected in 2.0 % patients. Patients with presence of CTC_EP in peripheral blood had significantly elevated levels of plasma IFN-α2, IL-3, MCP-3, β-NGF, SCF, SCGF-β, TNF-β and SDF-1 compared to patients without CTC_EP. CTC_EP exhibited overexpression of SDF-1 receptor and CXCR4, but not other corresponding cytokine receptor, and in multivariate analysis SDF-1 was independently associated with CTC_EP. There was an inverse correlation between CTC_EMT and plasma cytokines CTACK, β-NGF and TRAIL, while presence of either subtype of CTCs was associated with increased level of TGF-β2.

Conclusion

Using cytokine profiling, we identified cytokines associated with CTCs subpopulations in peripheral blood of PBC. Our data suggest that CXCR4-SDF-1 axis is involved in mobilization and trafficking of epithelial CTCs.
Literature
1.
Fidler IJ. The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer. 2003;3:453–8.CrossRefPubMed
2.
Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, Reuben JM,Doyle GV, Allard WJ, Terstappen LW, Hayes DF. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004;351:781–91.
3.
Lucci A, Hall CS, Lodhi AK, Bhattacharyya A, Anderson AE, Xiao L, Bedrosian I,Kuerer HM, Krishnamurthy S. Circulating tumour cells in non-metastatic breast cancer: a prospective study. Lancet Oncol. 2012;13:688–95.
4.
Zhang L, Riethdorf S, Wu G, Wang T, Yang K, Peng G, Liu J, Pantel K. Meta-analysis of the prognostic value of circulating tumor cells in breast cancer. Clin Cancer Res. 2012;18:5701–10.
5.
Zhao S, Liu Y, Zhang Q, Li H, Zhang M, Ma W,Zhao W, Wang J, Yang M. The prognostic role of circulating tumor cells (CTCs) detected by RT-PCR in breast cancer: a metaanalysis of published literature. Breast Cancer Res Tr. 2011;130:809–16.
6.
Kim MY, Oskarsson T, Acharyya S, Nguyen DX, Zhang XH, Norton L, Massagué J. Tumor self-seeding by circulating cancer cells. Cell. 2009;139:1315–26.
7.
Butler TP, Gullino PM. Quantitation of cell shedding into efferent blood of mammary adenocarcinoma. Cancer Res. 1975;35:512–6.PubMed
8.
Wong CW, Lee A, Shientag L, Yu J, Dong Y, Kao G, Al-Mehdi AB, Bernhard EJ, Muschel RJ. Apoptosis: an early event in metastatic inefficiency. Cancer Res. 2001;61:333–8.
9.
Baccelli I, Schneeweiss A, Riethdorf S, Stenzinger A, Schillert A, Vogel V, Klein C, Saini M, Bäuerle T, Wallwiener M, Holland-Letz T, Höfner T, Sprick M, Scharpff M, Marmé F, Sinn HP, Pantel K, Weichert W, Trumpp A. Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay. Nat Biotechnol. 2013;31:539–44.
10.
Zhan M, Zhao H, Han ZC. Signaling mechanisms of anoikis. Histol Histopathol. 2004;19:973–83.PubMed
11.
Mego M, Mani SA, Cristofanilli M. Molecular mechanisms of metastasis in breast cancer-clinical applications. Nat Rev Clin Oncol. 2010;7:693–701.CrossRefPubMed
12.
Mego M, Gao H, Cohen EN, Anfossi S, Giordano A, Sanda T, Fouad TM, De Giorgi U, Giuliano M, Woodward WA, Alvarez RH, Valero V, Ueno NT, Hortobagyi GN, Cristofanilli M, Reuben JM. Circulating tumor cells (CTC) are associated with defects in adaptive immunity in patients with inflammatory breast cancer. J Cancer. 2015. doi:10.​1158/​1538-7445.​SABCS14-P4-01-04.
13.
Zhang XH, Jin X, Malladi S, Zou Y, Wen YH, Brogi E, Smid M, Foekens JA, Massagué J. Selection of bone metastasis seeds by mesenchymal signals in the primary tumor stroma. Cell. 2013;154:1060–73.
14.
15.
Schall TJ, Proudfoot AE. Overcoming hurdles in developing successful drugs targeting chemokine receptors. Nat Rev Immunol. 2011;11:355–63.CrossRefPubMed
16.
17.
Cohen EN, Gao H, Anfossi S, Mego M, Reddy NG, Debeb B, Giordano A, Tin S, Wu Q, Garza RJ, Cristofanilli M, Mani SA, Croix DA, Ueno NT, Woodward WA, Luthra R, Krishnamurthy S, Reuben JM. Inflammation Mediated Metastasis: Immune Induced Epithelial-To-Mesenchymal Transition in Inflammatory Breast Cancer Cells. PLoS One. 2015;10, e0132710.
18.
Mego M, Karaba M, Minarik G, Benca J, Sedlácková T, Tothova L, Vlkova B,Cierna Z, Janega P, Luha J, Gronesova P, Pindak D, Fridrichova I, Celec P, Reuben JM, Cristofanilli M, Mardiak J. Relationship between circulating tumor cells, blood coagulation, and urokinase-plasminogen- activator system in early breast cancer patients. Breast J. 2015;21:155–60.
19.
Mego M, Zuo Z, Gao H, Cohen EN, Giordano A, Tin S, Anfossi S, Jackson S, Woodward W, Ueno NT, Valero V, Alvarez RH, Hortobagyi GN, Khoury JD, Cristofanilli M, Reuben JM. Circulating tumour cells are linked to plasma D-dimer levels in patients with metastatic breast cancer. Thromb Haemost. 2015;113:593–8.
20.
Mego M, Cierna Z, Janega P, Karaba M, Minarik G, Benca J, Sedlácková T, Sieberova G, Gronesova P, Manasova D, Pindak D, Sufliarsky J, Danihel L, Reuben JM, Mardiak J. Relationship between circulating tumor cells and epithelial to mesenchymal transition in early breast cancer. BMC Cancer. 2015;15:533.
21.
Cierna Z, Mego M, Janega P, Karaba M, Minarik G, Benca J, Sedlácková T, Cingelova S, Gronesova P, Manasova D, Pindak D, Sufliarsky J, Danihel L, Reuben JM, Mardiak J. Matrix metalloproteinase 1 and circulating tumor cells in early breast cancer. BMC Cancer. 2014;14:472.
22.
Fusi A, Liu Z, Kümmerlen V, Nonnemacher A, Jeske J, Keilholz U. Expression of chemokine receptors on circulating tumor cells in patients with solid tumors. J Transl Med. 2012;10:52.PubMedCentralCrossRefPubMed
23.
Mego M, Gao H, Lee BN, Cohen EN, Tin S, Giordano A, Wu Q, Liu P, Nieto Y, Champlin RE, Hortobagyi GN, Cristofanilli M, Ueno NT, Reuben JM. Prognostic Value of EMT-Circulating Tumor Cells in Metastatic Breast Cancer Patients Undergoing High-Dose Chemotherapy with Autologous Hematopoietic Stem Cell Transplantation. J Cancer. 2012;3:369–80.
24.
Kielian T. Microglia and chemokines in infectious diseases of the nervous system: views and reviews. Front Biosci. 2004;9:732–50.CrossRefPubMed
25.
Burger JA, Kipps TJ. CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment. Blood. 2006;107:1761–7.CrossRefPubMed
26.
Kang H, Mansel RE, Jiang WG. Genetic manipulation of stromal cell-derived factor-1 attests the pivotal role of the autocrine SDF-1-CXCR4 pathway in the aggressiveness of breast cancer cells. Int J Oncol. 2005;26:1429–34.PubMed
27.
Lee BC, Lee TH, Avraham S, Avraham HK. Involvement of the chemokine receptor CXCR4 and its ligand stromal cell-derived factor 1alpha in breast cancer cell migration through human brain microvascular endothelial cells. Mol Cancer Res. 2004;2:327–38.PubMed
28.
Okuyama Kishima M, de Oliveira CE, Banin-Hirata BK, Losi-Guembarovski R, Brajao de Oliveira K, Amarante MK, Watanabe MA. Immunohistochemical expression of CXCR4 on breast cancer and its clinical significance. Anal Cell Pathol. 2015;2015:891020.
29.
DeCastro AJ, Cherukuri P, Balboni A, DiRenzo J. ΔNP63α transcriptionally activates chemokine receptor 4 (CXCR4) expression to regulate breast cancer stem cell activity and chemotaxis. Mol Cancer Ther. 2015;14:225–35.PubMedCentralCrossRefPubMed
30.
Cabioglu N, Sahin AA, Morandi P, Meric-Bernstam F, Islam R, Lin HY, Bucana CD, Gonzalez-Angulo AM, Hortobagyi GN, Cristofanilli M. Chemokine receptors in advanced breast cancer: differential expression in metastatic disease sites with diagnostic and therapeutic implications. Ann Oncol. 2009;20:1013–9.
31.
Andre F, Cabioglu N, Assi H, Sabourin JC, Delaloge S, Sahin A, Broglio K, Spano JP, Combadiere C, Bucana C, Soria JC, Cristofanilli M. Expression of chemokine receptors predicts the site of metastatic relapse in patients with axillary node positive primary breast cancer. Ann Oncol. 2006;17:945–51.
32.
Tamamura H, Hori A, Kanzaki N, Hiramatsu K, Mizumoto M, Nakashima H, Yamamoto N, Otaka A, Fujii N. T140 analogs as CXCR4 antagonists identified as anti-metastatic agents in the treatment of breast cancer. FEBS Lett. 2003;550:79–83.
33.
Burger M, Hartmann T, Krome M, Rawluk J, Tamamura H, Fujii N, Kipps TJ, Burger JA. Small peptide inhibitors of the CXCR4 chemokine receptor (CD184) antagonize the activation, migration, and antiapoptotic responses of CXCL12 in chronic lymphocytic leukemia B cells. Blood. 2005;106:1824–30.
34.
Niedermeier M, Hennessy BT, Knight ZA, Henneberg M, Hu J, Kurtova AV, Wierda WG, Keating MJ, Shokat KM, Burger JA. Isoform-selective phosphoinositide 3’-kinase inhibitors inhibit CXCR4 signaling and overcome stromal cell-mediated drug resistance in chronic lymphocytic leukemia: a novel therapeutic approach. Blood. 2009;113:5549–57.
35.
Ablett MP, O’Brien CS, Sims AH, Farnie G, Clarke RB. A differential role for CXCR4 in the regulation of normal versus malignant breast stem cell activity. Oncotarget. 2014;5:599–612.PubMedCentralCrossRefPubMed
36.
Srivastava MK, Andersson Å, Zhu L, Harris-White M, Lee JM, Dubinett S, Sharma S. Myeloid suppressor cells and immune modulation in lung cancer. Immunotherapy. 2012;4:291–304.
37.
Tomellini E, Touil Y, Lagadec C, Julien S, Ostyn P, Ziental-Gelus N, Meignan S, Lengrand J, Adriaenssens E, Polakowska R, Le Bourhis X. Nerve growth factor and proNGF imultaneously promote symmetric self-renewal, quiescence, and epithelial to mesenchymal transition to enlarge the breast cancer stem cell compartment. Stem Cells. 2015;33:342–53.
38.
Kudo-Saito C, Shirako H, Takeuchi T, Kawakami Y. Cancer metastasis is accelerated through immunosuppression during Snail-induced EMT of cancer cells. Cancer Cell. 2009;15:195–206.CrossRefPubMed
39.
Saitoh M. Epithelial-mesenchymal transition is regulated at post-transcriptional levels by transforming growth factor-β signaling during tumor progression. Cancer Sci. 2015;106:481–8.PubMedCentralCrossRefPubMed
40.
van Nes JG, de Kruijf EM, Putter H, Faratian D, Munro A, Campbell F, Smit VT, Liefers GJ, Kuppen PJ, van de Velde CJ, Bartlett JM. Co-expression of SNAIL and TWIST determines prognosis in estrogen receptor-positive early breast cancer patients. Breast Cancer Res Treat. 2012;133:49–59.
41.
Yuen HF, Zhang SD, Wong AS, McCrudden CM, Huang YH, Chan KY, El-Tanani M, Khoo US. Regarding “Co-expression of SNAIL and TWIST determines prognosis in estrogen receptor-positive early breast cancer patients”. Breast Cancer Res Treat. 2012;131:351–2.
42.
Anwar TE, Kleer CG. Tissue-based identification of stem cells and epithelial-to-mesenchymal transition in breast cancer. Hum Pathol. 2013;44:1457–64.PubMedCentralCrossRefPubMed
43.
Soini Y, Tuhkanen H, Sironen R, Virtanen I, Kataja V, Auvinen P, Mannermaa A, Kosma VM. Transcription factors zeb1, twist and snai1 in breast carcinoma. BMC Cancer. 2011;11:73.
Metadata
Title
CXCR4-SDF-1 interaction potentially mediates trafficking of circulating tumor cells in primary breast cancer
Authors
M. Mego
D. Cholujova
G. Minarik
T. Sedlackova
P. Gronesova
M. Karaba
J. Benca
S. Cingelova
Z. Cierna
D. Manasova
D. Pindak
J. Sufliarsky
M. Cristofanilli
J. M. Reuben
J. Mardiak
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/s12885-016-2143-2

Other articles of this Issue 1/2016

BMC Cancer 1/2016 Go to the issue

Research article

FRAX597, a PAK1 inhibitor, synergistically reduces pancreatic cancer growth when combined with gemcitabine

Research article

The milk-derived fusion peptide, ACFP, suppresses the growth of primary human ovarian cancer cells by regulating apoptotic gene expression and signaling pathways

Research article

Nurse-led group consultation intervention reduces depressive symptoms in men with localised prostate cancer: a cluster randomised controlled trial

Research article

Dynamic changes of tumor gene expression during repeated pressurized intraperitoneal aerosol chemotherapy (PIPAC) in women with peritoneal cancer

Research article

Occult invasive cervical cancer after simple hysterectomy: a multi-center retrospective study of 89 cases

Research article

Regulation of the tumour suppressor PDCD4 by miR-499 and miR-21 in oropharyngeal cancers
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits