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BMC Cancer
Published in: BMC Cancer 1/2015

Open Access 01-12-2015 | Research article

SDF-1alpha concentration dependent modulation of RhoA and Rac1 modifies breast cancer and stromal cells interaction

Authors: Jennifer Pasquier, Nadine Abu-Kaoud, Houari Abdesselem, Aisha Madani, Jessica Hoarau-Véchot, Hamda Al. Thawadi, Fabien Vidal, Bettina Couderc, Gilles Favre, Arash Rafii

Published in: BMC Cancer | Issue 1/2015

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Abstract

Background

The interaction of SDF-1alpha with its receptor CXCR4 plays a role in the occurrence of distant metastasis in many solid tumors. This interaction increases migration from primary sites as well as homing at distant sites.

Methods

Here we investigated how SDF-1α could modulate both migration and adhesion of cancer cells through the modulation of RhoGTPases.

Results

We show that different concentrations of SDF-1α modulate the balance of adhesion and migration in cancer cells. Increased migration was obtained at 50 and 100 ng/ml of SDF-1α; however migration was reduced at 200 ng/ml. The adhesion between breast cancer cells and BMHC was significantly increased by SDF-1α treatment at 200 ng/ml and reduced using a blocking monoclonal antibody against CXCR4. We showed that at low SDF-1α concentration, RhoA was activated and overexpressed, while at high concentration Rac1 was promoting SDF-1α mediating-cell adhesion.

Conclusion

We conclude that SDF-1α concentration modulates migration and adhesion of breast cancer cells, by controlling expression and activation of RhoGTPases.
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Literature
1.
2.
Yeatman TJ, Nicolson GL. Molecular basis of tumor progression: mechanisms of organ-specific tumor metastasis. Semin Surg Oncol. 1993;9(3):256–63.PubMed
3.
Ben-Baruch A. Organ selectivity in metastasis: regulation by chemokines and their receptors. Clin Exp Metastas. 2008;25(4):345–56.CrossRef
4.
Dittmar T, Heyder C, Gloria-Maercker E, Hatzmann W, Zanker KS. Adhesion molecules and chemokines: the navigation system for circulating tumor (stem) cells to metastasize in an organ-specific manner. Clin Exp Metastas. 2008;25(1):11–32.CrossRef
5.
Lis R, Touboul C, Mirshahi P, Ali F, Mathew S, Nolan DJ, et al. Tumor associated mesenchymal stem cells protects ovarian cancer cells from hyperthermia through CXCL12. Int J Cancer. 2011;128(3):715–25.CrossRefPubMed
6.
Touboul C, Lis R, Al Farsi H, Raynaud CM, Warfa M, Althawadi H, et al. Mesenchymal stem cells enhance ovarian cancer cell infiltration through IL6 secretion in an amniochorionic membrane based 3D model. J Transl Med. 2013;11:28.CrossRefPubMedPubMedCentral
7.
Burger JA, Peled A. CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers. Leukemia. 2009;23(1):43–52.CrossRefPubMed
8.
Luker KE, Luker GD. Functions of CXCL12 and CXCR4 in breast cancer. Cancer Lett. 2006;238(1):30–41.CrossRefPubMed
9.
10.
Ibrahim T, Sacanna E, Gaudio M, Mercatali L, Scarpi E, Zoli W, et al. Role of RANK, RANKL, OPG, and CXCR4 tissue markers in predicting bone metastases in breast cancer patients. Clin Breast Cancer. 2011;11(6):369–75.CrossRefPubMed
11.
Crump MP, Gong JH, Loetscher P, Rajarathnam K, Amara A, Arenzana-Seisdedos F, et al. Solution structure and basis for functional activity of stromal cell-derived factor-1; dissociation of CXCR4 activation from binding and inhibition of HIV-1. EMBO J. 1997;16(23):6996–7007.CrossRefPubMedPubMedCentral
12.
13.
Saini V, Staren DM, Ziarek JJ, Nashaat ZN, Campbell EM, Volkman BF, et al. The CXC chemokine receptor 4 ligands ubiquitin and stromal cell-derived factor-1alpha function through distinct receptor interactions. J Biol Chem. 2011;286(38):33466–77.CrossRefPubMedPubMedCentral
14.
Schwartz V, Lue H, Kraemer S, Korbiel J, Krohn R, Ohl K, et al. A functional heteromeric MIF receptor formed by CD74 and CXCR4. FEBS Lett. 2009;583(17):2749–57.CrossRefPubMedPubMedCentral
15.
16.
Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature. 2001;410(6824):50–6.CrossRefPubMed
17.
Helbig G, Christopherson 2nd KW, Bhat-Nakshatri P, Kumar S, Kishimoto H, Miller KD, et al. NF-kappaB promotes breast cancer cell migration and metastasis by inducing the expression of the chemokine receptor CXCR4. J Biol Chem. 2003;278(24):21631–8.CrossRefPubMed
18.
Roccaro AM, Sacco A, Purschke WG, Moschetta M, Buchner K, Maasch C, et al. SDF-1 Inhibition Targets the Bone Marrow Niche for Cancer Therapy. Cell Rep. 2014;9:118–28.CrossRefPubMedPubMedCentral
19.
Cojoc M, Peitzsch C, Trautmann F, Polishchuk L, Telegeev GD, Dubrovska A. Emerging targets in cancer management: role of the CXCL12/CXCR4 axis. Onco Targets Ther. 2013;6:1347–61.PubMedPubMedCentral
20.
Bajetto A, Bonavia R, Barbero S, Piccioli P, Costa A, Florio T, et al. Glial and neuronal cells express functional chemokine receptor CXCR4 and its natural ligand stromal cell-derived factor 1. J Neurochem. 1999;73(6):2348–57.CrossRefPubMed
21.
Holland JD, Kochetkova M, Akekawatchai C, Dottore M, Lopez A, McColl SR. Differential functional activation of chemokine receptor CXCR4 is mediated by G proteins in breast cancer cells. Cancer Res. 2006;66(8):4117–24.CrossRefPubMed
22.
Gautam N, Downes GB, Yan K, Kisselev O. The G-protein betagamma complex. Cell Signal. 1998;10(7):447–55.CrossRefPubMed
23.
Azab AK, Azab F, Blotta S, Pitsillides CM, Thompson B, Runnels JM, et al. RhoA and Rac1 GTPases play major and differential roles in stromal cell-derived factor-1-induced cell adhesion and chemotaxis in multiple myeloma. Blood. 2009;114(3):619–29.CrossRefPubMedPubMedCentral
24.
25.
26.
Prendergast GC, Khosravi-Far R, Solski PA, Kurzawa H, Lebowitz PF, Der CJ. Critical role of Rho in cell transformation by oncogenic Ras. Oncogene. 1995;10(12):2289–96.PubMed
27.
Fritz G, Brachetti C, Bahlmann F, Schmidt M, Kaina B. Rho GTPases in human breast tumours: expression and mutation analyses and correlation with clinical parameters. Br J Cancer. 2002;87(6):635–44.CrossRefPubMedPubMedCentral
28.
Couderc B, Pradines A, Rafii A, Golzio M, Deviers A, Allal C, et al. In vivo restoration of RhoB expression leads to ovarian tumor regression. Cancer Gene Ther. 2008;15(7):456–64.CrossRefPubMed
29.
Sarrabayrouse G, Synaeve C, Leveque K, Favre G, Tilkin-Mariame AF. Statins stimulate in vitro membrane FasL expression and lymphocyte apoptosis through RhoA/ROCK pathway in murine melanoma cells. Neoplasia. 2007;9(12):1078–90.CrossRefPubMedPubMedCentral
30.
Medale-Giamarchi C, Lajoie-Mazenc I, Malissein E, Meunier E, Couderc B, Berge Y, et al. RhoB modifies estrogen responses in breast cancer cells by influencing expression of the estrogen receptor. Breast Cancer Res. 2013;15(1):R6.CrossRefPubMedPubMedCentral
31.
Touboul C, Vidal F, Pasquier J, Lis R, Rafii A. Role of mesenchymal cells in the natural history of ovarian cancer: a review. J Transl Med. 2014;12(1):271.CrossRefPubMedPubMedCentral
32.
Mirshahi P, Rafii A, Vincent L, Berthaut A, Varin R, Kalantar G, et al. Vasculogenic mimicry of acute leukemic bone marrow stromal cells. Leukemia. 2009;23(6):1039–48.CrossRefPubMed
33.
Rafii A, Mirshahi P, Poupot M, Faussat AM, Simon A, Ducros E, et al. Oncologic trogocytosis of an original stromal cells induces chemoresistance of ovarian tumours. PLoS One. 2008;3(12):e3894.CrossRefPubMedPubMedCentral
34.
Mousseau Y, Leclers D, Faucher-Durand K, Cook-Moreau J, Lia-Baldini AS, Rigaud M, et al. Improved agarose gel assay for quantification of growth factor-induced cell motility. Biotechniques. 2007;43(4):509–16.CrossRefPubMed
35.
Laguri C, Sadir R, Rueda P, Baleux F, Gans P, Arenzana-Seisdedos F, et al. The novel CXCL12gamma isoform encodes an unstructured cationic domain which regulates bioactivity and interaction with both glycosaminoglycans and CXCR4. PLoS One. 2007;2(10):e1110.CrossRefPubMedPubMedCentral
36.
Pasquier J, Rioult D, Abu-Kaoud N, Marie S, Rafii A, Guerrouahen BS, et al. P-glycoprotein-activity measurements in multidrug resistant cell lines: single-cell versus single-well population fluorescence methods. Biomed Res Int. 2013;2013:676845.PubMedPubMedCentral
37.
Ghiabi P, Jiang J, Pasquier J, Maleki M, Abu-Kaoud N, Rafii S, et al. Endothelial cells provide a notch-dependent pro-tumoral niche for enhancing breast cancer survival, stemness and pro-metastatic properties. PLoS One. 2014;9(11):e112424.CrossRefPubMedPubMedCentral
38.
Pasquier J, Thawadi HA, Ghiabi P, Abu-Kaoud N, Maleki M, Guerrouahen BS, et al. Microparticles mediated cross-talk between tumoral and endothelial cells promote the constitution of a pro-metastatic vascular niche through Arf6 up regulation. Cancer Microenviron. 2014;7:41–59.CrossRefPubMedPubMedCentral
39.
Pasquier J, Guerrouahen BS, Al Thawadi H, Ghiabi P, Maleki M, Abu-Kaoud N, et al. Preferential transfer of mitochondria from endothelial to cancer cells through tunneling nanotubes modulates chemoresistance. J Transl Med. 2013;11:94.CrossRefPubMedPubMedCentral
40.
Raynaud CM, Halabi N, Elliott DA, Pasquier J, Elefanty AG, Stanley EG, et al. Human embryonic stem cell derived mesenchymal progenitors express cardiac markers but do not form contractile cardiomyocytes. PLoS One. 2013;8(1):e54524.CrossRefPubMedPubMedCentral
41.
Albini A, Iwamoto Y, Kleinman HK, Martin GR, Aaronson SA, Kozlowski JM, et al. A rapid in vitro assay for quantitating the invasive potential of tumor cells. Cancer Res. 1987;47(12):3239–45.PubMed
42.
Albini A, Benelli R, Noonan DM, Brigati C. The “chemoinvasion assay”: a tool to study tumor and endothelial cell invasion of basement membranes. Int J Dev Biol. 2004;48(5–6):563–71.CrossRefPubMed
43.
44.
Onodera Y, Nam JM, Sabe H. Intracellular trafficking of integrins in cancer cells. Pharmacol Ther. 2013;140(1):1–9.CrossRefPubMed
45.
Krook MA, Nicholls LA, Scannell CA, Chugh R, Thomas DG, Lawlor ER. Stress-induced CXCR4 promotes migration and invasion of ewing sarcoma. Mol Cancer Res. 2014;12(6):953–64.CrossRefPubMedPubMedCentral
46.
Hassan S, Buchanan M, Jahan K, Aguilar-Mahecha A, Gaboury L, Muller WJ, et al. CXCR4 peptide antagonist inhibits primary breast tumor growth, metastasis and enhances the efficacy of anti-VEGF treatment or docetaxel in a transgenic mouse model. Int J Cancer. 2011;129(1):225–32.CrossRefPubMed
47.
Huang EH, Singh B, Cristofanilli M, Gelovani J, Wei C, Vincent L, et al. A CXCR4 antagonist CTCE-9908 inhibits primary tumor growth and metastasis of breast cancer. J Surg Res. 2009;155(2):231–6.CrossRefPubMed
48.
Smith MC, Luker KE, Garbow JR, Prior JL, Jackson E, Piwnica-Worms D, et al. CXCR4 regulates growth of both primary and metastatic breast cancer. Cancer Res. 2004;64(23):8604–12.CrossRefPubMed
49.
Liang Z, Yoon Y, Votaw J, Goodman MM, Williams L, Shim H. Silencing of CXCR4 blocks breast cancer metastasis. Cancer Res. 2005;65(3):967–71.PubMedPubMedCentral
50.
Venkiteswaran G, Lewellis SW, Wang J, Reynolds E, Nicholson C, Knaut H. Generation and dynamics of an endogenous, self-generated signaling gradient across a migrating tissue. Cell. 2013;155(3):674–87.CrossRefPubMed
51.
Kim BJ, Hannanta-anan P, Chau M, Kim YS, Swartz MA, Wu M. Cooperative roles of SDF-1alpha and EGF gradients on tumor cell migration revealed by a robust 3D microfluidic model. PLoS One. 2013;8(7):e68422.CrossRefPubMedPubMedCentral
52.
Netelenbos T, Zuijderduijn S, Van Den Born J, Kessler FL, Zweegman S, Huijgens PC, et al. Proteoglycans guide SDF-1-induced migration of hematopoietic progenitor cells. J Leukoc Biol. 2002;72(2):353–62.PubMed
53.
De Falco E, Porcelli D, Torella AR, Straino S, Iachininoto MG, Orlandi A, et al. SDF-1 involvement in endothelial phenotype and ischemia-induced recruitment of bone marrow progenitor cells. Blood. 2004;104(12):3472–82.CrossRefPubMed
54.
Rempel SA, Dudas S, Ge S, Gutierrez JA. Identification and localization of the cytokine SDF1 and its receptor, CXC chemokine receptor 4, to regions of necrosis and angiogenesis in human glioblastoma. Clin Cancer Res. 2000;6(1):102–11.PubMed
55.
Nolan DJ, Ginsberg M, Israely E, Palikuqi B, Poulos MG, James D, et al. Molecular signatures of tissue-specific microvascular endothelial cell heterogeneity in organ maintenance and regeneration. Dev Cell. 2013;26(2):204–19.CrossRefPubMed
56.
Kang Y, Siegel PM, Shu W, Drobnjak M, Kakonen SM, Cordon-Cardo C, et al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell. 2003;3(6):537–49.CrossRefPubMed
57.
Moorman JP, Luu D, Wickham J, Bobak DA, Hahn CS. A balance of signaling by Rho family small GTPases RhoA, Rac1 and Cdc42 coordinates cytoskeletal morphology but not cell survival. Oncogene. 1999;18(1):47–57.CrossRefPubMed
58.
Yu W, Shewan AM, Brakeman P, Eastburn DJ, Datta A, Bryant DM, et al. Involvement of RhoA, ROCK I and myosin II in inverted orientation of epithelial polarity. EMBO Rep. 2008;9(9):923–9.CrossRefPubMedPubMedCentral
59.
Kamura S, Matsumoto Y, Fukushi JI, Fujiwara T, Iida K, Okada Y, et al. Basic fibroblast growth factor in the bone microenvironment enhances cell motility and invasion of Ewing’s sarcoma family of tumours by activating the FGFR1-PI3K-Rac1 pathway. Br J Cancer. 2010;103(3):370–81.CrossRefPubMedPubMedCentral
60.
Barthel SR, Hays DL, Yazawa EM, Opperman M, Walley KC, Nimrichter L, et al. Definition of molecular determinants of prostate cancer cell bone extravasation. Cancer Res. 2013;73(2):942–52.CrossRefPubMed
61.
McGrail DJ, Ghosh D, Quach ND, Dawson MR. Differential mechanical response of mesenchymal stem cells and fibroblasts to tumor-secreted soluble factors. PLoS One. 2012;7(3), e33248.CrossRefPubMedPubMedCentral
62.
Wang JY, Yu P, Chen S, Xing H, Chen Y, Wang M, et al. Activation of Rac1 GTPase promotes leukemia cell chemotherapy resistance, quiescence and niche interaction. Mol Oncol. 2013;7(5):907–16.CrossRefPubMed
63.
Dormond O, Foletti A, Paroz C, Ruegg C. NSAIDs inhibit alpha V beta 3 integrin-mediated and Cdc42/Rac-dependent endothelial-cell spreading, migration and angiogenesis. Nat Med. 2001;7(9):1041–7.CrossRefPubMed
64.
Cox EA, Sastry SK, Huttenlocher A. Integrin-mediated adhesion regulates cell polarity and membrane protrusion through the Rho family of GTPases. Mol Biol Cell. 2001;12(2):265–77.CrossRefPubMedPubMedCentral
65.
66.
De Nigris D, Collins DL, Arbel T. Multi-modal image registration based on gradient orientations of minimal uncertainty. IEEE Trans Med Imaging. 2012;31(12):2343–54.CrossRefPubMed
Metadata
Title
SDF-1alpha concentration dependent modulation of RhoA and Rac1 modifies breast cancer and stromal cells interaction
Authors
Jennifer Pasquier
Nadine Abu-Kaoud
Houari Abdesselem
Aisha Madani
Jessica Hoarau-Véchot
Hamda Al. Thawadi
Fabien Vidal
Bettina Couderc
Gilles Favre
Arash Rafii
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2015
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-015-1556-7

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