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Breast Cancer Research
Published in: Breast Cancer Research 2/2013

Open Access 01-04-2013 | Research article

Arthritis augments breast cancer metastasis: role of mast cells and SCF/c-Kit signaling

Authors: Lopamudra Das Roy, Jennifer M Curry, Mahnaz Sahraei, Dahlia M Besmer, Amritha Kidiyoor, Helen E Gruber, Pinku Mukherjee

Published in: Breast Cancer Research | Issue 2/2013

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Abstract

Introduction

Breast cancer remains the second leading cause of cancer-related deaths for women in the United States. Metastasis is regulated not only by intrinsic genetic changes in malignant cells, but also by the microenvironment, especially those associated with chronic inflammation. We recently reported that mice with autoimmune arthritis have significantly increased incidence of bone and lung metastasis and decreased survival associated with breast cancer. In this study, we evaluated the mechanism underlying the increased metastasis.

Methods

We used two mouse models; one that develops spontaneous autoimmune arthritis (SKG mice) injected with metastatic breast cancer cells (4T1), and another that develops spontaneous breast cancer (MMTV-PyV MT mice) injected with type II collagen to induce autoimmune arthritis. Mast cell levels and metastasis were monitored.

Results

First, we confirmed that breast tumor-bearing arthritic mice have a significantly higher incidence of bone and lung metastasis than do their nonarthritic counterparts. Next, we showed increased recruitment of mast cells within the primary tumor of arthritic mice, which facilitates metastasis. Next, we report that arthritic mice without any tumors have higher numbers of mast cells in the bones and lungs, which may be the underlying cause for the enhanced lung and bone metastases observed in the arthritic mice. Next, we showed that once the tumor cells populate the metastatic niches (bones and lungs), they further increase the mast cell population within the niche and assist in enhancing metastasis. This may primarily be due to the interaction of c-Kit receptor present on mast cells and stem cell factor (SCF, the ligand for ckit) expressed on tumor cells. Finally, we showed that targeting the SCF/cKit interaction with an anti-ckit antibody reduces the differentiation of mast cells and consequently reduces metastasis.

Conclusion

This is the first report to show that mast cells may play a critical role in remodeling not only the tumor microenvironment but also the metastatic niche to facilitate efficient metastasis through SCF/cKit interaction in breast cancer with arthritis.
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Literature
1.
Siegel R, Naishadham D, Jemal A: Cancer statistics, 2012. CA Cancer J Clin. 2012, 62: 10-29. 10.3322/caac.20138.CrossRefPubMed
2.
de Visser KE, Coussens LM: The inflammatory tumor microenvironment and its impact on cancer development. Contrib Microbiol. 2006, 13: 118-137.CrossRefPubMed
3.
Azim H, Azim HA: Targeting RANKL in breast cancer: bone metastasis and beyond. Expert Rev Anticancer Ther. 2013, 13: 195-201. 10.1586/era.12.177.CrossRefPubMed
4.
Futakuchi M, Singh RK: Animal model for mammary tumor growth in the bone microenvironment. Breast Cancer. 2013
5.
Sosnoski DM, Krishnan V, Kraemer WJ, Dunn-Lewis C, Mastro AM: Changes in cytokines of the bone microenvironment during breast cancer metastasis. Int J Breast Cancer. 2012, 2012: 160265-CrossRefPubMedPubMedCentral
6.
Majithia V, Geraci SA: Rheumatoid arthritis: diagnosis and management. Am J Med. 2007, 120: 936-939. 10.1016/j.amjmed.2007.04.005.CrossRefPubMed
7.
Ji J, Liu X, Sundquist K, Sundquist J: Survival of cancer in patients with rheumatoid arthritis: a follow-up study in Sweden of patients hospitalized with rheumatoid arthritis 1 year before diagnosis of cancer. Rheumatology (Oxford). 2011, 50: 1513-1518. 10.1093/rheumatology/ker143.CrossRef
8.
Das Roy L, Pathangey L, Tinder T, Schettini J, Gruber H, Mukherjee P: Breast cancer-associated metastasis is significantly increased in a model of autoimmune arthritis. Breast Cancer Res. 2009, 11: R56-10.1186/bcr2345.CrossRefPubMedPubMedCentral
9.
Das Roy L, Ghosh S, Pathangey LB, Tinder TL, Gruber HE, Mukherjee P: Collagen induced arthritis increases secondary metastasis in MMTV-PyV MT mouse model of mammary cancer. BMC Cancer. 2011, 11: 365-10.1186/1471-2407-11-365.CrossRef
10.
Huang B, Lei Z, Zhang GM, Li D, Song C, Li B, Liu Y, Yuan Y, Unkeless J, Xiong H, Feng ZH: SCF-mediated mast cell infiltration and activation exacerbate the inflammation and immunosuppression in tumor microenvironment. Blood. 2008, 112: 1269-1279. 10.1182/blood-2008-03-147033.CrossRefPubMedPubMedCentral
11.
Kinet JP: The essential role of mast cells in orchestrating inflammation. Immunol Rev. 2007, 217: 5-7. 10.1111/j.1600-065X.2007.00528.x.CrossRefPubMed
12.
Metz M, Grimbaldeston MA, Nakae S, Piliponsky AM, Tsai M, Galli SJ: Mast cells in the promotion and limitation of chronic inflammation. Immunol Rev. 2007, 217: 304-328. 10.1111/j.1600-065X.2007.00520.x.CrossRefPubMed
13.
Sakaguchi N, Takahashi T, Hata H, Nomura T, Tagami T, Yamazaki S, Sakihama T, Matsutani T, Negishi I, Nakatsuru S, Sakaguchi S: Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice. Nature. 2003, 426: 454-460. 10.1038/nature02119.CrossRefPubMed
14.
Hata H, Sakaguchi N, Yoshitomi H, Iwakura Y, Sekikawa K, Azuma Y, Kanai C, Moriizumi E, Nomura T, Nakamura T, Sakaguchi S: Distinct contribution of IL-6, TNF-alpha, IL-1, and IL-10 to T cell-mediated spontaneous autoimmune arthritis in mice. J Clin Invest. 2004, 114: 582-588.CrossRefPubMedPubMedCentral
15.
Firestein G: Evolving concepts of rheumatoid arthritis. Nature. 2003, 423: 356-361. 10.1038/nature01661.CrossRefPubMed
16.
Maglione JE, Moghanaki D, Young LJ, Manner CK, Ellies LG, Joseph SO, Nicholson B, Cardiff RD, MacLeod CL: Transgenic polyoma middle-T mice model premalignant mammary disease. Cancer Res. 2001, 61: 8298-8305.PubMed
17.
Guy CT, Cardiff RD, Muller WJ: Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Mol Cell Biol. 1992, 12: 954-961.CrossRefPubMedPubMedCentral
18.
Brand D, Latham K, Rosloniec E: Collagen-induced arthritis. Nat Protoc. 2007, 2: 1269-1275. 10.1038/nprot.2007.173.CrossRefPubMed
19.
Fournier C: Where do T cells stand in rheumatoid arthritis?. Joint Bone Spine. 2005, 72: 527-532. 10.1016/j.jbspin.2004.12.012.CrossRefPubMed
20.
Sakaguchi N, Takahashi T, Hata H, Nomura T, Tagami T, Yamazaki S, Sakihama T, Matsutani T, Negishi I, Nakatsuru S, Sakaguchi S: Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice. Nature. 2003, 426: 454-460. 10.1038/nature02119.CrossRefPubMed
21.
Mukherjee P, Madsen CS, Ginardi AR, Tinder TL, Jacobs F, Parker J, Agrawal B, Longenecker BM, Gendler SJ: Mucin 1-specific immunotherapy in a mouse model of spontaneous breast cancer. J Immunother. 2003, 26: 47-62. 10.1097/00002371-200301000-00006.CrossRefPubMed
22.
Basu GD, Tinder TL, Bradley JM, Tu T, Hattrup CL, Pockaj BA, Mukherjee P: Cyclooxygenase-2 inhibitor enhances the efficacy of a breast cancer vaccine: role of IDO. J Immunol. 2006, 177: 2391-2402.CrossRefPubMed
23.
Basu G, Pathangey L, Tinder T, LaGioia M, Gendler S, Mukherjee P: COX-2 inhibitor induces apoptosis in breast cancer cells in an in vivo model of spontaneous metastatic breast cancer. Mol Cancer Res. 2004, 2: 632-642.PubMed
24.
Chen D, Xia J, Tanaka Y, Chen H, Koido S, Wernet O, Mukherjee P, Gendler SJ, Kufe D, Gong J: Immunotherapy of spontaneous mammary carcinoma with fusions of dendritic cells and mucin 1-positive carcinoma cells. Immunology. 2003, 109: 300-307. 10.1046/j.1365-2567.2003.01656.x.CrossRefPubMedPubMedCentral
25.
26.
Nakamori M, Fu X, Rousseau R, Chen SY, Zhang X: Destruction of nonimmunogenic mammary tumor cells by a fusogenic oncolytic herpes simplex virus induces potent antitumor immunity. Mol Ther. 2004, 9: 658-665. 10.1016/j.ymthe.2004.02.019.CrossRefPubMed
27.
Li H, Dutuor A, Fu X, Zhang X: Induction of strong antitumor immunity by an HSV-2-based oncolytic virus in a murine mammary tumor model. J Gene Med. 2007, 9: 161-169. 10.1002/jgm.1005.CrossRefPubMed
28.
Brand DD, Latham KA, Rosloniec EF: Collagen-induced arthritis. Nat Protoc. 2007, 2: 1269-1275. 10.1038/nprot.2007.173.CrossRefPubMed
29.
Roy LD, Sahraei M, Subramani DB, Besmer D, Nath S, Tinder TL, Bajaj E, Shanmugam K, Lee YY, Hwang SI, Gendler SJ, Mukherjee P: MUC1 enhances invasiveness of pancreatic cancer cells by inducing epithelial to mesenchymal transition. Oncogene. 2011, 30: 1449-1459. 10.1038/onc.2010.526.CrossRefPubMed
30.
Lee HN, Kim CH, Song GG, Cho SW: Effects of IL-3 and SCF on histamine production kinetics and cell phenotype in rat bone marrow-derived mast cells. Immune Netw. 2010, 10: 15-25. 10.4110/in.2010.10.1.15.CrossRefPubMedPubMedCentral
31.
Glinskii AB, Smith BA, Jiang P, Li XM, Yang M, Hoffman RM, Glinsky GV: Viable circulating metastatic cells produced in orthotopic but not ectopic prostate cancer models. Cancer Res. 2003, 63: 4239-4243.PubMed
32.
Woo M, Nordal R: Commissioning and evaluation of a new commercial small rodent x-ray irradiator. Biomed Imaging Intervent J. 2006, 2: 1-5.CrossRef
33.
Tanaka T, McRae BJ, Cho K, Cook R, Fraki JE, Johnson DA, Powers JC: Mammalian tissue trypsin-like enzymes: comparative reactivities of human skin tryptase, human lung tryptase, and bovine trypsin with peptide 4-nitroanilide and thioester substrates. J Biol Chem. 1983, 258: 13552-13557.PubMed
34.
Vanderslice P, Ballinger SM, Tam EK, Goldstein SM, Craik CS, Caughey GH: Human mast cell tryptase: multiple cDNAs and genes reveal a multigene serine protease family. Proc Natl Acad Sci USA. 1990, 87: 3811-3815. 10.1073/pnas.87.10.3811.CrossRefPubMedPubMedCentral
35.
Ludolph-Hauser D, Rueff F, Sommerhoff CP, Przybilla B: Tryptase, a marker for the activation and localization of mast cells. Hautarzt. 1999, 50: 556-561. 10.1007/s001050050958.CrossRefPubMed
36.
Kotake S, Udagawa N, Takahashi N, Matsuzaki K, Itoh K, Ishiyama S, Saito S, Inoue K, Kamatani N, Gillespie MT, Martin TJ, Suda T: IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest. 1999, 103: 1345-1352. 10.1172/JCI5703.CrossRefPubMedPubMedCentral
37.
Arun B, Goss P: The role of COX-2 inhibition in breast cancer treatment and prevention. Semin Oncol. 2004, 31: 22-29.CrossRefPubMed
38.
Ziegler J: Cancer and arthritis share underlying processes. J Natl Cancer Inst. 1998, 90: 802-803. 10.1093/jnci/90.11.802.CrossRefPubMed
39.
40.
Philip M, Rowley D, Schreiber H: Inflammation as a tumor promoter in cancer induction. Semin Cancer Biol. 2004, 14: 433-439. 10.1016/j.semcancer.2004.06.006.CrossRefPubMed
41.
Folkman J: Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995, 1: 27-31. 10.1038/nm0195-27.CrossRefPubMed
42.
Seki M, Uzuki M, Ohmoto H, Yoshino K, Maeda S, Kokubun S, Sakurai M, Sawai T: Matrix metalloproteinase (MMP-9) in patients with rheumatoid arthritis. Ryumachi. 1995, 35: 792-801.PubMed
43.
Ziolkowska M, Koc A, Luszczykiewicz G, Ksiezopolska-Pietrzak K, Klimczak E, Chwalinska-Sadowska H, Maslinski W: High levels of IL-17 in rheumatoid arthritis patients: IL-15 triggers in vitro IL-17 production via cyclosporin A-sensitive mechanism. J Immunol. 2000, 164: 2832-2838.CrossRefPubMed
44.
Tilg H, Kaser A: IL-6 and arthritis: a detrimental or beneficial mediator?. IDrugs. 1998, 1: 890-895.PubMed
45.
Ben-Baruch A: Inflammation-associated immune suppression in cancer: the roles played by cytokines, chemokines and additional mediators. Semin Cancer Biol. 2006, 16: 38-52. 10.1016/j.semcancer.2005.07.006.CrossRefPubMed
46.
Sansone P, Storci G, Tavolari S, Guarnieri T, Giovannini C, Taffurelli M, Ceccarelli C, Santini D, Paterini P, Marcu KB, Chieco P, Bonafè M: IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. J Clin Invest. 2007, 117: 3988-4002. 10.1172/JCI32533.CrossRefPubMedPubMedCentral
47.
Nam JS, Terabe M, Kang MJ, Chae H, Voong N, Yang YA, Laurence A, Michalowska A, Mamura M, Lonning S, Berzofsky JA, Wakefield LM: Transforming growth factor beta subverts the immune system into directly promoting tumor growth through interleukin-17. Cancer Res. 2008, 68: 3915-3923. 10.1158/0008-5472.CAN-08-0206.CrossRefPubMedPubMedCentral
48.
Juurikivi A, Sandler C, Lindstedt KA, Kovanen PT, Juutilainen T, Leskinen MJ, Maki T, Eklund KK: Inhibition of c-kit tyrosine kinase by imatinib mesylate induces apoptosis in mast cells in rheumatoid synovia: a potential approach to the treatment of arthritis. Ann Rheum Dis. 2005, 64: 1126-1131. 10.1136/ard.2004.029835.CrossRefPubMedPubMedCentral
49.
Kuonen F, Laurent J, Secondini C, Lorusso G, Stehle JC, Rausch T, Faes-Van't Hull E, Bieler G, Alghisi GC, Schwendener R, Andrejevic-Blant S, Mirimanoff RO, Rüegg C: Inhibition of the Kit ligand/c-Kit axis attenuates metastasis in a mouse model mimicking local breast cancer relapse after radiotherapy. Clin Cancer Res. 2012, 18: 4365-4374. 10.1158/1078-0432.CCR-11-3028.CrossRefPubMed
50.
Ceponis A, Konttinen YT, Takagi M, Xu JW, Sorsa T, Matucci-Cerinic M, Santavirta S, Bankl HC, Valent P: Expression of stem cell factor (SCF) and SCF receptor (c-kit) in synovial membrane in arthritis: correlation with synovial mast cell hyperplasia and inflammation. J Rheumatol. 1998, 25: 2304-2314.PubMed
51.
Galli SJ, Tsai M, Wershil BK: The c-kit receptor, stem cell factor, and mast cells: what each is teaching us about the others. Am J Pathol. 1993, 142: 965-974.PubMedPubMedCentral
52.
Bridges AJ, Malone DG, Jicinsky J, Chen M, Ory P, Engber W, Graziano FM: Human synovial mast cell involvement in rheumatoid arthritis and osteoarthritis: relationship to disease type, clinical activity, and antirheumatic therapy. Arthritis Rheum. 1991, 34: 1116-1124. 10.1002/art.1780340907.CrossRefPubMed
53.
Dean G, Hoyland JA, Denton J, Donn RP, Freemont AJ: Mast cells in the synovium and synovial fluid in osteoarthritis. Br J Rheumatol. 1993, 32: 671-675. 10.1093/rheumatology/32.8.671.CrossRefPubMed
54.
Theoharides TC, Conti P: Mast cells: the Jekyll and Hyde of tumor growth. Trends Immunol. 2004, 25: 235-241. 10.1016/j.it.2004.02.013.CrossRefPubMed
55.
Xiang M, Gu Y, Zhao F, Lu H, Chen S, Yin L: Mast cell tryptase promotes breast cancer migration and invasion. Oncol Rep. 2010, 23: 615-619.PubMed
Metadata
Title
Arthritis augments breast cancer metastasis: role of mast cells and SCF/c-Kit signaling
Authors
Lopamudra Das Roy
Jennifer M Curry
Mahnaz Sahraei
Dahlia M Besmer
Amritha Kidiyoor
Helen E Gruber
Pinku Mukherjee
Publication date
01-04-2013
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 2/2013
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr3412

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