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
Molecular Cancer
Published in: Molecular Cancer 1/2013

Open Access 01-12-2013 | Research

Chemokine receptor CX3CR1 contributes to macrophage survival in tumor metastasis

Authors: Jiao Zheng, Min Yang, Jianghua Shao, Yanju Miao, Jiahuai Han, Jie Du

Published in: Molecular Cancer | Issue 1/2013

Login to get access

Abstract

Background

Macrophages, the key component of the tumor microenvironment, are differentiated mononuclear phagocyte lineage cells that are characterized by specific phenotypic characteristics that have been implicated in tumor growth, angiogenesis, and invasion. CX3CR1, the chemoattractant cytokine CX3CL1 receptor, plays an important role in modulating inflammatory responses, including monocyte homeostasis and macrophage phenotype and function. However, the role of CX3CR1 in the regulation of the tumor inflammatory microenvironment is not fully understood.

Methods

Using in vivo hepatic metastasis model, human colon carcinoma specimens, immunohistochemical staining, TUNEL staining, flow cytometry analysis, Western blotting assay and co-culture in three-dimensional peptide gel, we determined the effects of CX3CR1 on angiogenic macrophage survival and tumor metastasis.

Results

In this study, we found that CX3CR1 was expressed in human colon carcinomas in a histologic grade- and stage-dependent manner, and CX3CR1 upregulation in TAMs was correlated with poor prognosis. Furthermore, we showed that in a microenvironment lacking CX3CR1, the liver metastasis of colon cancer cells was significantly inhibited. The underlying mechanism is associated with decrease accumulation of angiogenic macrophages that can be partly attributed to increased apoptosis in the tumor microenvironment, thus leading to impaired tumor angiogenesis in the liver and suppressed tumor metastasis.

Conclusions

Our results suggest a role of CX3CR1 in angiogenic macrophage survival in the tumor microenvironment contributing to tumor metastasis.
Appendix
Available only for authorised users
Literature
1.
Tlsty TD, Coussens LM: Tumor stroma and regulation of cancer development. Annu Rev Pathol. 2006, 1: 119-150. 10.1146/annurev.pathol.1.110304.100224CrossRefPubMed
2.
Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A: Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis. 2009, 30: 1073-1081. 10.1093/carcin/bgp127CrossRefPubMed
3.
Lorusso G, Ruegg C: The tumor microenvironment and its contribution to tumor evolution toward metastasis. Histochem Cell Biol. 2008, 130: 1091-1103. 10.1007/s00418-008-0530-8CrossRefPubMed
4.
5.
Solinas G, Germano G, Mantovani A, Allavena P: Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J Leukoc Biol. 2009, 86: 1065-1073. 10.1189/jlb.0609385CrossRefPubMed
6.
Qian BZ, Pollard JW: Macrophage diversity enhances tumor progression and metastasis. Cell. 2010, 141: 39-51. 10.1016/j.cell.2010.03.014CrossRefPubMed
7.
de Visser KE, Coussens LM: The inflammatory tumor microenvironment and its impact on cancer development. Contrib Microbiol. 2006, 13: 118-137.CrossRefPubMed
8.
Zhang J, Patel JM: Role of the CX3CL1-CX3CR1 axis in chronic inflammatory lung diseases. Int J Clin Exp Med. 2010, 3: 233-244.PubMedCentralPubMed
9.
Tacke F, Alvarez D, Kaplan TJ, Jakubzick C, Spanbroek R, Llodra J, Garin A, Liu J, Mack M, van Rooijen N: Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J Clin Invest. 2007, 117: 185-194. 10.1172/JCI28549PubMedCentralCrossRefPubMed
10.
Nahrendorf M, Swirski FK, Aikawa E, Stangenberg L, Wurdinger T, Figueiredo JL, Libby P, Weissleder R, Pittet MJ: The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J Exp Med. 2007, 204: 3037-3047. 10.1084/jem.20070885PubMedCentralCrossRefPubMed
11.
Li L, Huang L, Sung SS, Vergis AL, Rosin DL, Rose CE, Lobo PI, Okusa MD: The chemokine receptors CCR2 and CX3CR1 mediate monocyte/macrophage trafficking in kidney ischemia-reperfusion injury. Kidney Int. 2008, 74: 1526-1537. 10.1038/ki.2008.500PubMedCentralCrossRefPubMed
12.
Ishida Y, Gao JL, Murphy PM: Chemokine receptor CX3CR1 mediates skin wound healing by promoting macrophage and fibroblast accumulation and function. J Immunol. 2008, 180: 569-579.CrossRefPubMed
13.
Karlmark KR, Zimmermann HW, Roderburg C, Gassler N, Wasmuth HE, Luedde T, Trautwein C, Tacke F: The fractalkine receptor CXCR1 protects against liver fibrosis by controlling differentiation and survival of infiltrating hepatic monocytes. Hepatology. 2010, 52: 1769-1782. 10.1002/hep.23894CrossRefPubMed
14.
Landsman L, Bar-On L, Zernecke A, Kim KW, Krauthgamer R, Shagdarsuren E, Lira SA, Weissman IL, Weber C, Jung S: CX3CR1 is required for monocyte homeostasis and atherogenesis by promoting cell survival. Blood. 2009, 113: 963-972. 10.1182/blood-2008-07-170787CrossRefPubMed
15.
Gautier EL, Jakubzick C, Randolph GJ: Regulation of the migration and survival of monocyte subsets by chemokine receptors and its relevance to atherosclerosis. Arterioscler Thromb Vasc Biol. 2009, 29: 1412-1418. 10.1161/ATVBAHA.108.180505PubMedCentralCrossRefPubMed
16.
Morimoto-Tomita M, Ohashi Y, Matsubara A, Tsuiji M, Irimura T: Mouse colon carcinoma cells established for high incidence of experimental hepatic metastasis exhibit accelerated and anchorage-independent growth. Clin Exp Metastasis. 2005, 22: 513-521. 10.1007/s10585-005-3585-0CrossRefPubMed
17.
Yang M, Zheng J, Miao Y, Wang Y, Cui W, Guo J, Qiu S, Han Y, Jia L, Li H: Serum-glucocorticoid regulated kinase 1 regulates alternatively activated macrophage polarization contributing to angiotensin II-induced inflammation and cardiac fibrosis. Arterioscler Thromb Vasc Biol. 2012, 32: 1675-1686. 10.1161/ATVBAHA.112.248732CrossRefPubMed
18.
Kumar AH, Martin K, Turner EC, Buneker CK, Dorgham K, Deterre P, Caplice NM: Role of CX3CR1 receptor in monocyte/macrophage driven neovascularization. PLoS One. 2013, 8: e57230- 10.1371/journal.pone.0057230PubMedCentralCrossRefPubMed
19.
Balkwill F, Mantovani A: Inflammation and cancer: back to Virchow?. Lancet. 2001, 357: 539-545. 10.1016/S0140-6736(00)04046-0CrossRefPubMed
20.
Lin EY, Li JF, Gnatovskiy L, Deng Y, Zhu L, Grzesik DA, Qian H, Xue XN, Pollard JW: Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res. 2006, 66: 11238-11246. 10.1158/0008-5472.CAN-06-1278CrossRefPubMed
21.
Zabuawala T, Taffany DA, Sharma SM, Merchant A, Adair B, Srinivasan R, Rosol TJ, Fernandez S, Huang K, Leone G, Ostrowski MC: An ets2-driven transcriptional program in tumor-associated macrophages promotes tumor metastasis. Cancer Res. 2010, 70: 1323-1333. 10.1158/0008-5472.CAN-09-1474PubMedCentralCrossRefPubMed
22.
Mantovani A, Schioppa T, Porta C, Allavena P, Sica A: Role of tumor-associated macrophages in tumor progression and invasion. Cancer Metastasis Rev. 2006, 25: 315-322. 10.1007/s10555-006-9001-7CrossRefPubMed
23.
Lewis CE, Pollard JW: Distinct role of macrophages in different tumor microenvironments. Cancer Res. 2006, 66: 605-612. 10.1158/0008-5472.CAN-05-4005CrossRefPubMed
24.
Mantovani A, Allavena P, Sica A, Balkwill F: Cancer-related inflammation. Nature. 2008, 454: 436-444. 10.1038/nature07205CrossRefPubMed
25.
Movahedi K, Laoui D, Gysemans C, Baeten M, Stange G, Van den Bossche J, Mack M, Pipeleers D, In't Veld P, De Baetselier P, Van Ginderachter JA: Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Res. 2010, 70: 5728-5739. 10.1158/0008-5472.CAN-09-4672CrossRefPubMed
26.
Arnold L, Henry A, Poron F, Baba-Amer Y, van Rooijen N, Plonquet A, Gherardi RK, Chazaud B: Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis. J Exp Med. 2007, 204: 1057-1069. 10.1084/jem.20070075PubMedCentralCrossRefPubMed
27.
Muehlhoefer A, Saubermann LJ, Gu X, Luedtke-Heckenkamp K, Xavier R, Blumberg RS, Podolsky DK, MacDermott RP, Reinecker HC: Fractalkine is an epithelial and endothelial cell-derived chemoattractant for intraepithelial lymphocytes in the small intestinal mucosa. J Immunol. 2000, 164: 3368-3376.CrossRefPubMed
28.
Ruth JH, Volin MV, Haines GK, Woodruff DC, Katschke KJ, Woods JM, Park CC, Morel JC, Koch AE: Fractalkine, a novel chemokine in rheumatoid arthritis and in rat adjuvant-induced arthritis. Arthritis Rheum. 2001, 44: 1568-1581. 10.1002/1529-0131(200107)44:7<1568::AID-ART280>3.0.CO;2-1CrossRefPubMed
29.
Lucas AD, Bursill C, Guzik TJ, Sadowski J, Channon KM, Greaves DR: Smooth muscle cells in human atherosclerotic plaques express the fractalkine receptor CX3CR1 and undergo chemotaxis to the CX3C chemokine fractalkine (CX3CL1). Circulation. 2003, 108: 2498-2504. 10.1161/01.CIR.0000097119.57756.EFCrossRefPubMed
30.
Combadiere C, Potteaux S, Gao JL, Esposito B, Casanova S, Lee EJ, Debre P, Tedgui A, Murphy PM, Mallat Z: Decreased atherosclerotic lesion formation in CX3CR1/apolipoprotein E double knockout mice. Circulation. 2003, 107: 1009-1016. 10.1161/01.CIR.0000057548.68243.42CrossRefPubMed
31.
Robinson LA, Nataraj C, Thomas DW, Howell DN, Griffiths R, Bautch V, Patel DD, Feng L, Coffman TM: A role for fractalkine and its receptor (CX3CR1) in cardiac allograft rejection. J Immunol. 2000, 165: 6067-6072.CrossRefPubMed
32.
Estaquier J, Vallette F, Vayssiere JL, Mignotte B: The mitochondrial pathways of apoptosis. Adv Exp Med Biol. 2012, 942: 157-183.CrossRefPubMed
33.
Lin EY, Pollard JW: Tumor-associated macrophages press the angiogenic switch in breast cancer. Cancer Res. 2007, 67: 5064-5066. 10.1158/0008-5472.CAN-07-0912CrossRefPubMed
34.
Lin EY, Li JF, Bricard G, Wang W, Deng Y, Sellers R, Porcelli SA, Pollard JW: Vascular endothelial growth factor restores delayed tumor progression in tumors depleted of macrophages. Mol Oncol. 2007, 1: 288-302. 10.1016/j.molonc.2007.10.003PubMedCentralCrossRefPubMed
35.
Qian B, Deng Y, Im JH, Muschel RJ, Zou Y, Li J, Lang RA, Pollard JW: A distinct macrophage population mediates metastatic breast cancer cell extravasation, establishment and growth. PLoS One. 2009, 4: e6562- 10.1371/journal.pone.0006562PubMedCentralCrossRefPubMed
36.
Jung S, Aliberti J, Graemmel P, Sunshine MJ, Kreutzberg GW, Sher A, Littman DR: Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol Cell Biol. 2000, 20: 4106-4114. 10.1128/MCB.20.11.4106-4114.2000PubMedCentralCrossRefPubMed
Metadata
Title
Chemokine receptor CX3CR1 contributes to macrophage survival in tumor metastasis
Authors
Jiao Zheng
Min Yang
Jianghua Shao
Yanju Miao
Jiahuai Han
Jie Du
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2013
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-12-141

Other articles of this Issue 1/2013

Molecular Cancer 1/2013 Go to the issue

Research

FGFR3 has tumor suppressor properties in cells with epithelial phenotype

Research

Growth factor receptor-Src-mediated suppression of GRK6 dysregulates CXCR4 signaling and promotes medulloblastoma migration

Research

6-Formylindolo (3,2-b)carbazole (FICZ) enhances retinoic acid (RA)-induced differentiation of HL-60 myeloblastic leukemia cells

Research

Krüppel-like factor 4 regulates genetic stability in mouse embryonic fibroblasts

Research

Cathepsin B as a potential prognostic and therapeutic marker for human lung squamous cell carcinoma

Research

Fludarabine treatment favors the retention of miR-485-3p by prostate cancer cells: implications for survival
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