Stromal cell-derived factor-1 and CXCR4 receptor interaction in tumor growth and metastasis of breast cancer

Tokyo Metropolitan Komagome Hospital, Edo, Tōkyō, Japan
Biomedecine [?] Pharmacotherapy (Impact Factor: 2.02). 08/2006; 60(6):273-6. DOI: 10.1016/j.biopha.2006.06.004
Source: PubMed


Stromal cell-derived factor-1 (SDF-1)/CXCR4 interaction is critical for the trafficking of lymphocytes, homing and retention of hematopoietic stem cells within the bone marrow and is essential in fetal hematopoiesis. Binding of SDF-1 to CXCR4 activates a variety of intracellular signal transduction pathways and effector molecules that regulate cell survival, proliferation, chemotaxis, migration and adhesion. Recently, intensive research has demonstrated that SDF-1/CXCR4 interaction also regulates several key events in wide variety of cancers. Serum-depleted media in the presence of SDF-1 protected the breast cancer cells from apoptosis. CXCR4-low-expressing MCF-7 formed small tumor at inoculated site in SCID mice 8-9 weeks after inoculation while completely failed to metastasis into various organs. In contrast, CXCR4-high-expressing MDA-231 cells were most efficient in the formation of a large tumor and organ-metastasis within 3 weeks in SCID mice. This review briefly focuses on the role of SDF-1/CXCR4 interaction in tumor growth and metastasis of breast cancer cell both in vitro and in vivo.

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    • "Activation takes place in a proposed two-step two-site mechanism [14] mainly through N-terminal amino acids. As more than 70% of tumour cells show overexpression of CXCR4, the CXCR4/CXCL12 axis plays a pivotal role in tumour pathogenesis with breast, lung, colon and prostate cancer being some of many examples [15] [16] [17] [18] [19] [20] [21] [22] [23]. Tumour proliferation and survival are enhanced by paracrine signalling of tumour associated stromal cells expressing CXCL12 whereas metastases formation is caused by CXCL12 gradient formation in distant organs attracting CXCR4-expression tumour cells [22]. "
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    ABSTRACT: We have engineered GPCR (G protein-coupled receptor) knock-out and high GAG-binding affinity into CXCL12α to inhibit CXCL12α-induced cell migration. Compared to wtCXCL12, the mutant CXCL12α (Δ8 L29K V39K) exhibited a 5.6-fold and a 2.2-fold affinity increase for heparin and heparan sulfate, respectively. From NaCl-based heparin displacement chromatography we concluded that more amino acid replacements would lead to altered GAG (glycosaminoglycan) ligand specificity. GAG silencing by this mutant was shown in a murine seeding model of human cancer cells, whereby a greatly reduced number of liver metastases was detected when the animals were treated intravenously with 1mg/kg CXCL12α (Δ8 L29K V39K) before cancer cell application. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
    FEBS letters 08/2015; DOI:10.1016/j.febslet.2015.07.052 · 3.17 Impact Factor
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    • "Its function in metastasis begins with cancer cell mobility—the binding of CXCL12 to CXCR4 activates various intracellular signal transduction pathways and effector molecules that regulate chemotaxis, migration, and adhesion. Low-CXCR4-expressing MCF-7 cells fail to metastasize when injected into mice, whereas CXCR4-high MDA-231 cells are efficient in forming distant organ metastases [39]. Similarly, CCL21, through its receptor CCR7, triggers actin polymerization, pseudopodia formation, and the directional migration and invasion of breast cancer cells, particularly to lymph nodes, where CCL21 is highly expressed [40]. "
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    Research Journal of Immunology 08/2014; 2014:849720. DOI:10.1155/2014/849720
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    • "Certain malignant tumors tend to metastasize to special organs, and the synchronization and specific expression of chemokines and their receptors may play a significant role in the progression of tumors. Recent studies have shown that the C-X-C motif chemokine ligand 12 (CXCL12)-CXC receptor 4 (CXCR4) biological axis, which is composed of chemokine CXCL12 and its specific receptor, CXCR4, plays a significant role in the dissemination of numerous tumors and specific organ metastasis (10–12). In a previous study on ovarian cancer, out of 14 chemokine receptors only CXCR4 was expressed on the ovarian cancer surface, and CXCL12 was detected in the ascites of 63 patients. "
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