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
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.
Available from: Tiziana Adage
- "Activation takes place in a proposed two-step two-site mechanism  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         . 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 . "
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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.
Available from: Karen Nava
- "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 . 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 . "
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ABSTRACT: Chemokines are small proteins that primarily regulate the traffic of leukocytes under homeostatic conditions and during specific immune responses. The chemokine-chemokine receptor system comprises almost 50 chemokines and approximately 20 chemokine receptors; thus, there is no unique ligand for each receptor and the binding of different chemokines to the same receptor might have disparate effects. Complicating the system further, these effects depend on the cellular milieu. In cancer, although chemokines are associated primarily with the generation of a protumoral microenvironment and organ-directed metastasis, they also mediate other phenomena related to disease progression, such as angiogenesis and even chemoresistance. Therefore, the chemokine system is becoming a target in cancer therapeutics. We review the emerging data and correlations between chemokines/chemokine receptors and breast cancer, their implications in cancer progression, and possible therapeutic strategies that exploit the chemokine system.
Available from: Wenli Liu
- "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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ABSTRACT: Ovarian cancer is the most fatal gynecological cancer, with a 5-year survival rate of only 30%. Lysophosphatidic acid (LPA), which possesses growth factor-like functions, is a major regulatory factor in the peritoneal metastasis of ovarian cancer. LPA stimulates the expression of numerous genes that are associated with angiogenesis and metastasis. Ovarian epithelial carcinoma specifically expresses chemotactic factor C-X-C motif chemokine ligand 12 (CXCL12) and its receptor, CXC receptor 4 (CXCR4). The CXCL12-CXCR4 axis directly contributes to ovarian cancer cell proliferation, migration and invasion. The present study investigated the regulation of LPA on the CXCL12-CXCR4 axis and the effect of the LPA-mediated CXCL12-CXCR4 axis on the tumor proliferation, migration and invasion of ovarian cancer cell lines. The CXCR4 proteins expressed in the cell membrane and the cytoplasm of ovarian cancer cells, CAOV3 and SKOV3, were detected by immunocytochemistry. The expression of CXCR4 and CXCL12 was increased in the ovarian cancer cells in a dose- and time-dependent manner when treated with LPA compared with the control groups (P<0.05), as determined by reverse transcription polymerase chain reaction and flow cytometry. LPA (20 μM) and CXCL12 (100 ng/ml) enhanced the proliferation, migration and invasion of the ovarian cancer cells, CAOV3 and SKOV3, as identified by MTT, Transwell and Matrigel assays following co-treatment for 24 h. LPA promoted invasiveness of ovarian cancer by upregulating CXCL12-CXCR4 axis expression.
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