Role of chemokines and their receptors in cancer

Department of Medical Oncology, University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands.
Current Pharmaceutical Design (Impact Factor: 3.45). 09/2009; 15.
Source: OAI


Metastases are the cause of 90% of human cancer deaths. The current treatment of cancer with chemo,- and/or radiotherapy is based on cell death by DNA damage neglecting the fact that cancer cell invasion into surrounding tissues and metastasizing are fundamental features of neoplasms and the major reason for treatment failure. Metastasis is the result of several sequential steps and represents a highly organized, non-random, and organ-selective process. A number of in vitro and in vivo models show that tumor cells use chemokine-mediated mechanisms during this metastasizing process, comparable to those observed in the regulation of leukocyte trafficking. Furthermore, chemokines modulate tumor behavior such as the regulation of tumor-associated angiogenesis, activation of host tumor-specific immunological responses, and direct stimulation of tumor cell proliferation in an autocrine fashion. These findings may lead to new drugs that target chemokines or their receptors and will likely be of great additional value for treatment of cancer patients.

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    • "Hence, 70% of OC cases are detected in a late and metastatic disease stage, by which time survival rates have dropped to only 10%–30% (Hennessy et al, 2009). Metastasis is a multifactorial process with recent evidence emerging on the importance of chemokines and chemokine receptor interactions (Kruizinga et al, 2009; Barbieri et al, 2010). "
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    ABSTRACT: Background: In certain cancers, expression of CXCL16 and its receptor CXCR6 associate with lymphocyte infiltration, possibly aiding anti-tumour immune response. In other cancers, CXCL16 and CXCR6 associate with pro-metastatic activity. In the current study, we aimed to characterise the role of CXCL16, sCXCL16, and CXCR6 in ovarian cancer (OC). Methods: CXCL16/CXCR6 expression was analysed on tissue microarray containing 306 OC patient samples. Pre-treatment serum sCXCL16 was determined in 118 patients using ELISA. In vitro, (primary) OC cells were treated with an ADAM-10/ADAM-17 inhibitor (TAPI-2) and an ADAM-10-specific inhibitor (GI254023x), whereupon CXCL16 levels were evaluated on the cell membrane (immunofluorescent analysis, western blots) and in culture supernatants (ELISA). In addition, cell migration was assessed using scratch assays. Results: sCXCL16 independently predicted for poor survival (hazard ratio=2.28, 95% confidence interval=1.29–4.02, P=0.005), whereas neither CXCL16 nor CXCR6 expression correlated with survival. Further, CXCL16/CXCR6 expression and serum sCXCL16 levels did not associate with lymphocyte infiltration. In vitro inhibition of both ADAM-17 and ADAM-10, but especially the latter, decreased CXCL16 membrane shedding and strongly reduced cell migration of A2780 and cultured primary OC-derived malignant cells. Conclusions: High serum sCXCL16 is a prognostic marker for poor survival of OC patients, possibly reflecting ADAM-10 and ADAM-17 pro-metastatic activity. Therefore, serum sCXCL16 levels may be a pseudomarker that identifies patients with highly metastatic tumours.
    British Journal of Cancer 02/2014; 110(6). DOI:10.1038/bjc.2014.55 · 4.84 Impact Factor
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    • "In addition to mediating cellular migration, chemokines and their receptors have been shown to affect many cellular functions including survival, adhesion, invasion, proliferation, and circulating chemokine levels. A growing body of evidence supports a chemokine-mediated mechanism for the metastatic spread of tumor cells: in vitro and in vivo models have shown that chemokines regulate tumor-associated angiogenesis (a prerequisite for metastasis), activate host tumor-specific immunologic responses, and direct tumor cell proliferation in an autocrine fashion (Ben-Baruch, 2009; Gerber et al., 2009; Kruizinga et al., 2009). "
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    ABSTRACT: The tumor microenvironment is extremely complex that depends on tumor cell interaction with the responding host cells. Angiogenesis, or new blood vessel growth from preexisting vasculature, is a preeminent feature of successful tumor growth of all solid tumors. While a number of factors produced by both the tumor cells and host responding cells have been discovered that regulate angiogenesis, increasing evidence is growing to support the important role of CXC chemokines in this process. As a family of cytokines, the CXC chemokines are pleiotropic in their ability to regulate tumor-associated angiogenesis, as well as cancer cell metastases. In this chapter, we will discuss the disparate activity that CXC chemokines play in regulating cancer-associated angiogenesis and metastases.
    Advances in Cancer Research 01/2010; 106:91-111. DOI:10.1016/S0065-230X(10)06003-3 · 5.32 Impact Factor
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    ABSTRACT: Cell migration is a central part of physiological and pathophysiological processes including wound healing, immune defense, matrix remodeling and organ homeostasis. Different cell types have migratory potential including cells of the immune system and cells required in wound healing and tissue repair. These cells migrate locally through the tissue to the site of damage. The fibroblast is a central cell type of wound healing. In rheumatoid arthritis (RA), activated synovial fibroblasts (SFs) have the ability to invade joint cartilage, actively contributing to joint destruction in RA. Recently, RASFs have been shown to be able to migrate to non-affected areas and joints through the blood stream and to invade distant cartilage. RASFs most likely use similar mechanisms comparable to lymphocytes and tumor cells for long-distance and vascular trans-migration. Future experiments will address the goal to keep the transformed-appearing fibroblasts in the affected joints using therapeutical strategies that inhibit the pathophysiological changes of transformed-appearing RASFs but do not interfere with the physiological processes of 'normal' fibroblasts.
    Cell cycle (Georgetown, Tex.) 06/2010; 9(12):2286-91. DOI:10.4161/cc.9.12.11907 · 4.57 Impact Factor
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