CCL19 is constitutively expressed in the CNS, up-regulated in neuroinflammation, active and also inactive multiple sclerosis lesions

Krumbholz, Markus; Theil, Diethilde; Steinmeyer, F.; Cepok, Sabine; Hemmer, Bernhard; Hofbauer, Monika; Farina, Cinthia; Derfuss, Tobias; Junker, Andreas; Arzberger, Thomas; Sinicina, I.; Hartle, Caroline; Newcombe, Jia; Hohlfeld, Reinhard; Meinl, Edgar

doi:10.1016/j.jneuroim.2007.07.024

Cited by 122 publications

(111 citation statements)

References 57 publications

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“…Recent reports demonstrating that ligands for CCR7 are expressed in human lungs and brain 23,24 -the two common secondary sites besides the lymph nodes that are targeted by the breast cancer -together with the fact that CXCR4 ligand CCL12 is also produced by these and other organs, provide further support for this hypothesis.…”

Section: Discussionmentioning

confidence: 92%

Chemokine receptors CXCR4 and CCR7 promote metastasis by preventing anoikis in cancer cells

2009

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Chemokine receptors are essential mediators of the metastatic spread in various cancer types; however their precise function in the development of secondary tumors remains poorly understood. We report here a novel property of the chemokine receptors CXCR4 and CCR7 in inhibiting detachment-induced cell death -anoikis, which is believed to be one of the major blocks in the metastatic spread of various neoplasms. Activation of these chemokine receptors by their respective ligands, CXCL12 and CCL21 specifically reduced the sensitivity of metastatic breast cancer cells to anoikis by a distinct mechanism of selective regulation of pro-apoptotic Bmf and anti-apoptotic Bcl-xL proteins. Consequently, functional CXCR4 and CCR7 increased cell survival in the absence of correct ECM attachment both in vitro and in vivo. We also demonstrated that preventing chemokineinduced reduction in Bmf levels significantly attenuated breast cancer metastasis in an experimental mouse model. These results provide evidence for a previously unknown axis in malignant tumors, which connects chemokine receptors with deregulated apoptosis in the absence of the appropriate cell -ECM interaction and may offer novel targets for therapeutic intervention for the treatment of metastatic breast and potentially other tumors. Cell Death and Differentiation (2009) 16, 664-673; doi:10.1038/cdd.2008; published online 9 January 2009The main cause of cancer-related deaths is the spread of tumor cells to sites distant from the primary locus and the subsequent establishment of secondary lesions. The heterogeneity and complexity of malignant transformation make it difficult to identify common molecular mechanisms governing the metastatic progression of cancer and potentially account for the lack of effective treatments for malignant cancers. Recently, members of the chemokine receptor family of G-protein-coupled receptors (GPCRs) have been assigned a major role in this process (reviewed in Zlotnik 1 ). It is becoming increasingly clear that many members of this family regulate a complex milieu of interactions between tumor cells, stromal cells, tumor infiltrating leukocytes and endothelial cells and that better understanding of the specific actions of chemokines and their receptors in promoting malignancy will significantly contribute to combating cancer. 2 CXCR4 and CCR7 are the major chemokine receptors found on a wide range of tumor cells and high levels of these receptors are associated with higher grade and poor prognosis of breast, lung, colon and other cancers. 3 Blocking the interaction between CXCR4 and its ligand CXCL12, dramatically reduces breast and other cancer metastases in mouse models. 4 Our recent results have also provided a direct correlation between functional activation of CXCR4 and CCR7 and the invasive, metastatic phenotype of breast cancer cells 5 further supporting a highly important role for these molecules in tumor dissemination to distant sites. Initial studies suggested that these surface molecules induce directional migration of ma...

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Section: Discussionmentioning

confidence: 92%

Chemokine receptors CXCR4 and CCR7 promote metastasis by preventing anoikis in cancer cells

2009

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“…NK cell subsets express a different array of chemokine receptors in humans and mice. For example, human CD56 bright NK cells were shown to express high levels of CCR7 and CXCR3, so they can migrate in response to CCL19 and CXCL10, which are constitutively expressed in the CNS (81). Moreover, TGF-b is constitutively present in the CSF and was found to modulate macrophages (82).…”

Section: Nk Cell Modifications Associated With Cns Disordersmentioning

confidence: 99%

NK Cells in Central Nervous System Disorders

Poli

Kmiecik

Domingues

et al. 2013

The Journal of Immunology

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NK cells are important players in immunity against pathogens and neoplasms. As a component of the innate immune system, they are one of the first effectors on sites of inflammation. Through their cytokine production capacities, NK cells participate in the development of a potent adaptive immune response. Furthermore, NK cells were found to have regulatory functions to limit and prevent autoimmunity via killing of autologous immune cells. These paradoxical functions of NK cells are reflected in CNS disorders. In this review, we discuss the phenotypes and functional features of peripheral and brain NK cells in brain tumors and infections, neurodegenerative diseases, acute vascular and traumatic damage, as well as mental disorders. We also discuss the implication of NK cells in neurotoxicity and neuroprotection following CNS pathology, as well as the crosstalk between NK cells and brain-resident immune cells.

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“…Its two ligands, homeostatic chemokines CCL19 and CCL21, are preferentially expressed in secondary lymphoid tissues, and CCL19 is also expressed in the brain (19).…”

mentioning

confidence: 99%

Inflammatory chemokines and metastasis—tracing the accessory

et al. 2013

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The tumor microenvironment consists of stromal cells and leukocytes that contribute to cancer progression. Cross-talk between tumor cells and their microenvironment is facilitated by a variety of soluble factors, including growth factors, cytokines such as chemokines. Due to a wide expression of chemokine receptors on cells in the tumor microenvironment, including tumor cells, chemokines affect various processes such as leukocyte recruitment, angiogenesis, tumor cell survival, tumor cell adhesion, proliferation, vascular permeability, immune suppression, invasion and metastasis. Inflammatory chemokines are instrumental players in cancer-related inflammation and significantly contribute to numerous steps during metastasis. Recruitment of myeloid-derived cells to metastatic sites is mainly mediated by the inflammatory chemokines CCL2 and CCL5. Tumor cell homing and extravasation from the circulation in distant organs are also regulated by inflammatory chemokines. Recent experimental evidence demonstrated that besides leukocyte recruitment, tumor cell-derived CCL2 directly activated endothelial cells and together with monocytes facilitated tumor cell extravasation, in a CCL2-and CCL5-dependent manner. Furthermore, CX3CL1 expression in the bone facilitated metastasis of CX3CR1 expressing tumor cells to this site. Current findings in preclinical models strongly suggest that inflammatory chemokines play an important role during metastasis and targeting of the chemokine axis might have a therapeutic potential. 2

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CCL19 is constitutively expressed in the CNS, up-regulated in neuroinflammation, active and also inactive multiple sclerosis lesions

Cited by 122 publications

References 57 publications

Chemokine receptors CXCR4 and CCR7 promote metastasis by preventing anoikis in cancer cells

Chemokine receptors CXCR4 and CCR7 promote metastasis by preventing anoikis in cancer cells

NK Cells in Central Nervous System Disorders

Inflammatory chemokines and metastasis—tracing the accessory

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