The Experts below are selected from a list of 24288 Experts worldwide ranked by ideXlab platform
Shozo Hojo - One of the best experts on this subject based on the ideXlab platform.
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CXCL16 suppresses liver metastasis of colorectal cancer by promoting tnf α induced apoptosis by tumor associated macrophages
2014Co-Authors: Jiye Kee, Shozo Hojo, Koichi Tsuneyama, Isaya Hashimoto, Aya Ito, Yoshiko Igarashi, Kazuhiro Tsukada, Tatsuro Irimura, Naotoshi Shibahara, Ichiro TakasakiAbstract:Inhibition of metastasis through upregulation of immune surveillance is a major purpose of Chemokine gene therapy. In this study, we focused on a membrane-bound Chemokine CXCL16, which has shown a correlation with a good prognosis for colorectal cancer (CRC) patients. We generated a CXCL16-expressing metastatic CRC cell line and identified changes in TNF and apoptosis-related factors. To investigate the effect of CXCL16 on colorectal liver metastasis, we injected SL4-Cont and SL4-CXCL16 cells into intraportal vein in C57BL/6 mice and evaluated the metastasis. Moreover, we analyzed metastatic liver tissues using flow cytometry whether CXCL16 expression regulates the infiltration of M1 macrophages. CXCL16 expression enhanced TNF-α-induced apoptosis through activation of PARP and the caspase-3-mediated apoptotic pathway and through inactivation of the NF-κB-mediated survival pathway. Several genes were changed by CXCL16 expression, but we focused on IRF8, which is a regulator of apoptosis and the metastatic phenotype. We confirmed CXCL16 expression in SL4-CXCL16 cells and the correlation between CXCL16 and IRF8. Silencing of IRF8 significantly decreased TNF-α-induced apoptosis. Liver metastasis of SL4-CXCL16 cells was also inhibited by TNF-α-induced apoptosis through the induction of M1 macrophages, which released TNF-α. Our findings suggest that the accumulation of M1 macrophages and the enhancement of apoptosis by CXCL16 might be an effective dual approach against CRC liver metastasis. Collectively, this study revealed that CXCL16 regulates immune surveillance and cell signaling. Therefore, we provide the first evidence of CXCL16 serving as an intracellular signaling molecule.
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Chemokine CXCL16 suppresses liver metastasis of colorectal cancer via augmentation of tumor infiltrating natural killer t cells in a murine model
2013Co-Authors: Jiye Kee, Shozo Hojo, Isaya Hashimoto, Takashi Nakayama, Aya Ito, Yoshiko Igarashi, Kazuhiro Tsukada, Tatsuro Irimura, Naotoshi Shibahara, Osamu YoshieAbstract:Colorectal cancer (CRC) is a typical lifestyle-related disease, and it metastasizes mostly to the liver. It is important to understand the molecular mechanisms of CRC metastasis in order to design new and effective treatments for CRC patients. Chemokines are known to have antitumor effects as their chemoattractant properties stimulate the accumulation of infiltrating immune cells (TILs) in tumors. Chemokine (C-X-C motif) ligand 16 (CXCL16), also known as SR-PSOX, is a unique membrane-bound Chemokine that induces the expression of its specific receptor CXCR6. We previously reported that the expression of CXCL16 by cancer cells enhances the recruitment of TILs, thereby improving the prognosis of CRC. It has since been reported that CXCL16/CXCR6 expression is involved in the metastasis of various types of cancer. However, there is no report of the association between CXCL16 expression and liver metastasis in CRC. In this study, we investigated the role of cancer-derived CXCL16 and the possibility of gene therapy using CXCL16. Therefore, we examined the metastasis of colon 38 SL4 cells to the liver in an experimental model. Following injection of cancer cells into the intraportal vein, CXCL16-expressing CRC cells drastically inhibited liver metastasis. We also found that CD8 T cells and natural killer T (NKT) cells, known as CXCR6-expressing cells, increased in CXCL16-expressing metastatic tissue. Collectively, the inhibitory effect on metastasis to the liver by CXCL16 was observed in NKT cell-depleted mice but not in CD8 T cell-depleted mice. These results demonstrate the inhibitory effect of CXCL16 on liver metastasis via NKT cells in CRC.
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Chemokine receptors in cancer metastasis and cancer cell derived Chemokines in host immune response
2007Co-Authors: Keiichi Koizumi, Shozo Hojo, Takuya Akashi, Kazuo Yasumoto, Ikuo SaikiAbstract:The chemotactic cytokines called Chemokines are a superfamily of small secreted cytokines that were initially characterized through their ability to prompt the migration of leukocytes. Attention has been focused on the Chemokine receptors expressed on cancer cells because cancer cell migration and metastasis show similarities to leukocyte trafficking. CXC Chemokine receptor 4 (CXCR4) was first investigated as a Chemokine receptor that is associated with lung metastasis of breast cancers. Recently, CXCR4 was reported to be a key molecule in the formation of peritoneal carcinomatosis in gastric cancer. In the present review, we highlight current knowledge about the role of CXCR4 in cancer metastases. In contrast to Chemokine receptors expressed on cancer cells, little is known about the roles of cancer cell-derived Chemokines. Cancer tissue consists of both cancer cells and various stromal cells, and leukocytes that infiltrate into cancer are of particular importance in cancer progression. Although colorectal cancer invasion is regulated by the Chemokine CCL9-induced infiltration of immature myeloid cells into cancer, high-level expression of cancer cell-derived Chemokine CXCL16 increases infiltrating CD8+ and CD4+ T cells into cancer tissues, and correlates with a good prognosis. We discuss the conflicting biological effects of cancer cell-derived Chemokines on cancer progression, using CCL9 and CXCL16 as examples. (Cancer Sci 2007; 98: 1652–1658)
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high level expression of Chemokine CXCL16 by tumor cells correlates with a good prognosis and increased tumor infiltrating lymphocytes in colorectal cancer
2007Co-Authors: Shozo Hojo, Keiichi Koizumi, Koichi Tsuneyama, Yoshihisa Arita, Zhengguo Cui, Kanna Shinohara, Takayuki Minami, Isaya Hashimoto, Takashi Nakayama, Hiroaki SakuraiAbstract:CXCL16 is a new member of the Chemokine superfamily, which exists in a transmembrane as well as a soluble form. Its receptor CXCR6 is detected on CD4+ T cells, CD8+ T cells, and natural killer T cells. Here, we report a significant correlation of CXCL16 expression by tumor cells with the infiltration of T cells and prognosis in colorectal cancer (CRC). We first found that CXCL16 expression was consistently up-regulated more in tumor tissues than in normal mucosa derived from the same CRC patients. Four human CRC cell lines also expressed CXCL16 mRNA and secreted soluble CXCL16. We next examined the expression of CXCL16 and infiltration of lymphocytes in CRC specimens (n = 58) by immunohistochemistry. CRC patients with high levels of CXCL16 expression (n = 43) had higher levels of CD4+ and CD8+ tumor-infiltrating lymphocytes (TIL; P
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high level expression of Chemokine CXCL16 by tumor cells correlates with a good prognosis and increased tumor infiltrating lymphocytes in colorectal cancer
2007Co-Authors: Shozo Hojo, Keiichi Koizumi, Koichi Tsuneyama, Yoshihisa Arita, Zhengguo Cui, Kanna Shinohara, Takayuki Minami, Isaya Hashimoto, Takashi Nakayama, Hiroaki SakuraiAbstract:CXCL16 is a new member of the Chemokine superfamily, which exists in a transmembrane as well as a soluble form. Its receptor CXCR6 is detected on CD4(+) T cells, CD8(+) T cells, and natural killer T cells. Here, we report a significant correlation of CXCL16 expression by tumor cells with the infiltration of T cells and prognosis in colorectal cancer (CRC). We first found that CXCL16 expression was consistently up-regulated more in tumor tissues than in normal mucosa derived from the same CRC patients. Four human CRC cell lines also expressed CXCL16 mRNA and secreted soluble CXCL16. We next examined the expression of CXCL16 and infiltration of lymphocytes in CRC specimens (n = 58) by immunohistochemistry. CRC patients with high levels of CXCL16 expression (n = 43) had higher levels of CD4(+) and CD8(+) tumor-infiltrating lymphocytes (TIL; P < 0.01) than those with low levels of CXCL16 expression (n = 15). Furthermore, the high CXCL16 expression group showed significantly better prognosis than the low CXCL16 expression group (P < 0.05). Collectively, our data suggest that the expression of CXCL16 by tumor cells enhances the recruitment of TILs, thereby bringing about a better prognosis in CRC. Thus, CXCL16 is a new prognostic biomarker and may be useful for the development of a more effective therapeutic strategy for CRC.
Isaya Hashimoto - One of the best experts on this subject based on the ideXlab platform.
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CXCL16 suppresses liver metastasis of colorectal cancer by promoting tnf α induced apoptosis by tumor associated macrophages
2014Co-Authors: Jiye Kee, Shozo Hojo, Koichi Tsuneyama, Isaya Hashimoto, Aya Ito, Yoshiko Igarashi, Kazuhiro Tsukada, Tatsuro Irimura, Naotoshi Shibahara, Ichiro TakasakiAbstract:Inhibition of metastasis through upregulation of immune surveillance is a major purpose of Chemokine gene therapy. In this study, we focused on a membrane-bound Chemokine CXCL16, which has shown a correlation with a good prognosis for colorectal cancer (CRC) patients. We generated a CXCL16-expressing metastatic CRC cell line and identified changes in TNF and apoptosis-related factors. To investigate the effect of CXCL16 on colorectal liver metastasis, we injected SL4-Cont and SL4-CXCL16 cells into intraportal vein in C57BL/6 mice and evaluated the metastasis. Moreover, we analyzed metastatic liver tissues using flow cytometry whether CXCL16 expression regulates the infiltration of M1 macrophages. CXCL16 expression enhanced TNF-α-induced apoptosis through activation of PARP and the caspase-3-mediated apoptotic pathway and through inactivation of the NF-κB-mediated survival pathway. Several genes were changed by CXCL16 expression, but we focused on IRF8, which is a regulator of apoptosis and the metastatic phenotype. We confirmed CXCL16 expression in SL4-CXCL16 cells and the correlation between CXCL16 and IRF8. Silencing of IRF8 significantly decreased TNF-α-induced apoptosis. Liver metastasis of SL4-CXCL16 cells was also inhibited by TNF-α-induced apoptosis through the induction of M1 macrophages, which released TNF-α. Our findings suggest that the accumulation of M1 macrophages and the enhancement of apoptosis by CXCL16 might be an effective dual approach against CRC liver metastasis. Collectively, this study revealed that CXCL16 regulates immune surveillance and cell signaling. Therefore, we provide the first evidence of CXCL16 serving as an intracellular signaling molecule.
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Chemokine CXCL16 suppresses liver metastasis of colorectal cancer via augmentation of tumor infiltrating natural killer t cells in a murine model
2013Co-Authors: Jiye Kee, Shozo Hojo, Isaya Hashimoto, Takashi Nakayama, Aya Ito, Yoshiko Igarashi, Kazuhiro Tsukada, Tatsuro Irimura, Naotoshi Shibahara, Osamu YoshieAbstract:Colorectal cancer (CRC) is a typical lifestyle-related disease, and it metastasizes mostly to the liver. It is important to understand the molecular mechanisms of CRC metastasis in order to design new and effective treatments for CRC patients. Chemokines are known to have antitumor effects as their chemoattractant properties stimulate the accumulation of infiltrating immune cells (TILs) in tumors. Chemokine (C-X-C motif) ligand 16 (CXCL16), also known as SR-PSOX, is a unique membrane-bound Chemokine that induces the expression of its specific receptor CXCR6. We previously reported that the expression of CXCL16 by cancer cells enhances the recruitment of TILs, thereby improving the prognosis of CRC. It has since been reported that CXCL16/CXCR6 expression is involved in the metastasis of various types of cancer. However, there is no report of the association between CXCL16 expression and liver metastasis in CRC. In this study, we investigated the role of cancer-derived CXCL16 and the possibility of gene therapy using CXCL16. Therefore, we examined the metastasis of colon 38 SL4 cells to the liver in an experimental model. Following injection of cancer cells into the intraportal vein, CXCL16-expressing CRC cells drastically inhibited liver metastasis. We also found that CD8 T cells and natural killer T (NKT) cells, known as CXCR6-expressing cells, increased in CXCL16-expressing metastatic tissue. Collectively, the inhibitory effect on metastasis to the liver by CXCL16 was observed in NKT cell-depleted mice but not in CD8 T cell-depleted mice. These results demonstrate the inhibitory effect of CXCL16 on liver metastasis via NKT cells in CRC.
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high level expression of Chemokine CXCL16 by tumor cells correlates with a good prognosis and increased tumor infiltrating lymphocytes in colorectal cancer
2007Co-Authors: Shozo Hojo, Keiichi Koizumi, Koichi Tsuneyama, Yoshihisa Arita, Zhengguo Cui, Kanna Shinohara, Takayuki Minami, Isaya Hashimoto, Takashi Nakayama, Hiroaki SakuraiAbstract:CXCL16 is a new member of the Chemokine superfamily, which exists in a transmembrane as well as a soluble form. Its receptor CXCR6 is detected on CD4+ T cells, CD8+ T cells, and natural killer T cells. Here, we report a significant correlation of CXCL16 expression by tumor cells with the infiltration of T cells and prognosis in colorectal cancer (CRC). We first found that CXCL16 expression was consistently up-regulated more in tumor tissues than in normal mucosa derived from the same CRC patients. Four human CRC cell lines also expressed CXCL16 mRNA and secreted soluble CXCL16. We next examined the expression of CXCL16 and infiltration of lymphocytes in CRC specimens (n = 58) by immunohistochemistry. CRC patients with high levels of CXCL16 expression (n = 43) had higher levels of CD4+ and CD8+ tumor-infiltrating lymphocytes (TIL; P
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high level expression of Chemokine CXCL16 by tumor cells correlates with a good prognosis and increased tumor infiltrating lymphocytes in colorectal cancer
2007Co-Authors: Shozo Hojo, Keiichi Koizumi, Koichi Tsuneyama, Yoshihisa Arita, Zhengguo Cui, Kanna Shinohara, Takayuki Minami, Isaya Hashimoto, Takashi Nakayama, Hiroaki SakuraiAbstract:CXCL16 is a new member of the Chemokine superfamily, which exists in a transmembrane as well as a soluble form. Its receptor CXCR6 is detected on CD4(+) T cells, CD8(+) T cells, and natural killer T cells. Here, we report a significant correlation of CXCL16 expression by tumor cells with the infiltration of T cells and prognosis in colorectal cancer (CRC). We first found that CXCL16 expression was consistently up-regulated more in tumor tissues than in normal mucosa derived from the same CRC patients. Four human CRC cell lines also expressed CXCL16 mRNA and secreted soluble CXCL16. We next examined the expression of CXCL16 and infiltration of lymphocytes in CRC specimens (n = 58) by immunohistochemistry. CRC patients with high levels of CXCL16 expression (n = 43) had higher levels of CD4(+) and CD8(+) tumor-infiltrating lymphocytes (TIL; P < 0.01) than those with low levels of CXCL16 expression (n = 15). Furthermore, the high CXCL16 expression group showed significantly better prognosis than the low CXCL16 expression group (P < 0.05). Collectively, our data suggest that the expression of CXCL16 by tumor cells enhances the recruitment of TILs, thereby bringing about a better prognosis in CRC. Thus, CXCL16 is a new prognostic biomarker and may be useful for the development of a more effective therapeutic strategy for CRC.
Rolf Mentlein - One of the best experts on this subject based on the ideXlab platform.
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the Chemokine receptor cxcr6 evokes reverse signaling via the transmembrane Chemokine CXCL16
2017Co-Authors: Vivian Adamski, Janka Heldfeindt, Rolf Mentlein, Ralph Lucius, Michael Synowitz, Kirsten HattermannAbstract:Reverse signaling is a signaling mechanism where transmembrane or membrane-bound ligands transduce signals and exert biological effects upon binding of their specific receptors, enabling a bidirectional signaling between ligand and receptor-expressing cells. In this study, we address the question of whether the transmembrane Chemokine (C-X-C motif) ligand 16, CXCL16 is able to transduce reverse signaling and investigate the biological consequences. For this, we used human glioblastoma cell lines and a melanoma cell line as in vitro models to show that stimulation with recombinant C-X-C Chemokine receptor 6 (CXCR6) or CXCR6-containing membrane preparations induces intracellular (reverse) signaling. Specificity was verified by RNAi experiments and by transfection with expression vectors for the intact CXCL16 and an intracellularly-truncated form of CXCL16. We showed that reverse signaling via CXCL16 promotes migration in CXCL16-expressing melanoma and glioblastoma cells, but does not affect proliferation or protection from chemically-induced apoptosis. Additionally, fast migrating cells isolated from freshly surgically-resected gliomas show a differential expression pattern for CXCL16 in comparison to slowly-migrating cells, enabling a possible functional role of the reverse signaling of the CXCL16/CXCR6 pair in human brain tumor progression in vivo.
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inverse signaling of the transmembrane Chemokine CXCL16 contributes to proliferative and anti apoptotic effects in cultured human meningioma cells
2016Co-Authors: Kirsten Hattermann, Rolf Mentlein, Michael Synowitz, Maximilian H Mehdorn, Kareen Bartsch, Henrike Gebhardt, Anne Dorothee Schmitt, Janka HeldfeindtAbstract:Chemokines and their receptors play a decisive role in tumor progression and metastasis. We recently found a new signaling mechanism in malignant glioma cells mediated by transmembrane Chemokines that we termed “inverse signaling”. According to this hypothesis, soluble (s)-CXCL16 binds to the surface-expressed transmembrane (tm) -CXCL16, and induces signaling and different biological effects in the stimulated cells, so that the transmembrane ligand itself acts as a receptor for its soluble counterpart. Now, we hypothesized that “inverse signaling” via tm-CXCL16 might also take place in meningiomas, a completely different, benign tumor entity. We used quantitative reverse-transcription polymerase chain reaction, immunocytochemistry and western blot to detect CXCL16 and CXCR6 in human meningioma cells isolated from 28 human meningiomas. Subsequently, we stimulated cultured human tm-CXCL16-positive, CXCR6-negative meningioma cells with recombinant s-CXCL16 and analyzed binding, signaling and biological effects using RNAi silencing to verify specificity. In fact, cultured human meningioma cells considerably express CXCL16, but substantially lack CXCR6, the only known CXCL16 receptor. These receptor-negative cells could bind s-CXCL16, and responded to s-CXCL16 application with activation of the intracellular kinases ERK1/2 und Akt. As a consequence, we observed increased proliferation and rescue of apoptosis of cultured meningioma cells. Since binding and signaling were abolished by siRNA silencing, we concluded that tm-CXCL16 specifically acts as a receptor for s-CXCL16 also in human meningioma cells. These findings underline our recent report on the mechanism of inverse signaling as a broad biological process also observable in more benign tumor cells and contributing to tumor progression.
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the CXCL16 cxcr6 Chemokine axis in glial tumors
2013Co-Authors: Kirsten Hattermann, Andreas Ludwig, Janka Heldfeindt, Rolf MentleinAbstract:Abstract Since Chemokines and their receptors play a pivotal role in tumors, we investigated the CXCL16–CXCR6-axis in human astroglial tumors. The transmembrane Chemokine CXCL16 is heavily expressed by tumor, microglial and endothelial cells in situ and in vitro. In contrast, the receptor CXCR6 is restricted in glioblastomas to a small subset of proliferating cells positive for the stem-cell markers Musashi, Nanog, Sox2 and Oct4. In particular, the vast majority (about 90%) of Musashi-positive cells stained also for CXCR6. Thus, CXCL16 is highly expressed by glial tumor and stroma cells whereas CXCR6 defines a subset of cells with stem cell character.
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the Chemokine CXCL16 induces migration and invasion of glial precursor cells via its receptor cxcr6
2008Co-Authors: Kirsten Hattermann, Andreas Ludwig, Janka Heldfeindt, Volkmar Gieselmann, Rolf MentleinAbstract:Chemokines are implicated in developmental and inflammatory processes in the brain. The transmembrane Chemokine CXCL16 is produced in brain endothelial and reactive astroglial cells and released by shedding. Its receptor CXCR6 is detected during brain development highest at postnatal day 6, found in glial precursor cells differentiated from neural stem cells and in an A2B5-positive glial precursor cell line. Their stimulation by soluble CXCL16 induces the PI3-kinase/Akt and Erk pathways resulting in the activation of the transcription factor AP-1. As biological responses, soluble CXCL16 upregulates its own receptor, increases cell proliferation, stimulates cell migration in wound-healing and in spheroid confrontation assays. Invasion of CXCR6-positive glial cells into CXCL16-expressing spheroids can be blocked by sheddase inhibitors and CXCL16-antibody. Since CXCL16 is induced by cytokines at sites of inflammation, neurodegeneration, ischemia and malignant transformation, it should attract CXCR6-positive glial precursor cells, enhance their invasion and proliferation and thus favor astrogliosis.
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overexpression of CXCL16 and its receptor cxcr6 bonzo promotes growth of human schwannomas
2008Co-Authors: Janka Heldfeindt, Andreas Ludwig, Rolf Mentlein, Kirsten Hattermann, Brigitte Rehmke, Friederike Knerlich, H H Hugo, Maximilian H MehdornAbstract:Chemokines and their receptors play a decisive role in tumor progression and metastasis. Here, we describe the expression of the CXCL16-CXCR6-system in human schwannomas of different localization and in malignant peripheral nerve sheath tumors. The transmembrane Chemokine CXCL16 and its receptor CXCR6/Bonzo were overexpressed on the mRNA and protein levels in all tumor samples investigated as compared with normal peripheral or 8th cranial nerve tissues. Chromogenic immunostaining and confocal laser microscopy revealed that CXCL16 and CXCR6 were localized mainly on S-100 positive schwannoma cells. Cultured schwannoma cells responded to CXCL16-stimulation by phosphorylation of kinases p42/44 (Erk 2/1) that could be inhibited by the MEK1/2-inhibitor U0126 indicating an involvement of the mitogen-activated protein kinase signal transduction pathway. As a biological response, CXCL16 increased proliferation and induced migration of schwannomas. Hence, CXCL16 appears to be a novel growth factor for schwannomas of different localization. © 2008 Wiley-Liss, Inc.
Janka Heldfeindt - One of the best experts on this subject based on the ideXlab platform.
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the Chemokine receptor cxcr6 evokes reverse signaling via the transmembrane Chemokine CXCL16
2017Co-Authors: Vivian Adamski, Janka Heldfeindt, Rolf Mentlein, Ralph Lucius, Michael Synowitz, Kirsten HattermannAbstract:Reverse signaling is a signaling mechanism where transmembrane or membrane-bound ligands transduce signals and exert biological effects upon binding of their specific receptors, enabling a bidirectional signaling between ligand and receptor-expressing cells. In this study, we address the question of whether the transmembrane Chemokine (C-X-C motif) ligand 16, CXCL16 is able to transduce reverse signaling and investigate the biological consequences. For this, we used human glioblastoma cell lines and a melanoma cell line as in vitro models to show that stimulation with recombinant C-X-C Chemokine receptor 6 (CXCR6) or CXCR6-containing membrane preparations induces intracellular (reverse) signaling. Specificity was verified by RNAi experiments and by transfection with expression vectors for the intact CXCL16 and an intracellularly-truncated form of CXCL16. We showed that reverse signaling via CXCL16 promotes migration in CXCL16-expressing melanoma and glioblastoma cells, but does not affect proliferation or protection from chemically-induced apoptosis. Additionally, fast migrating cells isolated from freshly surgically-resected gliomas show a differential expression pattern for CXCL16 in comparison to slowly-migrating cells, enabling a possible functional role of the reverse signaling of the CXCL16/CXCR6 pair in human brain tumor progression in vivo.
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inverse signaling of the transmembrane Chemokine CXCL16 contributes to proliferative and anti apoptotic effects in cultured human meningioma cells
2016Co-Authors: Kirsten Hattermann, Rolf Mentlein, Michael Synowitz, Maximilian H Mehdorn, Kareen Bartsch, Henrike Gebhardt, Anne Dorothee Schmitt, Janka HeldfeindtAbstract:Chemokines and their receptors play a decisive role in tumor progression and metastasis. We recently found a new signaling mechanism in malignant glioma cells mediated by transmembrane Chemokines that we termed “inverse signaling”. According to this hypothesis, soluble (s)-CXCL16 binds to the surface-expressed transmembrane (tm) -CXCL16, and induces signaling and different biological effects in the stimulated cells, so that the transmembrane ligand itself acts as a receptor for its soluble counterpart. Now, we hypothesized that “inverse signaling” via tm-CXCL16 might also take place in meningiomas, a completely different, benign tumor entity. We used quantitative reverse-transcription polymerase chain reaction, immunocytochemistry and western blot to detect CXCL16 and CXCR6 in human meningioma cells isolated from 28 human meningiomas. Subsequently, we stimulated cultured human tm-CXCL16-positive, CXCR6-negative meningioma cells with recombinant s-CXCL16 and analyzed binding, signaling and biological effects using RNAi silencing to verify specificity. In fact, cultured human meningioma cells considerably express CXCL16, but substantially lack CXCR6, the only known CXCL16 receptor. These receptor-negative cells could bind s-CXCL16, and responded to s-CXCL16 application with activation of the intracellular kinases ERK1/2 und Akt. As a consequence, we observed increased proliferation and rescue of apoptosis of cultured meningioma cells. Since binding and signaling were abolished by siRNA silencing, we concluded that tm-CXCL16 specifically acts as a receptor for s-CXCL16 also in human meningioma cells. These findings underline our recent report on the mechanism of inverse signaling as a broad biological process also observable in more benign tumor cells and contributing to tumor progression.
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the CXCL16 cxcr6 Chemokine axis in glial tumors
2013Co-Authors: Kirsten Hattermann, Andreas Ludwig, Janka Heldfeindt, Rolf MentleinAbstract:Abstract Since Chemokines and their receptors play a pivotal role in tumors, we investigated the CXCL16–CXCR6-axis in human astroglial tumors. The transmembrane Chemokine CXCL16 is heavily expressed by tumor, microglial and endothelial cells in situ and in vitro. In contrast, the receptor CXCR6 is restricted in glioblastomas to a small subset of proliferating cells positive for the stem-cell markers Musashi, Nanog, Sox2 and Oct4. In particular, the vast majority (about 90%) of Musashi-positive cells stained also for CXCR6. Thus, CXCL16 is highly expressed by glial tumor and stroma cells whereas CXCR6 defines a subset of cells with stem cell character.
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the Chemokine CXCL16 induces migration and invasion of glial precursor cells via its receptor cxcr6
2008Co-Authors: Kirsten Hattermann, Andreas Ludwig, Janka Heldfeindt, Volkmar Gieselmann, Rolf MentleinAbstract:Chemokines are implicated in developmental and inflammatory processes in the brain. The transmembrane Chemokine CXCL16 is produced in brain endothelial and reactive astroglial cells and released by shedding. Its receptor CXCR6 is detected during brain development highest at postnatal day 6, found in glial precursor cells differentiated from neural stem cells and in an A2B5-positive glial precursor cell line. Their stimulation by soluble CXCL16 induces the PI3-kinase/Akt and Erk pathways resulting in the activation of the transcription factor AP-1. As biological responses, soluble CXCL16 upregulates its own receptor, increases cell proliferation, stimulates cell migration in wound-healing and in spheroid confrontation assays. Invasion of CXCR6-positive glial cells into CXCL16-expressing spheroids can be blocked by sheddase inhibitors and CXCL16-antibody. Since CXCL16 is induced by cytokines at sites of inflammation, neurodegeneration, ischemia and malignant transformation, it should attract CXCR6-positive glial precursor cells, enhance their invasion and proliferation and thus favor astrogliosis.
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overexpression of CXCL16 and its receptor cxcr6 bonzo promotes growth of human schwannomas
2008Co-Authors: Janka Heldfeindt, Andreas Ludwig, Rolf Mentlein, Kirsten Hattermann, Brigitte Rehmke, Friederike Knerlich, H H Hugo, Maximilian H MehdornAbstract:Chemokines and their receptors play a decisive role in tumor progression and metastasis. Here, we describe the expression of the CXCL16-CXCR6-system in human schwannomas of different localization and in malignant peripheral nerve sheath tumors. The transmembrane Chemokine CXCL16 and its receptor CXCR6/Bonzo were overexpressed on the mRNA and protein levels in all tumor samples investigated as compared with normal peripheral or 8th cranial nerve tissues. Chromogenic immunostaining and confocal laser microscopy revealed that CXCL16 and CXCR6 were localized mainly on S-100 positive schwannoma cells. Cultured schwannoma cells responded to CXCL16-stimulation by phosphorylation of kinases p42/44 (Erk 2/1) that could be inhibited by the MEK1/2-inhibitor U0126 indicating an involvement of the mitogen-activated protein kinase signal transduction pathway. As a biological response, CXCL16 increased proliferation and induced migration of schwannomas. Hence, CXCL16 appears to be a novel growth factor for schwannomas of different localization. © 2008 Wiley-Liss, Inc.
Andreas Ludwig - One of the best experts on this subject based on the ideXlab platform.
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the perioperative time course and clinical significance of the Chemokine CXCL16 in patients undergoing cardiac surgery
2016Co-Authors: Daniela Dreymueller, Andreas Ludwig, Andreas Goetzenich, Christoph Emontzpohl, Josefin Soppert, Christian StoppeAbstract:The Chemokine CXCL16 and its receptor CXCR6 have been linked to the pathogenesis of acute and chronic cardiovascular disease. However, data on the clinical significance of CXCL16 in patients undergoing cardiac surgery with acute myocardial ischemia/reperfusion (I/R) are still lacking. Therefore, we determined CXCL16 in the serum of cardiac surgery patients and investigated its kinetics and association with the extent of organ dysfunction. 48 patients underwent conventional cardiac surgery with myocardial I/R and the use of cardiopulmonary bypass (CPB) were consecutively enrolled in the present study. We investigated the peri- and post-operative profile of CXCL16. Clinical relevant data were assessed and documented throughout the entire observation period. To identify the influence of myocardial I/R and CPB on CXCL16 release data were compared to those received from patients that underwent off-pump procedure. Pre-operative serum CXCL16 levels were comparable to those obtained from healthy volunteers (1174 ± 55.64 pg/ml versus 1225 ± 70.94). However, CXCL16 levels significantly increased during surgery (1174 ± 55.64 versus 1442 ± 75.42 pg/ml; P = 0.0057) and reached maximum levels 6 hrs after termination of surgery (1174 ± 55.64 versus 1648 ± 74.71 pg/ml; P < 0.001). We revealed a positive correlation between the intraoperative serum levels of CXCL16 and the extent of organ dysfunction (r(2) = 0.356; P = 0.031). Patients with high CXCL16 release showed an increased extent of organ dysfunction compared to patients with low CXCL16 release. Our study shows that CXCL16 is released into the circulation as a result of cardiac surgery and that high post-operative CXCL16 levels are associated with an increased severity of post-operative organ dysfunctions.
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the CXCL16 cxcr6 Chemokine axis in glial tumors
2013Co-Authors: Kirsten Hattermann, Andreas Ludwig, Janka Heldfeindt, Rolf MentleinAbstract:Abstract Since Chemokines and their receptors play a pivotal role in tumors, we investigated the CXCL16–CXCR6-axis in human astroglial tumors. The transmembrane Chemokine CXCL16 is heavily expressed by tumor, microglial and endothelial cells in situ and in vitro. In contrast, the receptor CXCR6 is restricted in glioblastomas to a small subset of proliferating cells positive for the stem-cell markers Musashi, Nanog, Sox2 and Oct4. In particular, the vast majority (about 90%) of Musashi-positive cells stained also for CXCR6. Thus, CXCL16 is highly expressed by glial tumor and stroma cells whereas CXCR6 defines a subset of cells with stem cell character.
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the Chemokine CXCL16 induces migration and invasion of glial precursor cells via its receptor cxcr6
2008Co-Authors: Kirsten Hattermann, Andreas Ludwig, Janka Heldfeindt, Volkmar Gieselmann, Rolf MentleinAbstract:Chemokines are implicated in developmental and inflammatory processes in the brain. The transmembrane Chemokine CXCL16 is produced in brain endothelial and reactive astroglial cells and released by shedding. Its receptor CXCR6 is detected during brain development highest at postnatal day 6, found in glial precursor cells differentiated from neural stem cells and in an A2B5-positive glial precursor cell line. Their stimulation by soluble CXCL16 induces the PI3-kinase/Akt and Erk pathways resulting in the activation of the transcription factor AP-1. As biological responses, soluble CXCL16 upregulates its own receptor, increases cell proliferation, stimulates cell migration in wound-healing and in spheroid confrontation assays. Invasion of CXCR6-positive glial cells into CXCL16-expressing spheroids can be blocked by sheddase inhibitors and CXCL16-antibody. Since CXCL16 is induced by cytokines at sites of inflammation, neurodegeneration, ischemia and malignant transformation, it should attract CXCR6-positive glial precursor cells, enhance their invasion and proliferation and thus favor astrogliosis.
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homocysteine up regulates vascular transmembrane Chemokine CXCL16 and induces cxcr6 lymphocyte recruitment in vitro and in vivo
2008Co-Authors: Otilia Postea, Rory R Koenen, Mihail Hristov, Christian Weber, Andreas LudwigAbstract:Objective: Hyperhomocysteinemia induces endothelial dysfunction and promotes atherosclerotic vascular disease. Infiltrates of activated macrophages and lymphocytes are observed in human and experimental atherosclerotic lesions, their emigration being guided by endothelial-leukocyte adhesion molecules and chemoattractants. The CXC-Chemokine CXCL16 functions as an adhesion molecule by interacting with its receptor (CXCR6) and also as a scavenger for oxidized low density lipoprotein (oxLDL). We investigated the modulation of CXCL16 on cultured endothelial cells (EC) and the recruitment of CXCR6+ lymphocytes in response to homocysteine (Hcy), in vitro and in vivo. Methods and Results: Hcy-stimulated EC show a significant increase in CXCL16 mRNA and protein expression. Incubation of EC with d,l-Hcy and l-Hcy significantly increased CXCR6+ lymphocyte adhesion to EC while l-Cysteine (l-Cys) had no effect. Furthermore, EC stimulation with Hcy increased uptake of DiI-oxLDL. An anti-CXCL16 monoclonal antibody, antioxidants (Tiron) and PPAR-γ agonists (Pioglitazone) considerably reduced CXCR6+ lymphocyte adhesion and uptake of DiI-oxLDL. Upon injection in the peritoneal cavities of mice, l-Hcy and not l-Cys, increased the number of CXCR6+ lymphocytes, which was reduced by coinjection with Pioglitazone or anti-human CXCL16 antibody. Conclusions: Hyperhomocysteinemia up-regulates CXCL16 leading to increased recruitment of CXCR6+ lymphocytes and scavenging of modified lipids via a potential involvement of a PPAR-γ-dependent mechanism. CXCL16 may therefore contribute to the formation and progression of atherosclerotic lesions under conditions of hyperhomocysteinemia.
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overexpression of CXCL16 and its receptor cxcr6 bonzo promotes growth of human schwannomas
2008Co-Authors: Janka Heldfeindt, Andreas Ludwig, Rolf Mentlein, Kirsten Hattermann, Brigitte Rehmke, Friederike Knerlich, H H Hugo, Maximilian H MehdornAbstract:Chemokines and their receptors play a decisive role in tumor progression and metastasis. Here, we describe the expression of the CXCL16-CXCR6-system in human schwannomas of different localization and in malignant peripheral nerve sheath tumors. The transmembrane Chemokine CXCL16 and its receptor CXCR6/Bonzo were overexpressed on the mRNA and protein levels in all tumor samples investigated as compared with normal peripheral or 8th cranial nerve tissues. Chromogenic immunostaining and confocal laser microscopy revealed that CXCL16 and CXCR6 were localized mainly on S-100 positive schwannoma cells. Cultured schwannoma cells responded to CXCL16-stimulation by phosphorylation of kinases p42/44 (Erk 2/1) that could be inhibited by the MEK1/2-inhibitor U0126 indicating an involvement of the mitogen-activated protein kinase signal transduction pathway. As a biological response, CXCL16 increased proliferation and induced migration of schwannomas. Hence, CXCL16 appears to be a novel growth factor for schwannomas of different localization. © 2008 Wiley-Liss, Inc.