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Transcriptional profiling of cytokines and its receptors in primary murine lymphoblastoid cells (pML cells)

ABSTRACT: Transcriptional profiling of cytokines and its receptors in primary murine lymphoblastoid cells (pML cells), which are lymphomatous cells from HTLV-1 TAX transgenic mice. ATL is a T-cell malignancy caused by HTLV-I, and presents as an aggressive leukemia with characteristic widespread leukemic cell infiltration into visceral organs and skin. The molecular mechanisms associated with leukemic cell infiltration are poorly understood. We have employed mouse models of ATL to investigate the role of chemokines in this process. Transfer of splenic lymphomatous cells from transgenic to SCID mice rapidly reproduces a leukemia and lymphoma which is histologically identical to human disease. It could be shown that lymphomatous cells exhibit specific chemotactic activity in response to SDF-1α. Lymphomatous cells exhibited surface expression of CXCR4, the specific receptor of SDF-1α and chemotaxis was associated with down regulation of CXCR4 expression and phosphorylation of intracellular ERK1/2. AMD3100, a CXCR4 antagonist, was found to inhibit both SDF-1α - induced migration and phosphorylation of ERK1/2. Investigation of cultured cells from human ATL patients revealed identical findings. Employing the SCID mouse model it could be demonstrated that AMD3100 inhibited infiltration of lymphomatous cells into liver and lung tissues in vivo. These results demonstrate the involvement of the SDF-1α /CXCR4 interaction as one mechanism of leukemic cell migration and this may provide a novel target as part of combination therapy for ATL.

ORGANISM(S): Mus musculus

PROVIDER: GSE17341 | GEO | 2009/07/28

SECONDARY ACCESSION(S): PRJNA119025

REPOSITORIES: GEO

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Project description:In colorectal cancer, increased expression of the CXC chemokine receptor 4 (CXCR4) has been shown to provoke metastatic disease due to the interaction with its ligand stromal cell-derived factor 1 (SDF-1). Recently, a second SDF-1 receptor, CXCR7, was found to enhance tumor growth in solid tumors. Albeit signaling cascades via SDF-1/CXCR4 have been intensively studied, the significance of the SDF-1/CXCR7-induced intracellular communication triggering malignancy is still only marginally understood. In tumor tissue of 52 colorectal cancer (CRC) patients, we observed that expression of CXCR7 and CXCR4 increased with tumor stage, tumor size, and lymph node infiltration. Asking whether activation of CXCR4 or CXCR7 might result in a similar expression pattern, we performed microarray expression analyses using lentivirally CXCR4- and/or CXCR7-overexpressing SW480 colon cancer cell lines with and without stimulation by SDF-1α. Gene regulation via SDF-1α/CXCR4 and SDF-1α/CXCR7 was completely different and partly antidromic. Expressions of the differentially expressed genes AKR1C3, AXL, EGFR, IGFBP7, IL24, TNNC1, TRIP6 were confirmed by qPCR. Differentially regulated genes were assigned by GO to migration and lipid metabolic processes. Furthermore, using the in silico gene set enrichment analysis we showed for the first time that expressions of miR-217 and miR-218 were increased in CXCR4 and reduced in CXCR7 cells after stimulation with SDF-1α. As expected, their putative target mRNAs were inversely expressed. Functional assays exerted that exposure to SDF-1α resulted in strongly amplified invasiveness and chemosensitivity of CXCR4-expressing cells. CXCR7 overexpression led to reduced invasiveness which could only be marginally increased by SDF-1α. The CXCR4 antagonist plerixafor significantly reduced invasiveness of CXCR4-overexpressing cells only. Similarly, compared to control cells, CXCR4 cells showed increased sensitivity against 5-FU, while CXCR7 cells were more chemoresistant. These opposing results for CXCR4- or CXCR7-overexpressing colon carcinoma cells demand an unexpected attention in the clinical application of chemokine receptor antagonists like Plerixafor.

Project description:In colorectal cancer, increased expression of the CXC chemokine receptor 4 (CXCR4) has been shown to provoke metastatic disease due to the interaction with its ligand stromal cell-derived factor 1 (SDF-1). Recently, a second SDF-1 receptor, CXCR7, was found to enhance tumor growth in solid tumors. Albeit signaling cascades via SDF-1/CXCR4 have been intensively studied, the significance of the SDF-1/CXCR7-induced intracellular communication triggering malignancy is still only marginally understood. In tumor tissue of 52 colorectal cancer (CRC) patients, we observed that expression of CXCR7 and CXCR4 increased with tumor stage, tumor size, and lymph node infiltration. Asking whether activation of CXCR4 or CXCR7 might result in a similar expression pattern, we performed microarray expression analyses using lentivirally CXCR4- and/or CXCR7-overexpressing SW480 colon cancer cell lines with and without stimulation by SDF-1M-NM-1. Gene regulation via SDF-1M-NM-1/CXCR4 and SDF-1M-NM-1/CXCR7 was completely different and partly antidromic. Expressions of the differentially expressed genes AKR1C3, AXL, EGFR, IGFBP7, IL24, TNNC1, TRIP6 were confirmed by qPCR. Differentially regulated genes were assigned by GO to migration and lipid metabolic processes. Furthermore, using the in silico gene set enrichment analysis we showed for the first time that expressions of miR-217 and miR-218 were increased in CXCR4 and reduced in CXCR7 cells after stimulation with SDF-1M-NM-1. As expected, their putative target mRNAs were inversely expressed. Functional assays exerted that exposure to SDF-1M-NM-1 resulted in strongly amplified invasiveness and chemosensitivity of CXCR4-expressing cells. CXCR7 overexpression led to reduced invasiveness which could only be marginally increased by SDF-1M-NM-1. The CXCR4 antagonist plerixafor significantly reduced invasiveness of CXCR4-overexpressing cells only. Similarly, compared to control cells, CXCR4 cells showed increased sensitivity against 5-FU, while CXCR7 cells were more chemoresistant. These opposing results for CXCR4- or CXCR7-overexpressing colon carcinoma cells demand an unexpected attention in the clinical application of chemokine receptor antagonists like Plerixafor. 24 samples

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Transcriptional profiling of cytokines and its receptors in primary murine lymphoblastoid cells (pML cells)

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