Data from The Disparate Twins: A Comparative Study of CXCR4 and CXCR7 in SDF-1α–Induced Gene Expression, Invasion and Chemosensitivity of Colon Cancer
Doreen HeckmannPatrick MaierStephanie LaufsLi LiJonathan P. SleemanMarcus J. TrunkJörg H. LeupoldFrederik WenzW. Jens ZellerStefan FrüehaufHeike Allgayer
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<div>Abstract<p><b>Purpose:</b> 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.</p><p><b>Experimental Design:</b> In tumor tissue of 52 patients with colorectal cancer, we observed that expression of <i>CXCR7</i> and <i>CXCR4</i> increased with tumor stage and tumor size. Asking whether activation of CXCR4 or CXCR7 might result in a similar expression pattern, we performed microarray expression analyses using lentivirally <i>CXCR4</i>- and/or <i>CXCR7</i>-overexpressing SW480 colon cancer cell lines with and without stimulation by SDF-1α.</p><p><b>Results:</b> Gene regulation via SDF-1α/CXCR4 and SDF-1α/CXCR7 was completely different and partly antidromic. Differentially regulated genes were assigned by gene ontology to migration, proliferation, and lipid metabolic processes. Expressions of <i>AKR1C3, AXL, C5, IGFBP7, IL24, RRAS</i>, and <i>TNNC1</i> were confirmed by quantitative real-time PCR. Using the <i>in silico</i> gene set enrichment analysis, we showed that expressions of <i>miR-217</i> and <i>miR-218</i> were increased in CXCR4 and reduced in CXCR7 cells after stimulation with SDF-1α. Functionally, exposure to SDF-1α increased invasiveness of CXCR4 and CXCR7 cells, AXL knockdown hampered invasion. Compared with controls, CXCR4 cells showed increased sensitivity against 5-FU, whereas CXCR7 cells were more chemoresistant.</p><p><b>Conclusions:</b> These opposing results for CXCR4- or CXCR7-overexpressing colon carcinoma cells demand an unexpected attention in the clinical application of chemokine receptor antagonists such as plerixafor. <i>Clin Cancer Res; 20(3); 604–16. ©2013 AACR</i>.</p></div>Keywords:
CXC chemokine receptors
CXC chemokine receptors
L-selectin
CXCL16
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The proinflammatory CXC chemokines GRO, CINC-2alpha, and macrophage inflammatory protein (MIP)-2 are a closely related family of neutrophil chemoattractants. Here, we report that freshly isolated alveolar Type II (TII) cells express these chemokine mRNAs at much higher levels than do freshly isolated Type I cells or alveolar macrophages (AM). TII cells also express CXCR2, the receptor for these chemokines. Lung injury caused by acid or Pseudomonas aeruginosa (Pa) caused an increase in TII cell expression of chemokine mRNAs and GRO protein. We compared the time courses of chemokine mRNA expression in cultured TII cells and AM. In TII cells, GRO mRNA levels were stable over 4 h, but decreased to undetectable levels by 24 h. CINC-2alpha and MIP-2 mRNA levels were low in freshly isolated cells, increased over 2-4 h in culture, and by 24 h dropped to undetectable levels. In contrast, none of these chemokine mRNAs were detected in freshly isolated AM, but expression was induced by tissue culture. In summary, we have shown that TII alveolar epithelial cells produce three of the major proinflammatory CXC chemokines (GRO, CINC-2alpha, and MIP-2) and their cognate receptor CXCR2. Chemokine expression is upregulated in response to lung injury. These observations support a central role for the TII cell as an immunologic effector cell in the alveolus and raise intriguing questions about how CXC chemokines and receptors modulate diverse normal and pathologic cellular responses in the alveoli.
CXC chemokine receptors
Macrophage inflammatory protein
CXCL14
CXCL2
Alveolar macrophage
Proinflammatory cytokine
Interleukin 8
CXCR3
CXCL9
CXCL16
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Mucosal infections trigger an inflammatory response that includes the secretion of cytokines and the recruitment of neutrophils to the infected site. This thesis describes studies examining the molecular mechanisms of neutrophil migration to sites of mucosal bacterial infection.
Escherichia coli (E. coli) infection of epithelial cell layers stimulates chemokine secretion and chemokine receptor expression. Human epithelial cells produced an array of CXC chemokines (e.g., IL-8, GRO, ENA-78, IP-10, MIG) and CC chemokines (e.g., MCP-1, MIP, RANTES) in response to bacterial infection. The chemokine repertoire was shown to be influenced by the fimbrial expression of the infecting strain. Furthermore, E. coli infection increased the expression of chemokine receptors (CXCR1 and CXCR2) on epithelial cells. IL-8 was found to be the major chemoattractant involved in neutrophil migration across infected epithelial cell layers. Transuroepithelial neutrophil migration was also shown to be depending on the level of CXCR1 expression on neutrophils and epithelial cell layers.
The in vitro observations were confirmed in an experimental UTI model. Recombinant P or type 1 fimbriated E. coli stimulated chemokine responses and neutrophil recruitment more efficiently than the non-fimbriated controls. The relevance of IL-8 receptor expression was confirmed in vivo using IL-8 receptor knock-out (mIL-8Rh KO) mice. E. coli infection of mIL-8Rh KO mice caused the neutrophils to leave the blood vessels but they were unable to cross the epithelium and accumulated in the tissues. Bacterial clearance was impaired and tissues were destroyed. Subsequent human studies showed a decrease in CXCR1 expression on neutrophils from patients prone to acute pyelonephritis.
These results provide a first molecular clue to the host defect in patients prone to acute pyelonephritis.
CXC chemokine receptors
Interleukin 8
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Objective:This study was to investigate the expressions of CXCL12/CXCR4,and explore its correlation to clinicopathologic factors of colorectal cancer.Methods:Immunoh-istochemistry staining was performed to detect the expression of CXCR4 and CXCL12 in 65 primary lesions of colorectal cancer,30 normal colorectal tissues adjacent to cancer lesion.Results:The positive rates of CXCL4 and CXCR12 protein in colorectal cancer tissues were 67.7%and 60.0%,respectively.No expression of CXCL4 and CXCR12 in 30 specimens of normal colorectal epithelium.Stronger expressions of CXCR4 and CXCL12 protein were observed in colorectal cancer specimens,compared with that in normal tissues.CXCR4 and CXCL12 expression were closely related to tumor-infiltrating or lymph node metastasis(P0.01),but had no relationship with age,gender,lesion,lesion length,pathological type and histological differentiation (P0.05).Conclusions:Up-regulated CXCR4 expressionis associated with the carcinogenesis and metastasis of colorectal cancer.CXCL12/CXCR4 is intensively expressed in colorectal cancer.The levels of CXCR4 and CXCL12 are positively correlated to progression and metastasis of colorectal cancer.
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Background: The mortality rate of pancreatic cancer (PC) is equal to its incidence and the majority of PC patients die within a few months of diagnosis. Therefore, a search for new biomarkers useful in the diagnosis and prognosis of PC is ongoing. Objectives: The aim of our study was to compare the utility of CXCR2 and CXCR4 in the diagnosis and prediction of PC with classical tumor marker (carcinoembryonic antigen, CEA) and marker of inflammation–C-reactive protein (CRP). Patients and Methods: The study comprised 64 subjects — 32 PC patients and 32 healthy volunteers. Serum concentrations of tested proteins were analysed using immunological methods. Results: Serum CXCR2 and CXCR4 concentrations, similarly to those of CEA and CRP, were significantly elevated in PC patients compared to healthy controls. Moreover, concentrations of CXCR4 were significantly correlated with CXCR2 and CRP levels, while CRP concentrations were correlated with CXCR2 and CEA levels. The diagnostic sensitivity and the predictive value for negative (PV−ve) results for CXCR4 were similar to those of CEA and higher than those of CXCR2 and CRP, while the area under the ROC curve (AUC) for CXCR4 was the highest among all tested proteins (CXCR2, CEA, CRP). Moreover, serum CXCR2 was found to be a significant predictor of PC risk. Conclusions: CXCR4 is a better candidate for a tumor marker than CXCR2 in the diagnosis of PC, while serum CXCR2 is a significant predictor of PC risk.
CXC chemokine receptors
Carcinoembryonic antigen
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Significance: Efficient recruitment of neutrophils to an injured skin lesion is an important innate immune response for wound repair. Defects in neutrophil recruitment lead to impaired wound healing. Recent Advances: Chemokines and chemokine receptors are known to regulate neutrophil recruitment. Recent research advances reveal more mechanistic details about the regulation of chemokines and chemokine receptors on neutrophil egress from bone marrow, transmigration into the wound site, spatial navigation toward the necrotic skin tissue, and apoptosis-induced clearance by efferocytosis. Critical Issues: Skin injury triggers local and systemic alterations in the expression of multiple chemotactic molecules and the magnitude of chemokine receptor-mediated signaling. The responses of a number of CXC and CX3C chemokines and their receptors closely associate with the temporal and spatial recruitment of neutrophils to wound sites during the inflammatory phase and promote the clearance of necrotic neutrophils during the transition into the proliferative phase. Functional aberrancy in these chemokines and chemokine receptor systems is recognized as one of the important mechanisms underlying the pathology of impaired wound healing. Future Directions: Future research should aim to investigate the therapeutic modulation of neutrophil activity through the targeting of specific chemokines or chemokine receptors in the early inflammatory phase to improve clinical management of wound healing.
CXC chemokine receptors
CCL13
CCR10
CCL7
CXCR3
CXCL2
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[Purpose] To investigate expression of CXCR4 and its relationship with prognosis of colorectal cancer.[Methods] The expression of CXCR4 in 70 cases with colorectal cancer tissue and 14 cases with cancer adjacent tissue was detected by immunohistochemistry.[Results] The positive rate of CXCR4 in colorectal cancer(57.1%,40/70) was significantly higher than that in cancer adjacent tissue(14.3%,2/14)(P0.01).The positive expression of CXCR4 was related to Dukes' stage(P=0.041) and lymph node metastasis(P=0.018).The disease free survival rate in CXCR4 positive expression group was significantly better than that in negative expression group(P = 0.008).[Conclusion] CXCR4 is over expression in colorectal cancer,and it relate to carcinogenesis and prognosis of colorectal cancer.
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CXC chemokine receptors
Chemokine receptor CCR5
CXCL14
CCL21
CXCL2
Lymphopoiesis
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Chemokine receptors are used by HIV-1 for entry into CD4+ T cells. The β-chemokines are capable of inhibiting HIV replication. This study measured β-chemokine macrophage inflammatory protein (MIP)-1α and MIP-1β levels and determined the CCR5 and CXCR4 expression on T cells in HIV-1-infected patients treated with HAART. The time of known HIV infection and time of HAART use were similar between failure and successful groups. The CD4+ T cell nadir was 163 vs. 251 cells/mm3, p = 0.07, for failure and successful groups, respectively. The successfully treated group, when compared with the failure group, had a higher median CD4+ T cells count (667 vs. 257 cells/mm3; p = 0.003) as well as higher spontaneous MIP-1α (median of 4390 vs. 802 pg/ml, p = 0.03) and MIP-1β (median of 2416 vs. 1117 pg/ml, p = 0.001) levels. The untreated patients had a higher number and intensity of CCR5- and CXCR4-expressing T cells. Higher levels of chemokines were not related to nadir CD4+ T and current CD8+ T cell counts. Successfully treated patients were able to produce higher amounts of β-chemokines and normalize the coreceptor overexpression on T cells. These findings may have clinical implications, such as a new strategy of using chemokines as adjuvants in anti-HIV therapy.
Macrophage inflammatory protein
CCR3
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