Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: HUMANGGP:031995 (CXCL1)
 2,264 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Continuous expression of the MGSA/GROalpha, beta, or gamma chemokine bestows tumor-forming capacity to the immortalized murine melanocyte cell line, melan-a. The mechanism for this transformation is unclear, although both autocrine and paracrine processes are possible because melan-a cells as well as endothelial cells express a low level of the receptor for this ligand. To further define the role of MGSA/GRO proteins in melanocyte transformation, two types of experiments were designed to neutralize the biological effects of MGSA/GRO in the transfected melan-a clones: (1) the effect of neutralizing antiserum to MGSA/GRO proteins on melan-a tumor growth was assessed; (2) the tumor-forming capacity of melan-a clones expressing ELR motif-mutated forms of MGSA/GRO with compromised receptor affinity was compared to the tumor-forming capacity of clones expressing wild-type MGSA/GRO. These experiments revealed that SCID mice inoculated with MGSA/GROalpha- or gamma-expressing melan-a cells and subsequently treated with antiserum to the respective chemokine exhibited decreased tumor growth. This reduction in tumor growth was accompanied by declining angiogenic activity in MGSA/GROgamma-expressing tumors. Moreover, athymic nude mice injected with melan-a cells expressing ELR-mutant forms of MGSA/GROalpha exhibited markedly impaired tumor-forming capacity compared with those mice injected with melan-a clones expressing wild-type MGSA/GRO. These data suggest that continuous expression of MGSA/GRO proteins may facilitate tumor growth by stimulating the growth of microvessels into the tumor (paracrine) and by affecting melanocyte growth (autocrine).
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PMID:The tumorigenic and angiogenic effects of MGSA/GRO proteins in melanoma. 1064 98

Chemokines represent a large family of polypeptide signaling molecules that are notable for their role in chemotaxis, leukocyte homing, directional migration, and G protein coupled receptor activation. Chemo kines have recently been implicated in tumor progression and metastasis. The demonstration of chemokine expression and receptor activation in melanoma tumor cells themselves, and the tumor infiltrating leukocytes, may have important implications in terms of tumor progression and tumor cell homing to metastatic sites. In addition to their chemotactic and cell homing properties, chemokines and their receptors also play a part in other biologic functions relevant to oncogenesis, including cell proliferation, protease induction, tumor growth, and angiogenesis. Melanomas, and the cells derived from them, have been found to express a number of chemokines, including CXCL8 (interleukin-8), CXCL1-3 (MGSA-GROalpha-gamma), CCL5 (RANTES), and CCL2 (monocyte chemotactic protein-1), which have been implicated in tumor growth and progression. Furthermore, recent studies have demonstrated organ-specific patterns of melanoma metastasis that correlate with their expression of specific chemokine receptors, including CXCR4, CCR7, and CCR10. This review will focus on the current biology of chemokines and chemokine receptors in the context of understanding their potential roles in melanoma progression and metastasis, and is not meant to be a comprehensive review of chemokine biology. Continued understanding and progress in the determination of the role of chemokines and their receptors in tumorigenesis and metastasis, including melanoma, may lead to novel approaches in the treatment and management of this disease.
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PMID:The role of chemokines in melanoma tumor growth and metastasis. 1206 Mar 84

The CXC chemokine, CXCL1 (melanoma growth-stimulatory activity/growth-regulated protein alpha), plays a major role in inflammation, angiogenesis, tumorigenesis, and wound healing. Recently, chemokines have been extensively related to cellular transformation, tumor growth, homing, and metastasis. CXCL1 and its mouse homologue MIP-2 have been shown to be involved in the process of tumor formation. When chemokines such as CXCL1 and CXCL8 (IL-8) become disregulated so that they are chronically expressed, tissue damage, angiogenesis, and tumorigenesis can follow. This up-regulation of chemokines has been attributed to constitutive activation of NF-kappaB. The constitutive NF-kappaB activation is an emerging hallmark in various types of tumors including breast, colon, pancreatic, ovarian, as well as melanoma. Previous findings from our laboratory and other laboratories have demonstrated the role of endogenous activation of NF-kappaB in association with enhanced metastatic potential of malignant melanoma cells and suggest that targeting NF-kappaB may have potential therapeutic effects in clinical trials. An important step in this direction would be to delineate the important intracellular pathways and upstream kinases involved in up-regulation of NF-kappaB in melanoma cells. In this review, the signaling pathways involved in the disregulation of NF-kappaB and chemokine expression are discussed.
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PMID:Role of CXCL1 in tumorigenesis of melanoma. 1210 Dec 57

The branched-chain fatty acid valproate (valproic acid; VPA) displays antitumoral properties by blocking tumor growth, progression and invasion. Recent data have shown that VPA reduces the angiogenic activity of endothelial cells. The object of this study was to investigate whether endothelial modulation might also influence the level of chemotactic mediators. Endothelial cells were isolated from human umbilical cord veins (HUVEC) and treated with VPA-concentrations ranging from 0.125 mM to 1 mM. The mRNA level of CXC-chemokines was investigated by reverse transcriptase-polymerase chain reaction. The proliferative activity of HUVEC was measured as well. VPA evoked a striking increase in the neutrophil chemoattractants CXCL1, CXCL3, CXCL4, CXCL5 and a moderate increase in CXCL6 with maximal effects after a 3-day incubation period. Other CXC-chemokines and CXC-receptors remained unaffected. HUVEC growth was diminished time- and dose-dependently by VPA. We conclude that VPA treatment leads to alterations in the chemokine expression profile of endothelial cells. This might allow more neutrophils to reach the tumor area and trigger cytolysis.
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PMID:Valproic acid induces expression of neutrophil chemoattractants of the CXC chemokine family in endothelial cells. 1551 27

Activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) results in inhibition of tumor growth in various types of cancers, but the mechanism(s) by which PPAR-gamma induces growth arrest has not been completely defined. In a recent study, we demonstrate that treatment of A549 (human non small cell lung cancer cell line) tumor-bearing SCID mice with PPAR-gamma ligands troglitazone (Tro) and pioglitazone significantly inhibits primary tumor growth. In this study, immunohistochemical analysis of Tro-treated and Pio-treated tumors with factor VIII antibody revealed a significant reduction in blood vessel density compared to tumors in control animals, suggesting inhibition of angiogenesis. Further analysis showed that treatment of A549 cells in vitro with Tro or transient transfection of A549 cells with constitutively active PPAR-gamma (VP16-PPAR-gamma) construct blocked the production of the angiogenic ELR+CXC chemokines IL-8 (CXCL8), ENA-78 (CXCL5), and Gro-alpha (CXCL1). Similarly, an inhibitor of NF-kappa B activation (PDTC) also blocked CXCL8, CXCL5, and CXCL1 production, consistent with their NF-kappa B-dependent regulation. Conditioned media from A549 cells induce human microvascular endothelial cell (HMVEC) chemotaxis. However, conditioned media from Tro-treated A549 cells induced significantly less HMVEC chemotaxis compared to untreated A549 cells. Furthermore, PPAR-gamma activation inhibited NF-kappa B transcriptional activity, as assessed by TransAM reporter gene assay. Collectively, our data suggest that PPAR-gamma ligands can inhibit tumor-associated angiogenesis by blocking the production of ELR+CXC chemokines, which is mediated through antagonizing NF-kappaB activation. These antiangiogenic effects likely contribute to the inhibition of primary tumor growth by PPAR-gamma ligands.
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PMID:PPAR-gamma activation inhibits angiogenesis by blocking ELR+CXC chemokine production in non-small cell lung cancer. 1579 29

Erlotinib (Tarceva) is an orally available HER1 (epidermal growth factor receptor, EGFR) tyrosine kinase inhibitor advancing through clinical trials for the treatment of a range of human malignancies. In this study, we examine the capacity of erlotinib to modulate radiation response and investigate specific mechanisms underlying these interactions in human tumor cell lines and xenografts. The impact of erlotinib on cell cycle kinetics was analyzed using flow cytometry, and the impact on apoptosis was evaluated via fluorescein-labeled pan-caspase inhibition and poly(ADP-ribose) polymerase cleavage. Radiation-induced EGFR autophosphorylation and Rad51 expression were examined by Western blot analysis. Radiation survival was analyzed using a clonogenic assay and assessment of in vivo tumor growth was done using a mouse xenograft model system. Microarray studies were carried out using 20 K human cDNA microarray and select genes were validated using quantitative reverse transcription-PCR (RT-PCR). Independently, erlotinib and radiation induce accumulation of tumor cells in G(1) and G(2)-M phase, respectively, with a reduction of cells in S phase. When combined with radiation, erlotinib promotes a further reduction in S-phase fraction. Erlotinib enhances the induction of apoptosis, inhibits EGFR autophosphorylation and Rad51 expression following radiation exposure, and promotes an increase in radiosensitivity. Tumor xenograft studies confirm that systemic administration of erlotinib results in profound tumor growth inhibition when combined with radiation. cDNA microarray analysis assessing genes differentially regulated by erlotinib following radiation exposure identifies a diverse set of genes deriving from several functional classes. Validation is confirmed for several specific genes that may influence radiosensitization by erlotinib including Egr-1, CXCL1, and IL-1beta. These results identify the capacity of erlotinib to enhance radiation response at several levels, including cell cycle arrest, apoptosis induction, accelerated cellular repopulation, and DNA damage repair. Preliminary microarray data suggests additional mechanisms underlying the complex interaction between EGFR signaling and radiation response. These data suggest that the erlotinib/radiation combination represents a strategy worthy of further examination in clinical trials.
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PMID:Mechanisms of enhanced radiation response following epidermal growth factor receptor signaling inhibition by erlotinib (Tarceva). 1583 66

Vascular endothelial growth factor (VEGF) induces expression of Bcl-2 in tumor-associated microvascular endothelial cells. We have previously reported that up-regulated Bcl-2 expression in microvascular endothelial cells is sufficient to enhance intratumoral angiogenesis and to accelerate tumor growth. We initially attributed these results to Bcl-2-mediated endothelial cell survival. However, in recent experiments, we observed that conditioned medium from Bcl-2-transduced human dermal microvascular endothelial cells (HDMEC-Bcl-2) is sufficient to induce potent neovascularization in the rat corneal assay, whereas conditioned medium from empty vector controls (HDMEC-LXSN) does not induce angiogenesis. These results cannot be attributed to the role of Bcl-2 in cell survival. To understand this unexpected observation, we did gene expression arrays that revealed that the expression of the proangiogenic chemokines interleukin-8 (CXCL8) and growth-related oncogene-alpha (CXCL1) is significantly higher in HDMEC exposed to VEGF and in HDMEC-Bcl-2 than in controls. Inhibition of Bcl-2 expression with small interfering RNA-Bcl-2, or the inhibition of Bcl-2 function with small molecule inhibitor BL-193, down-regulated CXCL8 and CXCL1 expression and caused marked decrease in the angiogenic potential of endothelial cells without affecting cell viability. Nuclear factor-kappaB (NF-kappaB) is highly activated in HDMEC exposed to VEGF and HDMEC-Bcl-2 cells, and genetic and chemical approaches to block the activity of NF-kappaB down-regulated CXCL8 and CXCL1 expression levels. These results reveal a novel function for Bcl-2 as a proangiogenic signaling molecule and suggest a role for this pathway in tumor angiogenesis.
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PMID:Bcl-2 acts in a proangiogenic signaling pathway through nuclear factor-kappaB and CXC chemokines. 1595 49

The murine chemokine CXCL1/KC is known as a chemoattractant for neutrophil infiltration and as a promoter of tumor growth. To determine its relevance in tumorigenesis, we first asked whether okadaic acid (OKA), a natural tumor promoter and a potent protein phosphatase 1 and 2A inhibitor, stimulates KC expression and if it does, through what pathway, in a promotable mouse epidermal-like JB6 cell line commonly used for studying molecules related to tumor promotion. We found that OKA stimulated the de novo synthesis of KC mRNA and protein in a dose- and time-dependent manner. To determine the mechanism by which OKA stimulated the expression of KC at the transcriptional level, transient transfection assays using serially deleted sections of KC promoter fused to luciferase reporter gene were performed. These studies showed that transactivation of KC promoter by OKA specifically involved the region between -104 and -59 containing the two nuclear factor-kappaB (NF-kappaB) response elements (kappaB1 and kappaB2). Further analyses using the mutated NF-kappaB response elements kappaB1 and kappaB2 indicated that both regions were required for optimum transactivation of KC by OKA with the former NF-kappaB response element playing a more significant role in regulating KC expression. Gel-shift and supershift analyses demonstrated the involvement of three NF-kappaB subunits, p65, p50 and c-Rel, with p65 as the major subunit in the NF-kappaB dimer complex. Additionally, immunohistochemistry and western blot analyses confirmed the presence of p65 in the nucleus with its transactivation domain phosphorylated at serine 536. In summary, this is the first report to show that the tumor promoter OKA can stimulate the de novo synthesis and secretion of KC, and that this stimulation is mediated through the NF-kappaB pathway in JB6 cells.
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PMID:Production of chemokine CXCL1/KC by okadaic acid through the nuclear factor-kappaB pathway. 1600 Apr 1

Renal cell carcinoma (RCC) accounts for 3% of new cancer incidence and mortality in the United States. Studies in RCC have predominantly focused on VEGF in promoting tumor-associated angiogenesis. However, other angiogenic factors may contribute to the overall angiogenic milieu of RCC. We hypothesized that the CXCR2/CXCR2 ligand biological axis represents a mechanism by which RCC cells promote angiogenesis and facilitate tumor growth and metastasis. Therefore, we first examined tumor biopsies and plasma of patients with metastatic RCC for levels of CXCR2 ligands, and RCC tumor biopsies for the expression of CXCR2. The proangiogenic CXCR2 ligands CXCL1, CXCL3, CXCL5, and CXCL8, as well as VEGF were elevated in the plasma of these patients and found to be expressed within the tumors. CXCR2 was found to be expressed on endothelial cells within the tumors. To assess the role of ELR(+) CXC chemokines in RCC, we next used a model of syngeneic RCC (i.e., RENCA) in BALB/c mice. CXCR2 ligand and VEGF expression temporally increased in direct correlation with RENCA growth in CXCR2(+/+) mice. However, there was a marked reduction of RENCA tumor growth in CXCR2(-/-) mice, which correlated with decreased angiogenesis and increased tumor necrosis. Furthermore, in the absence of CXCR2, orthotopic RENCA tumors demonstrated a reduced potential to metastasize to the lungs of CXCR2(-/-) mice. These data support the notion that CXCR2/CXCR2 ligand biology is an important component of RCC tumor-associated angiogenesis and tumorigenesis.
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PMID:The role of CXCR2/CXCR2 ligand biological axis in renal cell carcinoma. 1621 Jun 41

Chronic inflammation is a well-known risk factor for cancer. Proinflammatory mediators such as prostaglandin E2 (PGE2) promote colorectal tumor growth by stimulating angiogenesis, cell invasion, and cell growth, and inhibiting apoptosis. Molecules that regulate tumor-associated angiogenesis provide promising therapeutic targets for treatment of colorectal cancer (CRC) as indicated by the recent development of the novel anti-angiogenic agent bevacizumab (Avastin). However, use of this drug only prolongs survival by several months, highlighting the importance of finding more effective treatment regimens. We report here that PGE2 induces expression of CXCL1 (growth-regulated oncogene alpha), a pro-angiogenic chemokine, in human CRC cells. More importantly, CXCL1 released from carcinoma cells induces microvascular endothelial cell migration and tube formation in vitro. Furthermore, PGE2 promotes tumor growth in vivo by induction of CXCL1 expression, which results in increased tumor microvessel formation. These results have potential clinical significance because we found that CXCL1 expression correlates with PGE2 levels in human CRCs. Collectively, our findings show for the first time that CXCL1 is regulated by PGE2 and indicate that CXCL1 inhibitors should be evaluated further as potential anti-angiogenic agents for treatment of CRC.
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PMID:CXCL1 induced by prostaglandin E2 promotes angiogenesis in colorectal cancer. 1656 91


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