CXCL11

Gene Summary

Gene:CXCL11; C-X-C motif chemokine ligand 11
Aliases: IP9, H174, IP-9, b-R1, I-TAC, SCYB11, SCYB9B
Location:4q21.1
Summary:Chemokines are a group of small (approximately 8 to 14 kD), mostly basic, structurally related molecules that regulate cell trafficking of various types of leukocytes through interactions with a subset of 7-transmembrane, G protein-coupled receptors. Chemokines also play fundamental roles in the development, homeostasis, and function of the immune system, and they have effects on cells of the central nervous system as well as on endothelial cells involved in angiogenesis or angiostasis. Chemokines are divided into 2 major subfamilies, CXC and CC. This antimicrobial gene is a CXC member of the chemokine superfamily. Its encoded protein induces a chemotactic response in activated T-cells and is the dominant ligand for CXC receptor-3. The gene encoding this protein contains 4 exons and at least three polyadenylation signals which might reflect cell-specific regulation of expression. IFN-gamma is a potent inducer of transcription of this gene. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2014]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:C-X-C motif chemokine 11
Source:NCBIAccessed: 16 March, 2017

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 16 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 16 March, 2017 using data from PubMed, MeSH and CancerIndex

Latest Publications: CXCL11 (cancer-related)

Lee CR, Kang JA, Kim HE, et al.
Secretion of IL-1β from imatinib-resistant chronic myeloid leukemia cells contributes to BCR-ABL mutation-independent imatinib resistance.
FEBS Lett. 2016; 590(3):358-68 [PubMed] Related Publications
Some cases of chronic myelogenous leukemia are resistant to tyrosine kinase inhibitors (TKIs) independently of mutation in BCR-ABL, but the detailed mechanism underlying this resistance has not yet been elucidated. In this study, we generated a TKI-resistant CML cell line, K562R, that lacks a mutation in BCR-ABL. Interleukin-1β (IL-1β) was more highly expressed in K562R than in the parental cell line K562S, and higher levels of IL-1β contributed to the imatinib resistance of K562R. In addition, IL-1β secreted from K562R cells affected stromal cell production of CXCL11, which in turn promoted migration of K562R cells into the stroma. Thus, elevated IL-1β production from TKI-resistant K562R cells may contribute to TKI resistance by increasing cell viability and promoting cell migration.

Agostini M, Janssen KP, Kim IJ, et al.
An integrative approach for the identification of prognostic and predictive biomarkers in rectal cancer.
Oncotarget. 2015; 6(32):32561-74 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Colorectal cancer is the third most common cancer in the world, a small fraction of which is represented by locally advanced rectal cancer (LARC). If not medically contraindicated, preoperative chemoradiotherapy, represent the standard of care for LARC patients. Unfortunately, patients shows a wide range of response rates in which approximately 20% has a complete pathological response, whereas in 20 to 40% the response is poor or absent.
RESULTS: The following specific gene signature, able to discriminate responders' patients from non-responders, were founded: AKR1C3, CXCL11, CXCL10, IDO1, CXCL9, MMP12 and HLA-DRA. These genes are mainly involved in immune system pathways and interact with drugs traditionally used in the adjuvant treatment of rectal cancer.
DISCUSSION: The present study suggests that new ideas for therapy could be found not only limited to studying genes differentially expressed between the two groups of patients but deepening the mechanisms, associated to response, in which they are involved.
METHODS: Gene expression studies performed by: Agostini et al., Rimkus et al. and Kim et al. have been merged through a meta-analysis of the raw data. Gene expression data-sets have been processed using A-MADMAN. Common differentially expressed gene (DEG) were identified through SAM analysis. To further characterize the identified DEG we deeply investigated its biological role using an integrative computational biology approach.

Kim HJ, Park J, Lee SK, et al.
Loss of RUNX3 expression promotes cancer-associated bone destruction by regulating CCL5, CCL19 and CXCL11 in non-small cell lung cancer.
J Pathol. 2015; 237(4):520-31 [PubMed] Free Access to Full Article Related Publications
Non-small cell lung cancer (NSCLC) frequently metastasizes to bone, which is associated with significant morbidity and a dismal prognosis. RUNX3 functions as a tumour suppressor in lung cancer and loss of expression occurs more frequently in invasive lung adenocarcinoma than in pre-invasive lesions. Here, we show that RUNX3 and RUNX3-regulated chemokines are linked to NSCLC-mediated bone resorption. Notably, the receptor activator of nuclear factor-κB ligand (RANKL)/osteoprotegerin (OPG) ratio, an index of osteoclastogenic stimulation, was significantly increased in human osteoblastic cells treated with conditioned media derived from RUNX3-knockdown NSCLC cells. We aimed to identify RUNX3-regulated factors that modify the osteoblastic RANKL/OPG ratio and found that RUNX3 knockdown led to CCL5 up-regulation and down-regulation of CCL19 and CXCL11 in NSCLC cells. Tumour size was noticeably increased and more severe osteolytic lesions were induced in the calvaria and tibiae of mice that received RUNX3-knockdown cells. In response to RUNX3 knockdown, serum and tissue levels of CCL5 increased, whereas CCL19 and CXCL11 decreased. Furthermore, CCL5 increased the proliferation, migration, and invasion of lung cancer cells in a dose-dependent manner; however, CCL19 and CXCL11 did not show any significant effects. The RANKL/OPG ratio in osteoblastic cells was increased by CCL5 but reduced by CCL19 and CXCL11. CCL5 promoted osteoclast differentiation, but CCL19 and CXCL11 reduced osteoclastogenesis in RANKL-treated bone marrow macrophages. These findings suggest that RUNX3 and related chemokines are useful markers for the prediction and/or treatment of NSCLC-induced bone destruction.

Liu RX, Wei Y, Zeng QH, et al.
Chemokine (C-X-C motif) receptor 3-positive B cells link interleukin-17 inflammation to protumorigenic macrophage polarization in human hepatocellular carcinoma.
Hepatology. 2015; 62(6):1779-90 [PubMed] Related Publications
UNLABELLED: B cells consistently represent abundant cellular components in tumors; however, direct evidence supporting a role for B cells in the immunopathogenesis of human cancers is lacking, as is specific knowledge of their trafficking mechanisms. Here, we demonstrate that chemokine (C-X-C motif) receptor 3-positive (CXCR3(+)) B cells constitute approximately 45% of B-cell infiltrate in human hepatocellular carcinoma (HCC) and that their levels are positively correlated with early recurrence of HCC. These cells selectively accumulate at the invading edge of HCC and undergo further somatic hypermutation and immunoglobulin G-secreting plasma cell differentiation. Proinflammatory interleukin-17(+) cells are important for the induction of epithelial cell-derived CXCR3 ligands CXCL9, CXCL10, and CXCL11, which subsequently promote the sequential recruitment and further maturation of CXCR3(+) B cells. More importantly, we provide evidence that CXCR3(+) B cells, but not their CXCR3(-) counterparts, may operate in immunoglobulin G-dependent pathways to induce M2b macrophage polarization in human HCC. Depletion of B cells significantly suppresses M2b polarization and the protumorigenic activity of tumor-associated macrophages and restores the production of antitumorigenic interleukin-12 by those cells in vivo.
CONCLUSION: Selective recruitment of CXCR3(+) B cells bridges proinflammatory interleukin-17 response and protumorigenic macrophage polarization in the tumor milieu, and blocking CXCR3(+) B-cell migration or function may help defeat HCC.

Ejaeidi AA, Craft BS, Puneky LV, et al.
Hormone receptor-independent CXCL10 production is associated with the regulation of cellular factors linked to breast cancer progression and metastasis.
Exp Mol Pathol. 2015; 99(1):163-72 [PubMed] Related Publications
Breast cancer (BC) is a major health problem for women around the world. Although advances in the field of molecular therapy have been achieved, the successful therapeutic management of BC, particularly metastatic disease, remains a challenge for patients and clinicians. One of the areas of current investigation is the circulating tumor cells (CTCs), which have a determinant role in the development of distant metastasis. At the present, many of the available treatment strategies for metastatic disease are of limited benefit. However, the elucidation of the mechanisms of tumor progression and metastasis may help to identify key molecules/components that may function as therapeutic targets in the future. In the present study, the functional analysis of CTCs revealed their ability to grow and proliferate to form colonies. Immunofluorescence staining of the CTCs' colonies exhibits elevated expression of cell growth and survival associated proteins such as, survivin, ERK and Akt1. More importantly, the functional screening of the chemokine profile in BC patients' sera revealed an HR-independent elevation of the chemokine CXCL10 when compared to healthy controls. The analysis of chemokines CXCL9 and CXCL11 demonstrated an HR-dependent production pattern. The levels of both CXCL9 and CXCL11 were markedly high in HR+ patients' sera when compared to HR- patients and healthy controls. The functional analysis of HR+ and HR- BC derived cell lines when cultivated in media supplemented with patients' sera demonstrated the alteration of tumor progression and metastasis related proteins. We noted the induction of survivin, β-catenin, MKP-1, pERK, CXCR4 and MMP-1 both at the protein and mRNA levels. The induction of those proteins was in keeping with patients' sera induced cell proliferation as measured by the MTT assay. In conclusion, our data emphasizes the role of chemokines, especially CXCL10, in BC progression and metastasis via the induction of signaling pathways, which mainly involve survivin, β-catenin, MKP-1 and MMP-1.

Hsiao JJ, Ng BH, Smits MM, et al.
Androgen receptor and chemokine receptors 4 and 7 form a signaling axis to regulate CXCL12-dependent cellular motility.
BMC Cancer. 2015; 15:204 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Identifying cellular signaling pathways that become corrupted in the presence of androgens that increase the metastatic potential of organ-confined tumor cells is critical to devising strategies capable of attenuating the metastatic progression of hormone-naïve, organ-confined tumors. In localized prostate cancers, gene fusions that place ETS-family transcription factors under the control of androgens drive gene expression programs that increase the invasiveness of organ-confined tumor cells. C-X-C chemokine receptor type 4 (CXCR4) is a downstream target of ERG, whose upregulation in prostate-tumor cells contributes to their migration from the prostate gland. Recent evidence suggests that CXCR4-mediated proliferation and metastasis of tumor cells is regulated by CXCR7 through its scavenging of chemokine CXCL12. However, the role of androgens in regulating CXCR4-mediated motility with respect to CXCR7 function in prostate-cancer cells remains unclear.
METHODS: Immunocytochemistry, western blot, and affinity-purification analyses were used to study how androgens influenced the expression, subcellular localization, and function of CXCR7, CXCR4, and androgen receptor (AR) in LNCaP prostate-tumor cells. Moreover, luciferase assays and quantitative polymerase chain reaction (qPCR) were used to study how chemokines CXCL11 and CXCL12 regulate androgen-regulated genes (ARGs) in LNCaP prostate-tumor cells. Lastly, cell motility assays were carried out to determine how androgens influenced CXCR4-dependent motility through CXCL12.
RESULTS: Here we show that, in the LNCaP prostate-tumor cell line, androgens coordinate the expression of CXCR4 and CXCR7, thereby promoting CXCL12/CXCR4-mediated cell motility. RNA interference experiments revealed functional interactions between AR and CXCR7 in these cells. Co-localization and affinity-purification experiments support a physical interaction between AR and CXCR7 in LNCaP cells. Unexpectedly, CXCR7 resided in the nuclear compartment and modulated AR-mediated transcription. Moreover, androgen-mediated cell motility correlated positively with the co-localization of CXCR4 and CXCR7 receptors, suggesting that cell migration may be linked to functional CXCR4/CXCR7 heterodimers. Lastly, CXCL12-mediated cell motility was CXCR7-dependent, with CXCR7 expression required for optimal expression of CXCR4 protein.
CONCLUSIONS: Overall, our results suggest that inhibition of CXCR7 function might decrease the metastatic potential of organ-confined prostate cancers.

Chung BM, Arutyunov A, Ilagan E, et al.
Regulation of C-X-C chemokine gene expression by keratin 17 and hnRNP K in skin tumor keratinocytes.
J Cell Biol. 2015; 208(5):613-27 [PubMed] Free Access to Full Article Related Publications
High levels of the intermediate filament keratin 17 (K17) correlate with a poor prognosis for several types of epithelial tumors. However, the causal relationship and underlying mechanisms remain undefined. A recent study suggested that K17 promotes skin tumorigenesis by fostering a specific type of inflammation. We report here that K17 interacts with the RNA-binding protein hnRNP K, which has also been implicated in cancer. K17 is required for the cytoplasmic localization of hnRNP K and for its role in regulating the expression of multiple pro-inflammatory mRNAs. Among these are the CXCR3 ligands CXCL9, CXCL10, and CXCL11, which together form a signaling axis with an established role in tumorigenesis. The K17-hnRNP K partnership is regulated by the ser/thr kinase RSK and required for CXCR3-dependent tumor cell growth and invasion. These findings functionally integrate K17, hnRNP K, and gene expression along with RSK and CXCR3 signaling in a keratinocyte-autonomous axis and provide a potential basis for their implication in tumorigenesis.

Neve Polimeno M, Ierano C, D'Alterio C, et al.
CXCR4 expression affects overall survival of HCC patients whereas CXCR7 expression does not.
Cell Mol Immunol. 2015; 12(4):474-82 [PubMed] Free Access to Full Article Related Publications
Hepatocellular carcinoma (HCC) is a heterogeneous disease with a poor prognosis and limited markers for predicting patient survival. Because chemokines and chemokine receptors play numerous and integral roles in HCC disease progression, the CXCR4-CXCL12-CXCR7 axis was studied in HCC patients. CXCR4 and CXCR7 expression was analyzed by immunohistochemistry in 86 HCC patients (training cohort) and validated in 42 unrelated HCC patients (validation cohort). CXCR4 levels were low in 22.1% of patients, intermediate in 30.2%, and high in 47.7%, whereas CXCR7 levels were low in 9.3% of patients, intermediate in 44.2% and high in 46.5% of the patients in the training cohort. When correlated to patient outcome, only CXCR4 affected overall survival (P=0.03). CXCR4-CXCL12-CXCR7 mRNA levels were examined in 33/86 patients. Interestingly, the common CXCR4-CXCR7 ligand CXCL12 was expressed at significantly lower levels in tumor tissues compared to adjacent normal liver (P=0.032). The expression and function of CXCR4 and CXCR7 was also analyzed in several human HCC cell lines. CXCR4 was expressed in Huh7, Hep3B, SNU398, SNU449 and SNU475 cells, whereas CXCR7 was expressed in HepG2, Huh7, SNU449 and SNU475 cells. Huh7, SNU449 and SNU475 cells migrated toward CXCL12, and this migration was inhibited by AMD3100/anti-CXCR4 and by CCX771/anti-CXCR7. Moreover, SNU449 and Huh7 cells exhibited matrix invasion in the presence of CXCL12 and CXCL11, a ligand exclusive to CXCR7. In conclusion, CXCR4 affects the prognosis of HCC patients but CXCR7 does not. Therefore, the CXCR4-CXCL12-CXCR7 axis plays a role in the interaction of HCC with the surrounding normal tissue and represents a suitable therapeutic target.

Huang H, Langenkamp E, Georganaki M, et al.
VEGF suppresses T-lymphocyte infiltration in the tumor microenvironment through inhibition of NF-κB-induced endothelial activation.
FASEB J. 2015; 29(1):227-38 [PubMed] Related Publications
Antiangiogenic treatment targeting the vascular endothelial growth factor (VEGF) signaling pathway is in clinical use, but its effect on vascular function and the tumor microenvironment is poorly understood. Here, we investigate cross-talk between VEGF and proinflammatory TNF-α signaling in endothelial cells and its impact on leukocyte recruitment. We found that cotreatment with VEGF decreased TNF-α-induced Jurkat cell adhesion to human microvascular endothelial cells by 40%. This was associated with inhibition of TNF-α-mediated regulation of 86 genes, including 2 T-lymphocyte-attracting chemokines, CXCL10 and CXCL11 [TNF-α concentration 1 ng/ml; 50% inhibition/inhibitory concentration (IC50) VEGF, 3 ng/ml]. Notably, VEGF directly suppressed TNF-α-induced gene expression through negative cross-talk with the NF-κB-signaling pathway, leading to an early decrease in IFN regulatory factor 1 (IRF-1) expression and reduced phosphorylation of signal transducer and activator of transcription 1 (p-Stat1) at later times. Inhibition of VEGF signaling in B16 melanoma tumor-bearing mice by sunitinib treatment resulted in up-regulation of CXCL10 and CXCL11 in tumor vessels, accompanied by up to 18-fold increased infiltration of CD3(+) T-lymphocytes in B16 tumors. Our results demonstrate a novel role of VEGF in negative regulation of NF-κB signaling and endothelial activation in the tumor microenvironment and provide evidence that pharmacological inhibition of VEGF signaling enhances T-lymphocyte recruitment through up-regulation of chemokines CXCL10 and CXCL11.

Jehs T, Faber C, Juel HB, et al.
Inflammation-induced chemokine expression in uveal melanoma cell lines stimulates monocyte chemotaxis.
Invest Ophthalmol Vis Sci. 2014; 55(8):5169-75 [PubMed] Related Publications
PURPOSE: Uveal melanoma (UM) is the most common primary intraocular tumor in adults and the presence of infiltrating leucocytes is associated with a poor prognosis. Little is known how infiltrating leucocytes influence the tumor cells. The purpose of this study was to investigate the effect of activated T cells on the expression of chemotactic cytokines in UM cells. Furthermore, we examined the ability of stimulated UM cells to attract monocytes.
METHODS: We used an in vitro coculture system in which UM cell lines and T cells were cultured together, but separated by a membrane. Uveal melanoma gene expression was quantified using a microarray. Protein expression in the supernatant was quantified with ELISA or cytometric bead array. For the monocyte migration assay, a transwell plate was used.
RESULTS: Gene-expression analysis of UM cell lines showed that coculture with activated T cells resulted in an upregulation of chemokines such as CXCL8, CXCL9, CXCL10, CXCL11, CCL2, CCL5, VEGF, intracellular adhesion molecule 1 (ICAM1), and granulocyte-macrophage colony-stimulating factor (GM-CSF). The upregulation of these molecules was confirmed at the protein level. This increase of chemokines coincided with an increased chemotactic capacity of the supernatant toward monocytes.
CONCLUSIONS: Cytokines derived from activated T cells shifted the UM cell transcriptome toward a more inflammatory state, including upregulation of several chemokines, which led to an increased migration of monocytes. Therefore, UM cells might actively participate in generating a tumor-promoting inflammatory microenvironment.

Tymoszuk P, Charoentong P, Hackl H, et al.
High STAT1 mRNA levels but not its tyrosine phosphorylation are associated with macrophage infiltration and bad prognosis in breast cancer.
BMC Cancer. 2014; 14:257 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: STAT1 has been attributed a function as tumor suppressor. However, in breast cancer data from microarray analysis indicated a predictive value of high mRNA expression levels of STAT1 and STAT1 target genes belonging to the interferon-related signature for a poor response to therapy. To clarify this issue we have determined STAT1 expression levels and activation by different methods, and investigated their association with tumor infiltration by immune cells. Additionally, we evaluated the interrelationship of these parameters and their significance for predicting disease outcome.
METHODS: Expression of STAT1, its target genes SOCS1, IRF1, CXCL9, CXCL10, CXCL11, IFIT1, IFITM1, MX1 and genes characteristic for immune cell infiltration (CD68, CD163, PD-L1, PD-L2, PD-1, CD45, IFN-γ, FOXP3) was determined by RT-PCR in two independent cohorts comprising 132 breast cancer patients. For a subset of patients, protein levels of total as well as serine and tyrosine-phosphorylated STAT1 were ascertained by immunohistochemistry or immunoblotting and protein levels of CXCL10 by ELISA.
RESULTS: mRNA expression levels of STAT1 and STAT1 target genes, as well as protein levels of total and serine-phosphorylated STAT1 correlated with each other in neoplastic tissue. However, there was no association between tumor levels of STAT1 mRNA and tyrosine-phosphorylated STAT1 and between CXCL10 serum levels and CXCL10 expression in the tumor. Tumors with increased STAT1 mRNA amounts exhibited elevated expression of genes characteristic for tumor-associated macrophages and immunosuppressive T lymphocytes. Survival analysis revealed an association of high STAT1 mRNA levels and bad prognosis in both cohorts. A similar prognostically relevant correlation with unfavorable outcome was evident for CXCL10, MX1, CD68, CD163, IFN-γ, and PD-L2 expression in at least one collective. By contrast, activation of STAT1 as assessed by the level of STAT1-Y701 phosphorylation was linked to positive outcome. In multivariate Cox regression, the predictive power of STAT1 mRNA expression was lost when including expression of CXCL10, MX1 and CD68 as confounders.
CONCLUSIONS: Our study confirms distinct prognostic relevance of STAT1 expression levels and STAT1 tyrosine phosphorylation in breast cancer patients and identifies an association of high STAT1 levels with elevated expression of STAT1 target genes and markers for infiltrating immune cells.

Kowalczuk O, Burzykowski T, Niklinska WE, et al.
CXCL5 as a potential novel prognostic factor in early stage non-small cell lung cancer: results of a study of expression levels of 23 genes.
Tumour Biol. 2014; 35(5):4619-28 [PubMed] Free Access to Full Article Related Publications
As the current staging system is imprecise for estimating prognosis of early stage non-small cell lung cancer (NSCLC), it is important to identify other methods for selecting high-risk patients after failed surgical treatment. The aim of the study was to evaluate the expression of 23 genes as putative prognostic markers in early stage NSCLC. The study was performed on 109 pairs of tumor and matched unaffected lung tissue surgical specimens taken from stage I and II NSCLC patients. We evaluated the mRNA level of 23 genes using the real-time PCR method. The difference in the expression between the tumor and normal tissue for each gene was analyzed using a general linear model. The influence of gene expression on survival was analyzed by using the proportional hazards model. Eighteen out of the 23 genes showed statistically significant differences in expression between the tumor and non-tumor tissue. For 12 genes (ITGB1, ITGB3, CXCL1, CXCL8, CXCL9, CXCL10, CXCL11, CXCR3, CXCR4, TNF, CHKA, AGFG1, and CTC1), the expression was lower, and for six genes (ITGA5, IL8, IL6, CXCL2, CXCL3, and CXCL12), it was higher in the tumor tissue as compared to the matched normal tissue. Expression changes were more pronounced in squamous cell carcinomas than in adenocarcinomas or large cell carcinomas. Of all the analyzed genes, only CXCL5 was found to statistically significantly (p = 0.04) influence both overall and disease-free survival. Among the 23 genes previously suggested to be relevant for early staged NSCLC patients' postoperative outcome, only CXCL5 showed a statistically significant prognostic effect.

Maliniemi P, Hahtola S, Ovaska K, et al.
Molecular characterization of subcutaneous panniculitis-like T-cell lymphoma reveals upregulation of immunosuppression- and autoimmunity-associated genes.
Orphanet J Rare Dis. 2014; 9:160 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Subcutaneous panniculitis-like T cell lymphomas represent a rare and difficult to diagnose entity of cutaneous T cell lymphomas. SPTL affects predominantly young adults and presents with multifocal subcutaneous nodules and frequently associated autoimmune features. The pathogenesis of SPTL is not completely understood.
METHODS: The aim of this study was to unravel molecular pathways critical to the SPTL pathogenesis. Therefore, we analyzed 23 skin samples from 20 newly diagnosed SPTL patients and relevant control samples of adipose and non-malignant panniculitis tissue by using gene expression microarray, quantitative PCR, and two-colour immunohistochemistry.
RESULTS: Interestingly, indoleamine 2,3-dioxygenase (IDO-1), an immunotolerance-inducing enzyme, was among the most highly overexpressed genes in all comparisons. The expression of Th1-specific cytokines, known to be associated with autoimmune inflammation (i.e. IFNG, CXCR3, CXCL9, CXCL10, CXCL11, and CCL5), were also significantly increased. Confirmed using immunohistochemistry, the morphologically malignant lymphocytes expressed CXCR3 and CXCL9. IDO-1 expression was found both in some morphologically malignant lymphocytes rimming the adipocytes and in surrounding CD11c(-) CD68(-) cells but not in CD11c(+) dendritic cells in the microenvironment. The proportion of FoxP3+ cells in SPTL exceeded that in the benign panniculitis samples.
CONCLUSIONS: Our results indicate that the up regulation of the tolerogenic IDO-1 together with the up regulation of IFNG, CXCR3 ligands, and CCL5 are features of SPTL lesions. We anticipate that the IFNG-inducible IDO-1 expression contributes to the formation of an immunosuppressive microenvironment, favorable for the malignant T cells. This study provides a relevant molecular basis for further studies exploring novel therapeutic means for subcutaneous T cell lymphoma.

Pasini FS, Zilberstein B, Snitcovsky I, et al.
A gene expression profile related to immune dampening in the tumor microenvironment is associated with poor prognosis in gastric adenocarcinoma.
J Gastroenterol. 2014; 49(11):1453-66 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The TNM Classification of Malignant Tumours (TNM) staging system is the primary means of determining a prognosis for gastric adenocarcinoma (GC). However, tumor behavior in the individual patient is unpredictable and in spite of treatment advances, a classification of 'advanced stage' still portends a poor prognosis. Thus, further insights from molecular analyses are needed for better prognostic stratification and determination of new therapeutic targets.
METHODS: A total of fifty-one fresh frozen tumor samples from patients with histopathologically confirmed diagnoses of GC, submitted to surgery with curative intent, were included in the study. Total RNA was extracted from an initial group of fifteen samples matched for known prognostic factors, categorized into two subgroups, according to patient overall survival: poor (<24 months) or favorable (at or above 24 months), and hybridized to Affymetrix Genechip human genome U133 plus 2.0 for genes associated with prognosis selection. Thirteen genes were selected for qPCR validation using those initial fifteen samples plus additional thirty-six samples.
RESULTS: A total of 108 genes were associated with poor prognosis, independent of tumor staging. Using systems biology, we suggest that this panel reflects the dampening of immune/inflammatory response in the tumor microenvironment level and a shift to Th2/M2 activity. A gene trio (OLR1, CXCL11 and ADAMDEC1) was identified as an independent marker of prognosis, being the last two markers validated in an independent patient cohort.
CONCLUSIONS: We determined a panel of three genes with prognostic value in gastric cancer, which should be further investigated. A gene expression profile suggestive of a dysfunctional inflammatory response was associated with unfavorable prognosis.

Bedognetti D, Spivey TL, Zhao Y, et al.
CXCR3/CCR5 pathways in metastatic melanoma patients treated with adoptive therapy and interleukin-2.
Br J Cancer. 2013; 109(9):2412-23 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Adoptive therapy with tumour-infiltrating lymphocytes (TILs) induces durable complete responses (CR) in ∼20% of patients with metastatic melanoma. The recruitment of T cells through CXCR3/CCR5 chemokine ligands is critical for immune-mediated rejection. We postulated that polymorphisms and/or expression of CXCR3/CCR5 in TILs and the expression of their ligands in tumour influence the migration of TILs to tumours and tumour regression.
METHODS: Tumour-infiltrating lymphocytes from 142 metastatic melanoma patients enrolled in adoptive therapy trials were genotyped for CXCR3 rs2280964 and CCR5-Δ32 deletion, which encodes a protein not expressed on the cell surface. Expression of CXCR3/CCR5 in TILs and CXCR3/CCR5 and ligand genes in 113 available parental tumours was also assessed. Tumour-infiltrating lymphocyte data were validated by flow cytometry (N=50).
RESULTS: The full gene expression/polymorphism model, which includes CXCR3 and CCR5 expression data, CCR5-Δ32 polymorphism data and their interaction, was significantly associated with both CR and overall response (OR; P=0.0009, and P=0.007, respectively). More in detail, the predicted underexpression of both CXCR3 and CCR5 according to gene expression and polymorphism data (protein prediction model, PPM) was associated with response to therapy (odds ratio=6.16 and 2.32, for CR and OR, respectively). Flow cytometric analysis confirmed the PPM. Coordinate upregulation of CXCL9, CXCL10, CXCL11, and CCL5 in pretreatment tumour biopsies was associated with OR.
CONCLUSION: Coordinate overexpression of CXCL9, CXCL10, CXCL11, and CCL5 in pretreatment tumours was associated with responsiveness to treatment. Conversely, CCR5-Δ32 polymorphism and CXCR3/CCR5 underexpression influence downregulation of the corresponding receptors in TILs and were associated with likelihood and degree of response.

Lau TS, Chung TK, Cheung TH, et al.
Cancer cell-derived lymphotoxin mediates reciprocal tumour-stromal interactions in human ovarian cancer by inducing CXCL11 in fibroblasts.
J Pathol. 2014; 232(1):43-56 [PubMed] Related Publications
We have investigated the role of cytokine lymphotoxin in tumour-stromal interactions in human ovarian cancer. We found that lymphotoxin overexpression is commonly shared by the cancer cells of various ovarian cancer subtypes, and lymphotoxin-beta receptor (LTBR) is expressed ubiquitously in both the cancer cells and cancer-associated fibroblasts (CAFs). In monoculture, we showed that ovarian cancer cells are not the major lymphotoxin-responsive cells. On the other hand, our co-culture studies demonstrated that the cancer cell-derived lymphotoxin induces chemokine expression in stromal fibroblasts through LTBR-NF-κB signalling. Amongst the chemokines being produced, we found that fibroblast-secreted CXCL11 promotes proliferation and migration of ovarian cancer cells via the chemokine receptor CXCR3. CXCL11 is highly expressed in CAFs in ovarian cancer biopsies, while CXCR3 is found in malignant cells in primary ovarian tumours. Additionally, the overexpression of CXCR3 is significantly associated with the tumour grade and lymph node metastasis of ovarian cancer, further supporting the role of CXCR3, which interacts with CXCL11, in promoting growth and metastasis of human ovarian cancer. Taken together, these results demonstrated that cancer-cell-derived lymphotoxin mediates reciprocal tumour-stromal interactions in human ovarian cancer by inducing CXCL11 in fibroblasts. Our findings suggest that lymphotoxin-LTBR and CXCL11-CXCR3 signalling represent therapeutic targets in ovarian cancer.

Giannice R, Erreni M, Allavena P, et al.
Chemokines mRNA expression in relation to the Macrophage Migration Inhibitory Factor (MIF) mRNA and Vascular Endothelial Growth Factor (VEGF) mRNA expression in the microenvironment of endometrial cancer tissue and normal endometrium: a pilot study.
Cytokine. 2013; 64(2):509-15 [PubMed] Related Publications
Tumor microenvironment inflammatory cells play a major role in cancer progression. Among these, the Tumor Associated Macrophages (TAMs) infiltration depends on the kind of chemokine, cytokines and growth factors secreted by the tumor cells and by the stroma in response to the cancer invasion. TAMs have been found to promote anti-tumor response in early stages and to stimulate neovascularization and metastases in advanced disease. In the microenvironment chemo-attractants of many human cancers, MIF and VEGF correlate with an increased TAMs recruitment. In addition, MIF enhances tumor cells metastases by modulating the immune responses and by promoting the angiogenesis related to VEGF. On the contrary the inhibition of MIF can lead to cell cycle arrest and apoptosis. Some chemokines (e.g. CXCL12, CXCL11, CXCL8) and their receptors, thanks to their ability to modulate migration and proliferation, are involved in the angiogenetic process. In this study we compared the expression of MIF mRNA with VEGF mRNA expression and with mRNA expression of other chemokines related to neo-angiogenesis, such as CXCL12, CXCL11, CXCL8 and CXCR4, in human endometrial cancer tissue (EC) and normal endometrium (NE). Fresh samples of EC tissue and NE were extracted from 15 patients with FIGO stage I-III undergoing primary surgery. Some of the tissue was sent for histology and part of it was treated with RNA later and stored at -80°C. Four patients dropped out. A significant up-regulation of MIF mRNA in EC tissue versus NE samples (P=0.01) was observed in all 11 patients. The MIF mRNA over-expression was coincident with a VEGF mRNA overexpression in 54% of patients (P=NS). MIF mRNA was inversely related to CXCL12 mRNA expression (P=0.01). MIF over-expression was significantly related to low grading G1-2 (P=0.01), endometrial type I (P=0.05), no lymphovascular spaces invasion (P=0.01) and 3years DFS (P=0.01). As reported in previous studies on patients with breast cancer, our data suggest that the up-regulation of MIF in patients with endometrial cancer might be related to the inhibition of distant and lymphatic spread.

Yu Y, Zhang Y, Hu S, et al.
Different patterns of cytokines and chemokines combined with IFN-γ production reflect Mycobacterium tuberculosis infection and disease.
PLoS One. 2012; 7(9):e44944 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: IFN-γ is presently the only soluble immunological marker used to help diagnose latent Mycobacterium tuberculosis (M.tb) infection. However, IFN-γ is not available to distinguish latent from active TB infection. Moreover, extrapulmonary tuberculosis, such as tuberculous pleurisy, cannot be properly diagnosed by IFN-γ release assay. As a result, other disease- or infection-related immunological biomarkers that would be more effective need to be screened and identified.
METHODOLOGY: A panel of 41 soluble immunological molecules (17 cytokines and 24 chemokines) was tested using Luminex liquid array-based multiplexed immunoassays. Samples, including plasma and pleural effusions, from healthy donors (HD, n = 12) or patients with latent tuberculosis infection (LTBI, n = 20), pulmonary tuberculosis (TB, n = 12), tuberculous pleurisy (TP, n = 15) or lung cancer (LC, n = 15) were collected and screened for soluble markers. Peripheral blood mononuclear cells (PBMCs) and pleural fluid mononuclear cells (PFMCs) were also isolated to investigate antigen-specific immune factors.
PRINCIPAL FINDINGS: For the 41 examined factors, our results indicated that three patterns were closely associated with infection and disease. (1) Significantly elevated plasma levels of IL-2, IP-10, CXCL11 and CXCL12 were present in both patients with tuberculosis and in a sub-group participant with latent tuberculosis infection who showed a higher level of IFN-γ producing cells by ELISPOT assay compared with other latently infected individuals. (2) IL-6 and IL-9 were only significantly increased in plasma from active TB patients, and the two factors were consistently highly secreted after M.tb antigen stimulation. (3) When patients developed tuberculous pleurisy, CCL1, CCL21 and IL-6 were specifically increased in the pleural effusions. In particular, these three factors were consistently highly secreted by pleural fluid mononuclear cells following M.tb-specific antigen stimulation. In conclusion, our data imply that the specific secretion of soluble immunological factors, in addition to IFN-γ, may be used to evaluate M.tb infection and tuberculosis disease.

Lee MJ, Vogt AP, Hsiao W, Osunkoya AO
CDX-2 expression in malignant germ cell tumors of the testes, intratubular germ cell neoplasia, and normal seminiferous tubules.
Tumour Biol. 2012; 33(6):2185-8 [PubMed] Related Publications
CDX-2 is a caudal-type homeobox gene, encoding a transcription factor that plays an important role in proliferation and differentiation of intestinal epithelial cells. The utility of antibodies to CDX2 in the identification of adenocarcinomas of the gastrointestinal tract, particularly colorectal adenocarcinomas, in both primary and metastatic settings is well established. It is well-known that patients with testicular tumors may occasionally lack an obvious palpable mass. However, the expression of CDX2 in malignant germ cell tumors of the testes which have metastatic potential has not been previously studied in a large series. A tissue microarray was constructed from 52 malignant germ cell tumors of the testes including: 29 cases of classic seminoma, 8 cases of embryonal carcinoma, 8 cases of yolk sac tumor, 4 cases of malignant teratoma, 2 cases of choriocarcinoma, and 1 case of spermatocytic seminoma. Ten cases of intratubular germ cell neoplasia and seven cases of benign testicles with normal seminiferous tubules were also included in tissue microarray. Immunohistochemical stains for CDX2 was performed and analyzed. Only nuclear staining was considered positive. Positive expression of CDX2 was identified in 2/2 cases (100 %) of choriocarcinoma, 4/8 cases (50 %) of teratoma, 3/8 cases (38 %) of embryonal carcinoma, 3/8 cases (38 %) of yolk sac tumor, and 1/29 cases (3 %) of classic seminoma. CDX2 was negative in all cases of intratubular germ cell neoplasia, normal seminiferous tubules, and the only case of spermatocytic seminoma. The role of CDX-2 in the differentiation of intestinal/enteric epithelial cells may contribute to the formation of trophoblastic, glandular, villous, or cystic structures in germ cell tumors of the testes. This study suggests that the expression of CDX2 in a variety of malignant germ cell tumors of the testes may be a potential pitfall in metastatic tumors of unknown primary, which are thought to be of gastrointestinal/colorectal origin but are actually from a clinically occult testicular tumor.

Yu JB, Zhang YC, Yang QP, et al.
Invasion-associated genes identified by gene expression profiling in extranodal natural killer/T-cell lymphoma, nasal type.
Leuk Lymphoma. 2013; 54(1):90-8 [PubMed] Related Publications
To identify invasion-associated genes in extranodal natural killer (NK)/T-cell lymphoma, we performed microarray analysis on seven tumor samples and two control pools (composed of normal NK cells and T cells, tonsil and spleen) using Affymetrix GeneChip. Compared with all control pools, 59 uniquely expressed genes were discovered in the tumor samples. Overexpressed genes related to proteolysis, cell motility and chemotaxis, including CTSL, uPAR, TIMP-1, CXCL9, CXCL11 and DEFB1, were identified. Comparing the gene expression profiles of five upper aerodigestive tract (UAT) cases with two non-UAT cases, we found some overexpressed genes in non-UAT cases related to proteolysis and cell adhesion function, including matrix metalloproteinase 9 (MMP-9). Immunohistochemistry detection was performed on 34 paraffin sections to evaluate the expression of selected genes. A correlation of urokinase-type plasminogen activator receptor (uPAR) expression with MMP-9 expression was revealed. Analysis of prognosis demonstrated that expressions of MMP-2 and MMP-9 were closely correlated with a poor prognosis. These invasion-associated genes may become targets for diagnostic and therapeutic procedures.

Flockhart RJ, Webster DE, Qu K, et al.
BRAFV600E remodels the melanocyte transcriptome and induces BANCR to regulate melanoma cell migration.
Genome Res. 2012; 22(6):1006-14 [PubMed] Free Access to Full Article Related Publications
Aberrations of protein-coding genes are a focus of cancer genomics; however, the impact of oncogenes on expression of the ~50% of transcripts without protein-coding potential, including long noncoding RNAs (lncRNAs), has been largely uncharacterized. Activating mutations in the BRAF oncogene are present in >70% of melanomas, 90% of which produce active mutant BRAF(V600E) protein. To define the impacts of oncogenic BRAF on the melanocyte transcriptome, massively parallel cDNA sequencing (RNA-seq) was performed on genetically matched normal human melanocytes with and without BRAF(V600E) expression. To enhance potential disease relevance by verifying expression of altered genes in BRAF-driven cancer tissue, parallel RNA-seq was also undertaken of two BRAF(V600E)-mutant human melanomas. BRAF(V600E) regulated expression of 1027 protein-coding transcripts and 39 annotated lncRNAs, as well as 70 unannotated, potentially novel, intergenic transcripts. These transcripts display both tissue-specific and multi-tissue expression profiles and harbor distinctive regulatory chromatin marks and transcription factor binding sites indicative of active transcription. Coding potential analysis of the 70 unannotated transcripts suggested that most may represent newly identified lncRNAs. BRAF-regulated lncRNA 1 (BANCR) was identified as a recurrently overexpressed, previously unannotated 693-bp transcript on chromosome 9 with a potential functional role in melanoma cell migration. BANCR knockdown reduced melanoma cell migration, and this could be rescued by the chemokine CXCL11. Combining RNA-seq of oncogene-expressing normal cells with RNA-seq of their corresponding human cancers may represent a useful approach to discover new oncogene-regulated RNA transcripts of potential clinical relevance in cancer.

Heinrich EL, Lee W, Lu J, et al.
Chemokine CXCL12 activates dual CXCR4 and CXCR7-mediated signaling pathways in pancreatic cancer cells.
J Transl Med. 2012; 10:68 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Previously assumed to be a select ligand for chemokine receptor CXCR4, chemokine CXCL12 is now known to activate both CXCR4 and CXCR7. However, very little is known about the co-expression of these receptors in cancer cells.
METHODS: We used immunohistochemistry to determine the extent of co-expression in pancreatic cancer tissue samples and immunoblotting to verify expression in pancreatic cancer cell lines. In cell culture studies, siRNA was used to knock down expression of CXCR4, CXCR7, K-Ras and β-arrestin -2 prior to stimulating the cells with CXCL12. Activation of the mitogen-activated protein kinase pathway (MAPK) was assessed using both a Raf-pull down assay and western blotting. The involvement of the receptors in CXCL12-mediated increases in cell proliferation was examined via an ATP-based proliferation assay.
RESULTS: First, we discovered frequent CXCR4/CXCR7 co-expression in human pancreatic cancer tissues and cell lines. Next, we observed consistent increases in ERK1/2 phosphorylation after exposure to CXCL12 or CXCL11, a CXCR7 agonist, in pancreatic cancer cell lines co-expressing CXCR4/CXCR7. To better characterize the receptor-mediated pathway(s), we knocked down CXCR4 or CXCR7, exposed the cells to CXCL12 and examined subsequent effects on ERK1/2. We observed that CXCR7 mediates the CXCL12-driven increase in ERK1/2 phosphorylation. Knockdown of CXCR4 expression however, decreased levels of K-Ras activity. Conversely, KRAS knockdown greatly reduced CXCL12-mediated increases in ERK1/2 phosphorylation. We then evaluated the role of β-arrestin-2, a protein directly recruited by chemokine receptors. We observed that β-arrestin-2 knockdown also inhibited increases in ERK1/2 phosphorylation mediated by both CXCR4 and CXCR7. Finally, we investigated the mechanism for CXCL12-enhanced cell proliferation and found that either receptor can modulate cell proliferation.
CONCLUSIONS: In summary, our data demonstrate that CXCR4 and CXCR7 are frequently co-expressed in human pancreatic cancer tissues and cell lines. We show that β-arrestin-2 and K-Ras dependent pathways coordinate the transduction of CXCL12 signals. Our results suggest that the development of therapies based on inhibiting CXCL12 signaling to halt the growth of pancreatic cancer should be focused at the ligand level in order to account for the contributions of both receptors to this signaling pathway.

Abajo A, Bitarte N, Zarate R, et al.
Identification of colorectal cancer metastasis markers by an angiogenesis-related cytokine-antibody array.
World J Gastroenterol. 2012; 18(7):637-45 [PubMed] Free Access to Full Article Related Publications
AIM: To investigate the angiogenesis-related protein expression profile characterizing metastatic colorectal cancer (mCRC) with the aim of identifying prognostic markers.
METHODS: The expression of 44 angiogenesis-secreted factors was measured by a novel cytokine antibody array methodology. The study evaluated vascular endothelial growth factor (VEGF) and its soluble vascular endothelial growth factor receptor (sVEGFR)-1 protein levels by enzyme immunoassay (EIA) in a panel of 16 CRC cell lines. mRNA VEGF and VEGF-A isoforms were quantified by quantitative reverse-transcription polymerase chain reaction (Q-RT-PCR) and vascular endothelial growth factor receptor (VEGFR)-2 expression was analyzed by flow cytometry.
RESULTS: Metastasis-derived CRC cell lines expressed a distinctive molecular profile as compared with those isolated from a primary tumor site. Metastatic CRC cell lines were characterized by higher expression of angiogenin-2 (Ang-2), macrophage chemoattractant proteins-3/4 (MCP-3/4), matrix metalloproteinase-1 (MMP-1), and the chemokines interferon γ inducible T cell α chemoattractant protein (I-TAC), monocyte chemoattractant protein I-309, and interleukins interleukin (IL)-2 and IL-1α, as compared to primary tumor cell lines. In contrast, primary CRC cell lines expressed higher levels of interferon γ (IFN-γ), insulin-like growth factor-1 (IGF-1), IL-6, leptin, epidermal growth factor (EGF), placental growth factor (PlGF), thrombopoietin, transforming growth factor β1 (TGF-β1) and VEGF-D, as compared with the metastatic cell lines. VEGF expression does not significantly differ according to the CRC cellular origin in normoxia. Severe hypoxia induced VEGF expression up-regulation but contrary to expectations, metastatic CRC cell lines did not respond as much as primary cell lines to the hypoxic stimulus. In CRC primary-derived cell lines, we observed a two-fold increase in VEGF expression between normoxia and hypoxia as compared to metastatic cell lines. CRC cell lines express a similar pattern of VEGF isoforms (VEGF₁₂₁, VEGF₁₆₅ and VEGF₁₈₉) despite variability in VEGF expression, where the major transcript was VEGF₁₂₁. No relevant expression of VEGFR-2 was found in CRC cell lines, as compared to that of human umbilical vein endothelial cells and sVEGFR-1 expression did not depend on the CRC cellular origin.
CONCLUSION: A distinct angiogenesis-related expression pattern characterizes metastatic CRC cell lines. Factors other than VEGF appear as prognostic markers and intervention targets in the metastatic CRC setting.

Klee EW, Bondar OP, Goodmanson MK, et al.
Candidate serum biomarkers for prostate adenocarcinoma identified by mRNA differences in prostate tissue and verified with protein measurements in tissue and blood.
Clin Chem. 2012; 58(3):599-609 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Improved tests are needed for detection and management of prostate cancer. We hypothesized that differential gene expression in prostate tissue could help identify candidate blood biomarkers for prostate cancer and that blood from men with advanced prostate disease could be used to verify the biomarkers presence in circulation.
METHODS: We identified candidate markers using mRNA expression patterns from laser-capture microdissected prostate tissue and confirmed tissue expression using immunohistochemistry (IHC) for the subset of candidates having commercial antisera. We analyzed tissue extracts with tandem mass spectrometry (MS/MS) and measured blood concentrations using immunoassays and MS/MS of trypsin-digested, immunoextracted peptides.
RESULTS: We selected 35 novel candidate prostate adenocarcinoma biomarkers. For all 13 markers having commercial antisera for IHC, tissue expression was confirmed; 6 showed statistical discrimination between nondiseased and malignant tissue, and only 5 were detected in tissue extracts by MS/MS. Sixteen of the 35 candidate markers were successfully assayed in blood. Four of 8 biomarkers measured by ELISA and 3 of 10 measured by targeted MS showed statistically significant increases in blood concentrations of advanced prostate cancer cases, compared with controls.
CONCLUSIONS: Seven novel biomarkers identified by gene expression profiles in prostate tissue were shown to have statistically significant increased concentrations in blood from men with advanced prostate adenocarcinoma compared with controls: apolipoprotein C1, asporin, cartilage oligomeric matrix protein, chemokine (C-X-C motif) ligand 11 (CXCL11), CXCL9, coagulation factor V, and proprotein convertase subtilisin/kexin 6.

Farquharson AJ, Steele RJ, Carey FA, Drew JE
Novel multiplex method to assess insulin, leptin and adiponectin regulation of inflammatory cytokines associated with colon cancer.
Mol Biol Rep. 2012; 39(5):5727-36 [PubMed] Related Publications
The role of altered levels of insulin, leptin and adiponectin in contributing to the observed increased risk of colon cancer associated with obesity remains to be determined. Elevated insulin and leptin associated with obesity are linked to inflammatory responses. Conversely, adiponectin levels are reduced in obese individuals and this hormone is generally associated with anti-inflammatory responses. Inflammatory cytokines are key components of processes linked with carcinogenesis. Insulin, leptin and adiponectin receptor expression profiles were assessed in human normal, adenomatous polyp and tumour tissue. Insulin, leptin and adiponectin regulation of inflammatory cytokines previously identified as being associated with early events in colon carcinogenesis were further investigated here using a surrogate colon epithelial cell line and a custom designed GeXP assay of the inflammatory cytokines (CCL20, CXCL1, CXCL2, CXCL3, CXCL11, IL1RN, CXCL4, IL8, CCL19, CCL21, CCL23, CCL5, IL10RB and TNFRSF1A). Mean insulin, leptin and adiponectin receptor expression levels were lower in adenomatous polyp samples in comparison with normal and tumour tissue. In contrast to leptin, insulin significantly reduced CCL20 and CXCL11 and increased CXCL3 expression. Full length adiponectin, but not globular adiponectin, induced CCL5, CXCL1, CXCL3 and CCL20 gene expression. GeXP assay permitted measurement of changes in gene expression of cytokines in response to insulin and adiponectin, indicating the potential for insulin and adiponectin regulation of mediators of inflammation associated with early events in colon carcinogenesis.

Tsoi LC, Qin T, Slate EH, Zheng WJ
Consistent Differential Expression Pattern (CDEP) on microarray to identify genes related to metastatic behavior.
BMC Bioinformatics. 2011; 12:438 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: To utilize the large volume of gene expression information generated from different microarray experiments, several meta-analysis techniques have been developed. Despite these efforts, there remain significant challenges to effectively increasing the statistical power and decreasing the Type I error rate while pooling the heterogeneous datasets from public resources. The objective of this study is to develop a novel meta-analysis approach, Consistent Differential Expression Pattern (CDEP), to identify genes with common differential expression patterns across different datasets.
RESULTS: We combined False Discovery Rate (FDR) estimation and the non-parametric RankProd approach to estimate the Type I error rate in each microarray dataset of the meta-analysis. These Type I error rates from all datasets were then used to identify genes with common differential expression patterns. Our simulation study showed that CDEP achieved higher statistical power and maintained low Type I error rate when compared with two recently proposed meta-analysis approaches. We applied CDEP to analyze microarray data from different laboratories that compared transcription profiles between metastatic and primary cancer of different types. Many genes identified as differentially expressed consistently across different cancer types are in pathways related to metastatic behavior, such as ECM-receptor interaction, focal adhesion, and blood vessel development. We also identified novel genes such as AMIGO2, Gem, and CXCL11 that have not been shown to associate with, but may play roles in, metastasis.
CONCLUSIONS: CDEP is a flexible approach that borrows information from each dataset in a meta-analysis in order to identify genes being differentially expressed consistently. We have shown that CDEP can gain higher statistical power than other existing approaches under a variety of settings considered in the simulation study, suggesting its robustness and insensitivity to data variation commonly associated with microarray experiments.
AVAILABILITY: CDEP is implemented in R and freely available at: http://genomebioinfo.musc.edu/CDEP/.
CONTACT: zhengw@musc.edu.

Tham SM, Ng KH, Pook SH, et al.
Tumor and microenvironment modification during progression of murine orthotopic bladder cancer.
Clin Dev Immunol. 2011; 2011:865684 [PubMed] Free Access to Full Article Related Publications
The aim of this study was to monitor changes in the expression of immune-related genes in the bladder after tumor implantation. Mice were orthotopically implanted with MB49-PSA cells (C57BL/6 mice) on day 1 and terminated on days 7, 14, 21, and 28. Another mouse model (MBT-2/C3H mice) was examined at day 7. Gene expression analysis was performed using a TaqMan Low Density Mouse Immune Panel (Applied Biosystems, USA) on RNA extracted from the bladders. Selected genes were reconfirmed by real-time PCR analysis and RT-PCR on the mRNA from other animals. Immune suppressive (IL13, IL1β, PTGS2, NOS2, IL10, CTLA4, and CCL22) and immune stimulatory genes (CSF2, GZMB, IFNγ, CXCL10, TNFα, CD80, IL12a, and IL6) and AGTR2 were increased by day 7. By day 28, IL10, CCL2, CCL5, CXCL11, CTLA4, GZMB, IFNγ, CSF2, and IL6 were significantly increased. Therapeutic strategies involving TH1 induction and TH2 dampening may improve responses to immunotherapy.

Monnier J, Boissan M, L'Helgoualc'h A, et al.
CXCR7 is up-regulated in human and murine hepatocellular carcinoma and is specifically expressed by endothelial cells.
Eur J Cancer. 2012; 48(1):138-48 [PubMed] Related Publications
Development of hepatocellular carcinoma (HCC) is a complex and progressive disease that involves cycles of liver cell death, inflammation, and tissue regeneration/remodelling. Chemokines and chemokine receptors play numerous and integral roles in the disease progression of HCC. Here we investigated the novel chemokine receptor CXCR7/RDC1 in HCC progression, its two known ligands CXCL12 and CXCL11, as well as the other CXCL12 receptor, CXCR4. Our results show that in a cohort of 408 human HCCs, CXCR7 and CXCL11 were significantly higher in tumours compared to normal liver controls (5- and 10-fold, respectively). Immunohistochemical (IHC) staining on human HCC sections confirmed that both CXCL11 and CXCR7 were much higher in cancer tissues. Furthermore, IHC staining revealed that CXCR7 protein was only expressed in endothelial cells whereas CXCL11 exhibited a much broader tissue expression. At the cellular level we observed that in vitro, human microvascular endothelial cells (HMEC-1) up-regulated CXCR7 under hypoxic and acidic pH conditions, which are well known characteristics of the HCC tumour micro-environment. As for its ligand, we observed that IFNγ robustly induced CXCL11 in hepatic stellate cells, hepatocytes, and HMEC-1s. In addition, in the mouse Diethylnitrosamine model of hepatocarcinogenesis we observed a very strong induction of CXCR7 and CXCL11 transcripts, confirming that CXCR7/CXCL11 up-regulation is conserved between human and mice liver cancer. Altogether, our results strongly support the hypothesis that the CXCL11/CXCR7 pathway is involved HCC progression.

Zabel BA, Lewén S, Berahovich RD, et al.
The novel chemokine receptor CXCR7 regulates trans-endothelial migration of cancer cells.
Mol Cancer. 2011; 10:73 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Migration of metastatic tumor cells from the bloodstream into lymph nodes is thought to be facilitated by expression of the chemokine receptors CCR7, CXCR4 and, for B cell-derived tumors, CXCR5. Expression of their respective chemokine ligands (CCL19, CCL21, CXCL12 and CXCL13) by endothelial cells inside the lymph nodes facilitates the trans-endothelial migration (TEM) of these cells through high endothelial venules into the lymph node parenchyma. It is known that CXCR7, a second CXCL12 receptor, regulates TEM of CXCR4+CXCR7+ tumor cells towards a CXCL12 source. In this study, we set out to assess the potential stimulation by CXCL12 of tumor cell TEM towards other chemokines and whether CXCR7 might be able to regulate such effects.
METHODS: The human Burkitt's lymphoma cell line NC-37, which expresses CXCR4, CXCR5, CXCR7 and CCR7, was selected as a model system. TEM of these cells through a human HUVEC endothelial cell monolayer was used as the main model system for these studies. Regulation of their TEM behavior by various concentrations of the various cognate chemokines for the above-mentioned receptors, placed in either the source or target wells of modified Boyden chamber migration plates, was assessed by quantifying the number of cells migrated under each experimental condition.
RESULTS: Exposure of CXCR4⁺CXCR7⁺ cancer cells to CXCL12 greatly potentiated their TEM towards the chemokines CCL19 and CXCL13. This CXCL12-potentiated TEM was inhibited by the second CXCR7 chemokine ligand, CXCL11, as well as CXCR7-specific small molecule antagonists and antibodies. In contrast, the CXCR4 antagonist AMD3100 was less effective at inhibiting CXCL12-potentiated TEM. Thus, CXCR7 antagonists may be effective therapeutic agents for blocking CXCL12-mediated migration of CXCR4⁺CXCR7⁺ tumor cells into lymph nodes, regardless of whether the cancer cells follow a CXCL12 gradient or whether serum CXCL12 stimulates their migration towards CCR7 and CXCR5 chemokines in the lymph nodes.

Xia J, Wang J, Chen N, et al.
Expressions of CXCR7/ligands may be involved in oral carcinogenesis.
J Mol Histol. 2011; 42(2):175-80 [PubMed] Related Publications
Oral carcinogenesis is a multistep process and requires accumulation and interplay of a series of molecular events. Chemokines and their receptors have been suggested to play important roles in the initiation or progression of cancers. Until now, no report focuses on their alterations in premalignant stage of oral squamous cell carcinoma (OSCC). Compared with normal tissues, mRNA levels of 9 chemokines and 3 chemokine receptors including CXCR7 in oral leukoplakia (OLK) were increased more than two folds by microarray analysis. Then, CXCR7 was selected for further confirmation and immunohistochemistry examination during multistage oral carcinogenesis. CXCR7 was expressed in 85% of OLK and 86% of OSCC. However, only 8% (1 of 13 cases) of normal tissue displayed CXCR7 immunostaining. The positive ratios of CXCR7, CXCL12 and CXCL11 in OLK and OSCC tissues respectively, were significantly higher than that in normal epithelia (P < 0.05), although no significant difference was found between OLK and OSCC. Meanwhile, CXCR7 always concomitantly expressed with it ligands in OLK and OSCC tissues. Our results indicated that CXCR7-CXCL12/CXCL11 axis might play important roles in oral carcinogenesis.

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