The Chemokine CXCL16 and Its Receptor, CXCR6, as Markers and Promoters of Inflammation-Associated Cancers

Clinical observations and mouse models have suggested that inflammation can be pro-tumorigenic. Since chemokines are critical in leukocyte trafficking, we hypothesized that chemokines play essential roles in inflammation-associated cancers. Screening for 37 chemokines in prostate cancer cell lines and xenografts revealed CXCL16, the ligand for the receptor CXCR6, as the most consistently expressed chemokine. Immunohistochemistry and/or immunofluorescence and confocal imaging of 121 human prostate specimens showed that CXCL16 and CXCR6 were co-expressed, both on prostate cancer cells and adjacent T cells. Expression levels of CXCL16 and CXCR6 on cancer cells correlated with poor prognostic features including high-stage and high-grade, and expression also correlated with post-inflammatory changes in the cancer stroma as revealed by loss of alpha-smooth muscle actin. Moreover, CXCL16 enhanced the growth of CXCR6-expressing cancer and primary CD4 T cells. We studied expression of CXCL16 in an additional 461 specimens covering 12 tumor types, and found that CXCL16 was expressed in multiple human cancers associated with inflammation. Our study is the first to describe the expression of CXCL16/CXCR6 on both cancer cells and adjacent T cells in humans, and to demonstrate correlations between CXCL16 and CXCR6 vs. poor both prognostic features and reactive changes in cancer stoma. Taken together, our data suggest that CXCL16 and CXCR6 may mark cancers arising in an inflammatory milieu and mediate pro-tumorigenic effects of inflammation through direct effects on cancer cell growth and by inducing the migration and proliferation of tumor-associated leukocytes

The relationship between the systemic inflammatory response, tumour proliferative activity, T-lymphocytic infiltration and COX-2 expression and survival in patients with transitional cell carcinoma of the urinary bladder

The relationship between the systemic inflammatory response, tumour proliferative activity, T-lymphocytic infiltration, and COX-2 expression and survival was examined in patients with transitional cell carcinoma of the urinary bladder (n=103). Sixty-one patients had superficial disease and 42 patients had invasive disease. Cancer-specific survival was shorter in those patients with invasive compared with superficial bladder cancer (P<0.001). On univariate analysis, stratified by stage, increased Ki-67 labelling index (P<0.05), increased COX-2 expression (P<0.05), C-reactive protein (P<0.05) and adjuvant therapy (P<0.01) were associated with poorer cancer-specific survival. On multivariate analysis of these significant factors, stratified by stage, only C-reactive protein (HR 2.89, 95% CI 1.42–5.91, P=0.004) and adjuvant therapy (HR 0.29, 95% CI 0.14–0.62, P=0.001) were independently associated with poorer cancer-specific survival. These results would suggest that tumour-based factors such as grade, COX-2 expression or T-lymphocytic infiltration are subordinate to systemic factors such as C-reactive protein in determining survival in patients with transitional cell carcinoma of the urinary bladder

CXCR4 Mediated Chemotaxis Is Regulated by 5T4 Oncofetal Glycoprotein in Mouse Embryonic Cells

5T4 oncofetal molecules are highly expressed during development and upregulated in cancer while showing only low levels in some adult tissues. Upregulation of 5T4 expression is a marker of loss of pluripotency in the early differentiation of embryonic stem (ES) cells and forms an integrated component of an epithelial-mesenchymal transition, a process important during embryonic development and metastatic spread of epithelial tumors. Investigation of the transcriptional changes in early ES differentiation showed upregulation of CXCL12 and down-regulation of a cell surface protease, CD26, which cleaves this chemokine. CXCL12 binds to the widely expressed CXCR4 and regulates key aspects of development, stem cell motility and tumour metastasis to tissues with high levels of CXCL12. We show that the 5T4 glycoprotein is required for optimal functional cell surface expression of the chemokine receptor CXCR4 and CXCL12 mediated chemotaxis in differentiating murine embryonic stem cells and embryo fibroblasts (MEF). Cell surface expression of 5T4 and CXCR4 molecules is co-localized in differentiating ES cells and MEF. By contrast, differentiating ES and MEF derived from 5T4 knockout (KO) mice show only intracellular CXCR4 expression but infection with adenovirus encoding mouse 5T4 restores CXCL12 chemotaxis and surface co-localization with 5T4 molecules. A series of chimeric constructs with interchanged domains of 5T4 and the glycoprotein CD44 were used to map the 5T4 sequences relevant for CXCR4 membrane expression and function in 5T4KO MEF. These data identified the 5T4 transmembrane domain as sufficient and necessary to enable CXCR4 cell surface expression and chemotaxis. Furthermore, some monoclonal antibodies against m5T4 can inhibit CXCL12 chemotaxis of differentiating ES cells and MEF which is not mediated by simple antigenic modulation. Collectively, these data support a molecular interaction of 5T4 and CXCR4 occurring at the cell surface which directly facilitates the biological response to CXCL12. The regulation of CXCR4 surface expression by 5T4 molecules is a novel means to control responses to the chemokine CXCL12 for example during embryogenesis but can also be selected to advantage the spread of a 5T4 positive tumor from its primary site

Microbial Communities in Long-Term, Water-Flooded Petroleum Reservoirs with Different in situ Temperatures in the Huabei Oilfield, China

The distribution of microbial communities in the Menggulin (MGL) and Ba19 blocks in the Huabei Oilfield, China, were studied based on 16S rRNA gene analysis. The dominant microbes showed obvious block-specific characteristics, and the two blocks had substantially different bacterial and archaeal communities. In the moderate-temperature MGL block, the bacteria were mainly Epsilonproteobacteria and Alphaproteobacteria, and the archaea were methanogens belonging to Methanolinea, Methanothermobacter, Methanosaeta, and Methanocella. However, in the high-temperature Ba19 block, the predominant bacteria were Gammaproteobacteria, and the predominant archaea were Methanothermobacter and Methanosaeta. In spite of shared taxa in the blocks, differences among wells in the same block were obvious, especially for bacterial communities in the MGL block. Compared to the bacterial communities, the archaeal communities were much more conserved within blocks and were not affected by the variation in the bacterial communities

Inflammatory mediators in breast cancer: Coordinated expression of TNFα & IL-1β with CCL2 & CCL5 and effects on epithelial-to-mesenchymal transition

<p>Abstract</p> <p>Background</p> <p>The inflammatory chemokines CCL2 (MCP-1) & CCL5 (RANTES) and the inflammatory cytokines TNFα & IL-1β were shown to contribute to breast cancer development and metastasis. In this study, we wished to determine whether there are associations between these factors along stages of breast cancer progression, and to identify the possible implications of these factors to disease course.</p> <p>Methods</p> <p>The expression of CCL2, CCL5, TNFα and IL-1β was determined by immunohistochemistry in patients diagnosed with: (1) Benign breast disorders (=healthy individuals); (2) Ductal Carcinoma <it>In Situ </it>(DCIS); (3) Invasive Ducal Carcinoma without relapse (IDC-no-relapse); (4) IDC-with-relapse. Based on the results obtained, breast tumor cells were stimulated by the inflammatory cytokines, and epithelial-to-mesenchymal transition (EMT) was determined by flow cytometry, confocal analyses and adhesion, migration and invasion experiments.</p> <p>Results</p> <p>CCL2, CCL5, TNFα and IL-1β were expressed at very low incidence in normal breast epithelial cells, but their incidence was significantly elevated in tumor cells of the three groups of cancer patients. Significant associations were found between CCL2 & CCL5 and TNFα & IL-1β in the tumor cells in DCIS and IDC-no-relapse patients. In the IDC-with-relapse group, the expression of CCL2 & CCL5 was accompanied by further elevated incidence of TNFα & IL-1β expression. These results suggest progression-related roles for TNFα and IL-1β in breast cancer, as indeed indicated by the following: (1) Tumors of the IDC-with-relapse group had significantly higher persistence of TNFα and IL-1β compared to tumors of DCIS or IDC-no-relapse; (2) Continuous stimulation of the tumor cells by TNFα (and to some extent IL-1β) has led to EMT in the tumor cells; (3) Combined analyses with relevant clinical parameters suggested that IL-1β acts jointly with other pro-malignancy factors to promote disease relapse.</p> <p>Conclusions</p> <p>Our findings suggest that the coordinated expression of CCL2 & CCL5 and TNFα & IL-1β may be important for disease course, and that TNFα & IL-1β may promote disease relapse. Further <it>in vitro </it>and <it>in vivo </it>studies are needed for determination of the joint powers of the four factors in breast cancer, as well as analyses of their combined targeting in breast cancer.</p

Dynamic Emotional and Neural Responses to Music Depend on Performance Expression and Listener Experience

Apart from its natural relevance to cognition, music provides a window into the intimate relationships between production, perception, experience, and emotion. Here, emotional responses and neural activity were observed as they evolved together with stimulus parameters over several minutes. Participants listened to a skilled music performance that included the natural fluctuations in timing and sound intensity that musicians use to evoke emotional responses. A mechanical performance of the same piece served as a control. Before and after fMRI scanning, participants reported real-time emotional responses on a 2-dimensional rating scale (arousal and valence) as they listened to each performance. During fMRI scanning, participants listened without reporting emotional responses. Limbic and paralimbic brain areas responded to the expressive dynamics of human music performance, and both emotion and reward related activations during music listening were dependent upon musical training. Moreover, dynamic changes in timing predicted ratings of emotional arousal, as well as real-time changes in neural activity. BOLD signal changes correlated with expressive timing fluctuations in cortical and subcortical motor areas consistent with pulse perception, and in a network consistent with the human mirror neuron system. These findings show that expressive music performance evokes emotion and reward related neural activations, and that music's affective impact on the brains of listeners is altered by musical training. Our observations are consistent with the idea that music performance evokes an emotional response through a form of empathy that is based, at least in part, on the perception of movement and on violations of pulse-based temporal expectancies

Sequence of the hyperplastic genome of the naturally competent Thermus scotoductus SA-01

<p>Abstract</p> <p>Background</p> <p>Many strains of <it>Thermus </it>have been isolated from hot environments around the world. <it>Thermus scotoductus </it>SA-01 was isolated from fissure water collected 3.2 km below surface in a South African gold mine. The isolate is capable of dissimilatory iron reduction, growth with oxygen and nitrate as terminal electron acceptors and the ability to reduce a variety of metal ions, including gold, chromate and uranium, was demonstrated. The genomes from two different <it>Thermus thermophilus </it>strains have been completed. This paper represents the completed genome from a second <it>Thermus </it>species - <it>T. scotoductus</it>.</p> <p>Results</p> <p>The genome of <it>Thermus scotoductus </it>SA-01 consists of a chromosome of 2,346,803 bp and a small plasmid which, together are about 11% larger than the <it>Thermus thermophilus </it>genomes. The <it>T. thermophilus </it>megaplasmid genes are part of the <it>T. scotoductus </it>chromosome and extensive rearrangement, deletion of nonessential genes and acquisition of gene islands have occurred, leading to a loss of synteny between the chromosomes of <it>T. scotoductus and T. thermophilus</it>. At least nine large inserts of which seven were identified as alien, were found, the most remarkable being a denitrification cluster and two operons relating to the metabolism of phenolics which appear to have been acquired from <it>Meiothermus ruber</it>. The majority of acquired genes are from closely related species of the Deinococcus-Thermus group, and many of the remaining genes are from microorganisms with a thermophilic or hyperthermophilic lifestyle. The natural competence of <it>Thermus scotoductus </it>was confirmed experimentally as expected as most of the proteins of the natural transformation system of <it>Thermus thermophilus </it>are present. Analysis of the metabolic capabilities revealed an extensive energy metabolism with many aerobic and anaerobic respiratory options. An abundance of sensor histidine kinases, response regulators and transporters for a wide variety of compounds are indicative of an oligotrophic lifestyle.</p> <p>Conclusions</p> <p>The genome of <it>Thermus scotoductus </it>SA-01 shows remarkable plasticity with the loss, acquisition and rearrangement of large portions of its genome compared to <it>Thermus thermophilus</it>. Its ability to naturally take up foreign DNA has helped it adapt rapidly to a subsurface lifestyle in the presence of a dense and diverse population which acted as source of nutrients. The genome of <it>Thermus scotoductus </it>illustrates how rapid adaptation can be achieved by a highly dynamic and plastic genome.</p

Macrophages in Breast Cancer: Do Involution Macrophages Account for the Poor Prognosis of Pregnancy-Associated Breast Cancer?

Macrophage influx is associated with negative outcomes for women with breast cancer and has been demonstrated to be required for metastasis of mammary tumors in mouse models. Pregnancy-associated breast cancer is characterized by particularly poor outcomes, however the reasons remain obscure. Recently, post-pregnancy mammary involution has been characterized as having a wound healing signature. We have proposed the involution-hypothesis, which states that the wound healing microenvironment of the involuting gland is tumor promotional. Macrophage influx is one of the prominent features of the involuting gland, identifying the macrophage a potential instigator of tumor progression and a novel target for breast cancer treatment and prevention

Breast cancer metastasis to the bone: mechanisms of bone loss

Breast cancer frequently metastasizes to the skeleton, interrupting the normal bone remodeling process and causing bone degradation. Osteolytic lesions are the end result of osteoclast activity; however, osteoclast differentiation and activation are mediated by osteoblast production of RANKL (receptor activator for NFκB ligand) and several osteoclastogenic cytokines. Osteoblasts themselves are negatively affected by cancer cells as evidenced by an increase in apoptosis and a decrease in proteins required for new bone formation. Thus, bone loss is due to both increased activation of osteoclasts and suppression of osteoblasts. This review summarizes the current understanding of the osteolytic mechanisms of bone metastases, including a discussion of current therapies