Cancer cell CCL5 mediates bone marrow independent angiogenesis in breast cancer

It has recently been suggested that the chemokine receptor (CCR5) is required for bone marrow (BM) derived endothelial progenitor cell (EPC) mediated angiogenesis. Here we show that suppression of either cancer cell produced CCL5, or host CCR5 leads to distinctive vascular and tumor growth defects in breast cancer. Surprisingly, CCR5 restoration in the BM alone was not sufficient to rescue the wild type phenotype, suggesting that impaired tumor growth associated with inhibiting CCL5/CCR5 is not due to defects in EPC biology. Instead, to promote angiogenesis cancer cell CCL5 may signal directly to endothelium in the tumor-stroma. In support of this hypothesis, we have also shown: (i) that endothelial cell CCR5 levels increases in response to tumor-conditioned media; (ii) that the amount of CCR5+ tumor vasculature correlates with invasive grade; and (iii) that inhibition of CCL5/CCR5 signaling impairs endothelial cell migration, associated with a decrease in activation of mTOR/AKT pathway members. Finally, we show that treatment with CCR5 antagonist results in less vasculature, impaired tumor growth, reduced metastases and improved survival. Taken as a whole, this work demonstrates that directly inhibiting CCR5 expressing vasculature constitutes a novel strategy for inhibiting angiogenesis and blocking metastatic progression in breast cancer

Prädiktion des Erfolges einer endoskopischen Drittventrikulostomie (ETV) unter besonderer Berücksichtigung des intraoperativ entnommenen Liquorbefundes

Bei einem Hydrozephalus handelt es sich um eine mitunter folgenschwere Erkrankung, die, wird sie nicht rechtzeitig behandelt, zu schwersten neurologischen Schäden oder sogar zum Tod des Patienten führen kann. Gegenwärtig stehen zwei Behandlungsstrategien des Hydrozephalus zur Verfügung: Die Implantation eines CSF-Shuntsystems oder die Durchführung einer endoskopischen Drittventrikulostomie (ETV). Insbesondere bei Patienten mit einer obstruktiven Form des Hydrozephalus, beispielsweise infolge einer idiopathischen Aquäduktstenose oder eines obstruktiv-tumorösen Prozesses, erwies sich die ETV als ausgesprochen erfolgreich. Vergleichbare Ergebnisse für einen kommunizierenden Hydrozephalus wurden hingegen bisher nicht erhalten. Zusätzlich werden Patientenmerkmale wie Alter und Vorhandensein eines vorherigen Shuntsystems als weitere Einflussfaktoren auf den Operationserfolg diskutiert. Um bestehenden Unsicherheiten bezüglich der Indikationsstellung für eine ETV beizukommen, entwickelten Kulkarni et al. den ETV Success Score (ETVSS), zur Anwendung in einer pädiatrischen Studienpopulation. [3, 11, 13, 24, 34, 35, 38, 39, 49, 61, 62, 73, 75, 82, 100, 116, 123] Ziel dieser Arbeit war neben der Validierung des ETVSS in einer gemischten Studienpopulation die Entwicklung eines Vorhersagemodells für die 6-Monats-Erfolgsrate der ETV bei pädiatrischen und adulten Patienten, wobei insbesondere eine mögliche positive Prädiktion von Liquorbefunden auf den Operationserfolg untersucht wurde. Die vorliegende Arbeit umfasst 408 ETV bei insgesamt 378 Patienten, mit einer Erfolgsrate von 76,9 % nach sechs und 63,6 % nach durchschnittlich 50 Monaten. Als statistisch signifikante Einflussfaktoren auf den Erfolg wurden das Patientenalter, die Ätiologie des Hydrozephalus, das Vorhandensein eines vorherigen Shuntsystems sowie die Zusammensetzung des Liquor erfasst. Basierend auf diesen Erkenntnissen wurden drei logistische Regressionsmodelle entwickelt, welche neben grundlegenden demografischen sowie klinischen Merkmalen auch Bildgebungs- und Liquorparameter berücksichtigen. Für alle drei Modelle wurde eine zuverlässige Abbildung der Erfolgsunterschiede erreicht, jedoch ergab sich kein signifikanter Mehrwert für die Bildgebungs- und Liquorbefunde. Eine adäquate Prädiktionsfähigkeit des ETVSS in einer gemischten Studienpopulation konnte auch nach Ausgleich des altersbedingten Variabilitätsverlusts nicht gezeigt werden

Torsion Angle Preferences in Druglike Chemical Space: A Comprehensive Guide

Crystal structure databases offer ample opportunities to derive small molecule conformation preferences, but the derived knowledge is not systematically applied in drug discovery research. We address this gap by a comprehensive and extendable expert system enabling quick assessment of the probability of a given conformation to occur. It is based on a hierarchical system of torsion patterns that cover a large part of druglike chemical space. Each torsion pattern has associated frequency histograms generated from CSD and PDB data and, derived from the histograms, traffic-light rules for frequently observed, rare, and highly unlikely torsion ranges. Structures imported into the corresponding software are annotated according to these rules. We present the concept behind the tree of torsion patterns, the design of an intuitive user interface for the management and usage of the torsion library, and we illustrate how the system helps analyze and understand conformation properties of substructures widely used in medicinal chemistry

Torsion Angle Preferences in Druglike Chemical Space: A Comprehensive Guide

Crystal structure databases offer ample opportunities to derive small molecule conformation preferences, but the derived knowledge is not systematically applied in drug discovery research. We address this gap by a comprehensive and extendable expert system enabling quick assessment of the probability of a given conformation to occur. It is based on a hierarchical system of torsion patterns that cover a large part of druglike chemical space. Each torsion pattern has associated frequency histograms generated from CSD and PDB data and, derived from the histograms, traffic-light rules for frequently observed, rare, and highly unlikely torsion ranges. Structures imported into the corresponding software are annotated according to these rules. We present the concept behind the tree of torsion patterns, the design of an intuitive user interface for the management and usage of the torsion library, and we illustrate how the system helps analyze and understand conformation properties of substructures widely used in medicinal chemistry

Chromosomal Aberrations Associated with Sequential Steps of the Metastatic Cascade in Colorectal Cancer Patients

International audienceBACKGROUND:Genomic information can help to identify colorectal tumors with high and low metastatic potential, thereby improving prediction of benefit of local and/or systemic treatment. Here we investigated chromosomal aberrations in relation to the different stages of the metastatic cascade: dissemination of tumor cells into the mesenteric vein, metastatic outgrowth in the liver, intravasation of the peripheral blood circulation, and development of further distant metastasis.METHODS:Peripheral and mesenteric blood from colorectal cancer patients (n = 72) were investigated for circulating tumor cells, and DNA extracted from their primary tumors was subjected to array comparative genomic hybridization profiling. The results were validated with an independent set of primary colorectal tumors (n = 53) by quantitative reverse transcription PCR.RESULTS:Mesenteric intravasation and liver metastasis were correlated with losses of chromosomes 16p (72%), 16q (27%), and 19 (54%), gain along 1q31 (45%) and 20q (60%), tumor cell infiltration into the peripheral blood circulation, and further distant metastasis with gain of chromosome 8q (59%) and 12 (47%, P < 0.01). Chromosome 12 gain was associated with poor overall survival in the initial (2.8 vs >7 years) and validation cohort (3.3 vs >6 years). The prospective study presented here is a hypothesis-generating study and confirmation with larger cohorts is required.CONCLUSIONS:This is the first study that investigated colorectal cancer in its different stages of metastasis in correlation with copy number changes of the primary tumor. This information might be helpful to identify patients with limited metastatic spread who may profit from liver metastasis resection and may lead to the discovery of new therapeutic targets.Microarray data have been deposited in NCBI's Gene Expression Omnibus and are accessible through GEO Series accession number GSE82228

Heterogeneity of miR-10b expression in circulating tumor cells

Circulating tumor cells (CTCs) in the blood of cancer patients are recognized as important potential targets for future anticancer therapies. As mediators of metastatic spread, CTCs are also promising to be used as &euro; liquid biopsyto aid clinical decision-making. Recent work has revealed potentially important genotypic and phenotypic heterogeneity within CTC populations, even within the same patient. MicroRNAs (miRNAs) are key regulators of gene expression and have emerged as potentially important diagnostic markers and targets for anti-cancer therapy. Here, we describe a robust in situ hybridization (ISH) protocol, incorporating the CellSearch &reg; CTC detection system, enabling clinical investigation of important miRNAs, such as miR-10b on a cell by cell basis. We also use this method to demonstrate heterogeneity of such as miR-10b on a cell-by-cell basis. We also use this method to demonstrate heterogeneity of miR-10b in individual CTCs from breast, prostate and colorectal cancer patients