Tumour associated macrophages in Diffuse Large B cell lymphoma

Tumour associated macrophages (TAMs) have been associated with prognosis in a wide variety of tumours with most studies showing a high number of macrophages equating with poor prognosis. This is postulated to be due to TAMs providing support to the tumour through a wide variety of mechanisms including suppression of the immune response, promotion of angiogenesis and provision of growth supporting signals. Previous work within the group has characterised some of the mechanisms by which Burkitt lymphoma cells attract macrophages to the tumour and some of the mechanisms by which these macrophages support tumour cell growth. This thesis extends some of the work carried out in Burkitt lymphoma to Diffuse Large B cell lymphoma (DLBCL) and examines TAMs in this tumour type. Diffuse Large B cell lymphoma is the commonest high grade lymphoma in the Western world. Like Burkitt lymphoma it is characterised by diffuse sheets of lymphoid blasts. In contrast to Burkitt lymphoma, it represents a less well-defined entity that encompasses tumours with variable morphology, genetic abnormalities and outcome. Rates of proliferation and apoptosis vary between individual tumours, and unlike Burkitt lymphoma not all cases are characterised by a prominent macrophage infiltrate. Previous work within the group has shown a relationship in Burkitt lymphoma between apoptosis, macrophage infiltration and proliferation suggesting that apoptosis recruits macrophages to provide support to the tumour cells. This relationship was studied here in a large cohort of patients with DLBCL and the same relationship shown to exist in this tumour also. Following this observation, a bioinformatic approach was taken to define a gene expression signature of the TAM in DLBCL in situ in an unbiased way. Using large publicly available human tumour gene expression datasets, a graph clustering approach using the tool Biolayout Express 3D was used to explore the transcriptome of DLCBL and other human tumours. Signatures of immune cells and stromal cells, functional pathways and tumour specific signatures were defined from individual tumour type transcriptomes by study of clusters of co-expressed genes. Further work used a novel graph clustering approach based on mean Pearson correlations to define a ‘core’ transcriptome signature shared across many unrelated tumour types and in which elements of the tumour stroma were prominent. To validate the TAM signature derived from the DLBCL dataset, protein expression of selected elements of the signature were analysed at the protein level by immunohistochemistry in an unrelated cohort of DLBCL. Selected markers from the DLBCL TAM signature were then assessed for relationship to outcome in a cohort of patients treated with CHOP chemotherapy. Of the proteins studied, a significant difference in outcome was demonstrated only for leukocyte associated immunoglobulin receptor 1 (LAIR1) expression by TAMs, where low intensity staining for LAIR1 in TAMs was associated with better overall survival. LAIR1 is a collagen-binding inhibitory receptor expressed only in cells of haemopoetic lineage whose role is little studied in macrophages. The final results chapter presents some preliminary data from co-culture experiments in which the expression of LAIR-1 on the ‘macrophage-like’ cell line THP-1 is studied in various polarisation states and the ability of these cells to support or constrain tumour cell growth studied in the presence or absence of collagen

Coexpression analysis of large cancer datasets provides insight into the cellular phenotypes of the tumour microenvironment

Background: Biopsies taken from individual tumours exhibit extensive differences in their cellular composition due to the inherent heterogeneity of cancers and vagaries of sample collection. As a result genes expressed in specific cell types, or associated with certain biological processes are detected at widely variable levels across samples in transcriptomic analyses. This heterogeneity also means that the level of expression of genes expressed specifically in a given cell type or process, will vary in line with the number of those cells within samples or activity of the pathway, and will therefore be correlated in their expression.Results: Using a novel 3D network-based approach we have analysed six large human cancer microarray datasets derived from more than 1,000 individuals. Based upon this analysis, and without needing to isolate the individual cells, we have defined a broad spectrum of cell-type and pathway-specific gene signatures present in cancer expression data which were also found to be largely conserved in a number of independent datasets.Conclusions: The conserved signature of the tumour-associated macrophage is shown to be largely-independent of tumour cell type. All stromal cell signatures have some degree of correlation with each other, since they must all be inversely correlated with the tumour component. However, viewed in the context of established tumours, the interactions between stromal components appear to be multifactorial given the level of one component e.g. vasculature, does not correlate tightly with another, such as the macrophage

Zum Faser- und Eigenschaftsabbau bei Verarbeitung und Recycling diskontinuierlich faserverstaerkter Kunststoffe Anwendung des Mikrobiegeversuchs zur Faserfestigkeitsbestimmung am Beispiel methodischer Untersuchungen des Eigenschaftsabbaus diskontinuierlich faserverstaerkter Kunststoffe

Fiber damage in discontinuous fiber reinforced plastics may occur during compounding, processing and recycling, caused by fiber-fiber interactions, fiber-machine interactions od fiber-additive interactions. Here, a micro-bending test method is described for determination of the residual fiber strength. Based on these measurements, conclusions are drawn to prevent fiber breaking, e,g, by selection of special additives, e.g. pigments, that may not induce fiber breaking. Furthermore, focusing on recycling of fiber composites, the hydrolytic degradation of fiber strength of PA6-GF35 and SMC samples has been investigated.SIGLEAvailable from: <a href=http://kluedo.ub.uni-kl.de/volltexte/2003/1582/pdf/diss.pdf target=NewWindow>http://kluedo.ub.uni-kl.de/volltexte/2003/1582/pdf/diss.pdf</a> / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman