To clarify the relationships between marginal zone lymphomas (MZLs) and Waldenström macroglobulinemia/lymphoplasmacytic lymphomas (WM/LPLs), immunoglobulin heavy chain variable gene (IGHV) features were analyzed and the occurrence of MYD88 L265P mutations was identified in a series of 123 patients: 53 MZLs from the spleen (SMZLs), 11 from lymph nodes (NMZLs), 28 mucosa-associated lymphatic tissue (MALT) lymphomas and 31 WM/LPLs. SMZLs were characterized by overrepresentation of IGHV1-2 gene rearrangements with a canonical motif, without selection pressure and with long CDR3 segments. NMZLs had increased frequencies of IGHV3 genes. The IGHV gene was unmutated in most cases, often with long CDR3 segments. MALT lymphomas were usually associated with a mutated IGHV gene, but with the absence of selection pressure. WM/LPLs were associated with an IGHV3-23 overrepresentation and high IGHV mutation rate, with features of selection pressure and short CDR3 segments. MYD88 L265P mutations were almost restricted exclusively to WM/LPL patients. Taken all diagnoses together, all patients with MYD88 L265P mutations had an immunoglobulin M peak and almost all patients except one had bone marrow infiltration. These results demonstrate that the history of antigen exposure of the four entities studied was different and MYD88 L265P was specifically associated with WM/LPLs. WM/LPL may thus be functionally associated with constitutive nuclear factor-κB activation.
Several studies have substantiated the hypothesis that tumor progression is not only driven by the tumor cells themselves but also by their interaction with intrinsic and surrounding stromal cells. Tumor-associated macrophages and microglial cells (TAMs) represent one major stromal cell component of glioblastomas. Additionally, in many gliomas, chemokines are highly expressed and some chemokines were already linked to settlement of TAMs in tumors. However, although chemoattraction mechanisms mediated by chemokines and their receptors are well documented, information on their expression and role in TAMs, particularly in patients, is limited. Therefore, we investigated the transcription of the chemokine-receptor combinations CXCL12-CXCR4-CXCR7, CXCL16-CXCR6 and CX3CL1-CX3CR1 in freshly isolated TAMs from 20 human glioblastomas in relation to in vitro polarized M1- and M2-macrophages. We demonstrated that TAMs express both M1- and M2-markers. Compared to in vitro polarized macrophages, the M1-marker interleukin (IL)-6 was similarly expressed, whereas IL-1β and tumor necrosis factor (TNF)-α were found at lower levels. The M2-marker IL-10 was comparably expressed, while CD163 and transforming growth factor (TGF)-β were detected with one tenth lower intensities in TAMs. All investigated chemokines/receptors were transcribed at moderate to high levels in TAMs as well as in vitro polarized macrophages. However, CX3CR1 was markedly higher and CXCR7 was somewhat higher expressed in TAMs, whereas M2-macrophages were characterized by the highest CXCL12 and a moderate CX3CL1 expression. Collectively, TAMs share properties of M1- and M2-macrophages and show a considerably higher expression of the chemokine receptors CXCR7 and CX3CR1.
Desflurane anesthesia produces changes in cytosolic protein expression up to 72 h after anesthesia in the rat brain, indicating yet unknown persisting effects.
resolution. Nevertheless, the integrated analysis of these multiple layers of nucleic acid information is still at its beginning. In this context it is important to recognize, that information encoded in nucleic acids is in many aspects "fluent": genomic information transits from DNA via epigenomic regulation and expression patterns of RNA to its ultimate function. Moreover, during tumor evolution the information at all these levels transits from the germline state via driving changes to complex aberration patterns. Additionally, the information transits from mother to daughter cells which in turn receive further information from environmental factors. Thus, "a" lymphoma is indeed an ecosystem with multiple interacting levels of informational dysregulation which unlikely is comprehensively described by targeted re-sequencing on DNA level or transcriptional profiling alone.Thanks to the interdisciplinary cooperation of clinicians, pathologists, geneticists and bionformaticians within the interdisciplinary Germanwide MMML-network we have profiled meanwhile more than 250 germinal-center B-cell derived by sequencing and more than 800 B-cell lymphomas by array-based means for genomic, expression and methylation changes. This lecture will give examples on the strategies aiming at integrating these complementary levels of nucleic-acid-based OMICs data as well as novel insights into the biology of lymphomas provided by such integrative analyses.
BackgroundChemokines and their receptors play a decisive role in tumor progression and metastasis. We recently found a new signaling mechanism in malignant glioma cells mediated by transmembrane chemokines that we termed “inverse signaling”. According to this hypothesis, soluble (s)-CXCL16 binds to the surface-expressed transmembrane (tm) -CXCL16, and induces signaling and different biological effects in the stimulated cells, so that the transmembrane ligand itself acts as a receptor for its soluble counterpart. Now, we hypothesized that “inverse signaling” via tm-CXCL16 might also take place in meningiomas, a completely different, benign tumor entity.MethodsWe used quantitative reverse-transcription polymerase chain reaction, immunocytochemistry and western blot to detect CXCL16 and CXCR6 in human meningioma cells isolated from 28 human meningiomas. Subsequently, we stimulated cultured human tm-CXCL16-positive, CXCR6-negative meningioma cells with recombinant s-CXCL16 and analyzed binding, signaling and biological effects using RNAi silencing to verify specificity.ResultsIn fact, cultured human meningioma cells considerably express CXCL16, but substantially lack CXCR6, the only known CXCL16 receptor. These receptor-negative cells could bind s-CXCL16, and responded to s-CXCL16 application with activation of the intracellular kinases ERK1/2 und Akt. As a consequence, we observed increased proliferation and rescue of apoptosis of cultured meningioma cells. Since binding and signaling were abolished by siRNA silencing, we concluded that tm-CXCL16 specifically acts as a receptor for s-CXCL16 also in human meningioma cells.ConclusionThese findings underline our recent report on the mechanism of inverse signaling as a broad biological process also observable in more benign tumor cells and contributing to tumor progression.
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