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1.
Environ Pollut ; 319: 120960, 2023 Feb 15.
Article in English | MEDLINE | ID: mdl-36587783

ABSTRACT

While meta-analyses are common in the health and some biological sciences, there is a lack of such analyses for petroleum-related marine research. Oil is a highly complex substance consisting of thousands of different compounds. Measurement limitations, different protocols and a lack of standards in recording and reporting various elements of laboratory experiments impede attempts to homogenize and compare data and identify trends. Nevertheless, oil toxicology research would benefit from meta-analyses, through which we could develop meaningful research questions and design robust experiments. Here we report findings from an effort to quantitatively summarize results from oil toxicology studies on arctic and subarctic marine invertebrates. We discovered that the vast majority of studies was conducted on crustaceans, followed by molluscs. Analyzing the sensitivity of response measures across taxa we found that the most sensitive responses tend to rank low in ecological relevance, while less sensitive response measures tend to be more ecologically relevant. We further uncovered that crustaceans appear to be more sensitive to mechanically dispersed than chemically dispersed oil while the opposite seems true for molluscs, albeit not statistically significant. Both crustaceans and molluscs show a higher sensitivity to fresh than to weathered oil. No differences in the sensitivities of crustacean life stages were found. However, due to a lack of data, many questions remain unanswered. Our study revealed that while trends in responses can be elucidated, heterogeneous experimental protocols and reporting regimes prevent a proper meta-analysis.


Subject(s)
Petroleum Pollution , Petroleum , Water Pollutants, Chemical , Animals , Petroleum/toxicity , Arctic Regions , Aquatic Organisms , Invertebrates , Water Pollutants, Chemical/toxicity , Water Pollutants, Chemical/analysis
2.
Leukemia ; 36(2): 464-475, 2022 02.
Article in English | MEDLINE | ID: mdl-34417556

ABSTRACT

Chronic lymphocytic leukemia (CLL) is a B-cell malignancy mainly occurring at an advanced age with no single major genetic driver. Transgenic expression of TCL1 in B cells leads after a long latency to a CLL-like disease in aged Eµ-TCL1 mice suggesting that TCL1 overexpression is not sufficient for full leukemic transformation. In search for secondary genetic events and to elucidate the clonal evolution of CLL, we performed whole exome and B-cell receptor sequencing of longitudinal leukemia samples of Eµ-TCL1 mice. We observed a B-cell receptor stereotypy, as described in patients, confirming that CLL is an antigen-driven disease. Deep sequencing showed that leukemia in Eµ-TCL1 mice is mostly monoclonal. Rare oligoclonality was associated with inability of tumors to develop disease upon adoptive transfer in mice. In addition, we identified clonal changes and a sequential acquisition of mutations with known relevance in CLL, which highlights the genetic similarities and therefore, suitability of the Eµ-TCL1 mouse model for progressive CLL. Among them, a recurrent gain of chromosome 15, where Myc is located, was identified in almost all tumors in Eµ-TCL1 mice. Interestingly, amplification of 8q24, the chromosomal region containing MYC in humans, was associated with worse outcome of patients with CLL.


Subject(s)
Clonal Evolution , Gain of Function Mutation , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins/metabolism , Animals , Chromosomes , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Mice , Mice, Inbred C57BL , Mice, Transgenic , Proto-Oncogene Proteins/genetics
3.
Immunity ; 54(12): 2825-2841.e10, 2021 12 14.
Article in English | MEDLINE | ID: mdl-34879221

ABSTRACT

T cell exhaustion limits anti-tumor immunity and responses to immunotherapy. Here, we explored the microenvironmental signals regulating T cell exhaustion using a model of chronic lymphocytic leukemia (CLL). Single-cell analyses identified a subset of PD-1hi, functionally impaired CD8+ T cells that accumulated in secondary lymphoid organs during disease progression and a functionally competent PD-1int subset. Frequencies of PD-1int TCF-1+ CD8+ T cells decreased upon Il10rb or Stat3 deletion, leading to accumulation of PD-1hi cells and accelerated tumor progression. Mechanistically, inhibition of IL-10R signaling altered chromatin accessibility and disrupted cooperativity between the transcription factors NFAT and AP-1, promoting a distinct NFAT-associated program. Low IL10 expression or loss of IL-10R-STAT3 signaling correlated with increased frequencies of exhausted CD8+ T cells and poor survival in CLL and in breast cancer patients. Thus, balance between PD-1hi, exhausted CD8+ T cells and functional PD-1int TCF-1+ CD8+ T cells is regulated by cell-intrinsic IL-10R signaling, with implications for immunotherapy.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Immunotherapy/methods , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , Receptors, Interleukin-10/metabolism , T-Lymphocyte Subsets/immunology , Animals , Cell Line, Tumor , Cells, Cultured , Cellular Microenvironment , Hepatocyte Nuclear Factor 1-alpha/metabolism , Humans , Immunity , Mice , Mice, Inbred C57BL , NFATC Transcription Factors/metabolism , Programmed Cell Death 1 Receptor/metabolism , Receptors, Interleukin-10/genetics , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/metabolism , Signal Transduction , Transcription Factor AP-1/metabolism
4.
Cancers (Basel) ; 13(8)2021 Apr 15.
Article in English | MEDLINE | ID: mdl-33920868

ABSTRACT

Indoleamine-2,3-dioxygenase 1 (IDO1), a tryptophan (Trp)-catabolizing enzyme producing metabolites such as kynurenine (Kyn), is expressed by myeloid-derived suppressor cells (MDSCs) and associated with cancer immune escape. IDO1-expressing monocytic MDSCs were shown to accumulate in patients with chronic lymphocytic leukemia (CLL) and to suppress T cell activity and induce suppressive regulatory T cells (Tregs) in vitro. In the Eµ-TCL1 mouse model of CLL, we observed a strong upregulation of IDO1 in monocytic and granulocytic MDSCs, and a significantly increased Kyn to Trp serum ratio. To explore the potential of IDO1 as a therapeutic target for CLL, we treated mice after adoptive transfer of Eµ-TCL1 leukemia cells with the IDO1 modulator 1-methyl-D-tryptophan (1-MT) which resulted in a minor reduction in leukemia development which disappeared over time. 1-MT treatment further led to a partial rescue of the immune cell changes that are induced with CLL development. Similarly, treatment of leukemic mice with the clinically investigated IDO1 inhibitor epacadostat reduced the frequency of Tregs and initially delayed CLL development slightly, an effect that was, however, lost at later time points. In sum, despite the observed upregulation of IDO1 in CLL, its inhibition is not sufficient to control leukemia development in the Eµ-TCL1 adoptive transfer model.

5.
Cell ; 182(5): 1252-1270.e34, 2020 09 03.
Article in English | MEDLINE | ID: mdl-32818467

ABSTRACT

Aryl hydrocarbon receptor (AHR) activation by tryptophan (Trp) catabolites enhances tumor malignancy and suppresses anti-tumor immunity. The context specificity of AHR target genes has so far impeded systematic investigation of AHR activity and its upstream enzymes across human cancers. A pan-tissue AHR signature, derived by natural language processing, revealed that across 32 tumor entities, interleukin-4-induced-1 (IL4I1) associates more frequently with AHR activity than IDO1 or TDO2, hitherto recognized as the main Trp-catabolic enzymes. IL4I1 activates the AHR through the generation of indole metabolites and kynurenic acid. It associates with reduced survival in glioma patients, promotes cancer cell motility, and suppresses adaptive immunity, thereby enhancing the progression of chronic lymphocytic leukemia (CLL) in mice. Immune checkpoint blockade (ICB) induces IDO1 and IL4I1. As IDO1 inhibitors do not block IL4I1, IL4I1 may explain the failure of clinical studies combining ICB with IDO1 inhibition. Taken together, IL4I1 blockade opens new avenues for cancer therapy.


Subject(s)
L-Amino Acid Oxidase/metabolism , Receptors, Aryl Hydrocarbon/metabolism , Adult , Aged , Animals , Cell Line , Cell Line, Tumor , Disease Progression , Female , Glioma/immunology , Glioma/metabolism , Glioma/therapy , HEK293 Cells , Humans , Immune Checkpoint Inhibitors/pharmacology , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/therapy , Male , Mice , Mice, Inbred C57BL , Middle Aged , Rats
6.
Cancers (Basel) ; 11(6)2019 Jun 13.
Article in English | MEDLINE | ID: mdl-31200555

ABSTRACT

Chronic lymphocytic leukemia (CLL) is known for its strong dependency on the tumor microenvironment. We found progranulin (GRN), a protein that has been linked to inflammation and cancer, to be upregulated in the serum of CLL patients compared to healthy controls, and increased GRN levels to be associated with an increased hazard for disease progression and death. This raised the question of whether GRN is a functional driver of CLL. We observed that recombinant GRN did not directly affect viability, activation, or proliferation of primary CLL cells in vitro. However, GRN secretion was induced in co-cultures of CLL cells with stromal cells that enhanced CLL cell survival. Gene expression profiling and protein analyses revealed that primary mesenchymal stromal cells (MSCs) in co-culture with CLL cells acquire a cancer-associated fibroblast-like phenotype. Despite its upregulation in the co-cultures, GRN treatment of MSCs did not mimic this effect. To test the relevance of GRN for CLL in vivo, we made use of the Eµ-TCL1 CLL mouse model. As we detected strong GRN expression in myeloid cells, we performed adoptive transfer of Eµ-TCL1 leukemia cells to bone marrow chimeric Grn-/- mice that lack GRN in hematopoietic cells. Thereby, we observed that CLL-like disease developed comparable in Grn-/- chimeras and respective control mice. In conclusion, serum GRN is found to be strongly upregulated in CLL, which indicates potential use as a prognostic marker, but there is no evidence that elevated GRN functionally drives the disease.

8.
Tumour Biol ; 37(9): 12485-12495, 2016 Sep.
Article in English | MEDLINE | ID: mdl-27337954

ABSTRACT

Increased expression of insulin-like growth factor 2 (IGF2) is found in tumors of colorectal cancer (CRC) patients exhibiting a gained region on chromosome 11q15 and is implicated in poor patient survival. This study analyzes in vitro phenotypic- and gene expression changes associated with IGF2 shRNA-mediated knockdown. Initially, doxycycline inducible IGF2 knockdown cell lines were generated in the CRC cell lines SW480 and LS174T. The cells were analyzed for changes in proliferation, cell cycle, apoptosis, adhesion, and invasion. Expression profiling analysis was performed, and, for a subset of the identified genes, expression was validated by qRT-PCR and Western blot. IGF2 knockdown inhibited cell proliferation in both cell lines induced G1 cell cycle blockade and decreased adhesion to several extracellular matrix proteins. Knockdown of IGF2 did not alter invasiveness in SW480 cells, while a slight increase in apoptosis was seen only in the LS174T cell line. Knockdown of IGF2 in SW480 deregulated 58 genes, several of which were associated with proliferation and cell-cell/cell-ECM contacts. A subset of these genes, including CDK2, YAP1, and BIRC5 (Survivin), are members of a common network. This study supports the concept of direct autocrine/paracrine tumor cell activation through IGF2 and a shows role of IGF2 in CRC proliferation, adhesion and, to a limited extent, apoptosis.


Subject(s)
Colorectal Neoplasms/pathology , Insulin-Like Growth Factor II/physiology , Adaptor Proteins, Signal Transducing/genetics , Antigens, CD , Cadherins/genetics , Cell Adhesion , Cell Line, Tumor , Cell Proliferation , Colorectal Neoplasms/genetics , Colorectal Neoplasms/mortality , Cyclin-Dependent Kinase 2/physiology , Desmoplakins/genetics , Humans , Insulin-Like Growth Factor II/genetics , Phosphoproteins/genetics , RNA, Small Interfering/genetics , Transcription Factors , YAP-Signaling Proteins , gamma Catenin
9.
J Cancer Res Clin Oncol ; 142(1): 225-37, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26243458

ABSTRACT

PURPOSE: CITED4 is one member of a family of transcriptional cofactors, several of which are deregulated in a variety of tumors, including colorectal cancer (CRC). We modulated CITED4 expression, in vitro, and analyzed the associated phenotypic and gene expression changes. METHODS: CITED4-overexpressing and shRNA-mediated knockdown cell lines and control cell lines were established in the CRC cell line SW480. The cells were analyzed for changes in proliferation, apoptosis/cell cycle, migration, invasion, colony formation and adhesion. mRNA expression changes were determined by microarray and pathway analysis, and several deregulated genes were validated by qRT-PCR and Western blotting. Based on results obtained from these studies, the status of the actin cytoskeleton was evaluated by phalloidin/vinculin staining. RESULTS: Phenotypically, the CITED4-overexpressing cell line showed only moderate changes in adhesion. Microarray analysis identified several deregulated genes, including several G protein-coupled receptors. Phenotypic analysis of the CITED4 shRNA knockdown cell line demonstrated decreased cell proliferation and G2 cell cycle blockage. Microarray analysis identified many deregulated genes, and pathway analysis discovered genes linked to actin-associated adherens junctions/tight junctions (claudin-4, claudin-7, ezrin, MET, ß-catenin). Phenotypically, no morphological changes of the actin cytoskeleton were seen. CONCLUSIONS: Upregulation of CITED4 in SW480 resulted in no obvious phenotype. CITED4 shRNA-mediated knockdown led to decreased cellular proliferation and modulation of a large number of genes, including the c-MET tyrosine kinase and several actin-associated adherens junctions/tight junction genes.


Subject(s)
Adherens Junctions/genetics , Biomarkers, Tumor/genetics , Cell Proliferation , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Gene Silencing , Tight Junctions/genetics , Transcription Factors/metabolism , Actins/metabolism , Apoptosis , Biomarkers, Tumor/metabolism , Blotting, Western , Colorectal Neoplasms/genetics , Gene Expression Profiling , Humans , RNA, Messenger/genetics , RNA, Small Interfering/genetics , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Transcription Factors/antagonists & inhibitors , Transcription Factors/genetics , Tumor Cells, Cultured
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