scholarly journals ApoE-TREM2 axis induces pathogenic senescent-like myeloid cells in prostate cancer

2021 ◽  
Author(s):  
Arianna Calcinotto ◽  
Nicolò Bancaro ◽  
Martina Troiani ◽  
Rydell Arzola ◽  
Angela Rita Elia ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Histone Deacetylase Inhibitors ◽  
Tumour Progression ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Treatment Resistance ◽  
Tumour Microenvironment ◽  
Tumour Cells ◽  
Mrna Levels ◽  
Immature Myeloid Cells

Abstract Tumour cells promote the expansion and intra-tumoural recruitment of Myeloid-derived suppressor cells (MDSCs), a subset of immature myeloid cells, that support tumour cell proliferation and confer treatment resistance. While immature myeloid cells have a very short lifespan, whether pathogenic MDSCs can persist in the tumour microenvironment remains unknown. Here, we report the identification of a subset of long-lasting MDSCs that upregulate markers of cellular senescence and the TREM2 receptor. Senescent-like MDSCs possess higher pro-inflammatory capabilities compared to canonical MDSCs. Genetic and pharmacological elimination of senescent-like MDSCs decreases tumour progression in different mouse models of prostate cancer. Mechanistically, we find that Apolipoprotein E (ApoE) secreted by prostate tumour cells binds TREM2 in senescent-like MDSCs, thereby regulating the survival of these cells. ApoE and TREM2 mRNA levels are upregulated in prostate cancers and correlate with poor patients’ prognosis. Taken together, these results reveal a novel mechanism by which the tumour microenvironment shapes the intra-tumoural immune response. Pathogenic senescent-like MDSCs persist longer in the tumour microenvironment and can be eliminated by histone deacetylase inhibitors enhancing the efficacy of standard therapy in prostate cancer.

scholarly journals Activation of blood coagulation in cancer: implications for tumour progression

2013 ◽  
Vol 33 (5) ◽  
Author(s):  
Luize G. Lima ◽  
Robson Q. Monteiro
Keyword(s):  
Blood Coagulation ◽  
Tumour Progression ◽  
Primary Tumour ◽  
Tumour Microenvironment ◽  
Tumour Cells ◽  
Protease Activated Receptors ◽  
Tumour Metastasis ◽  
Coagulation Proteins ◽  
Associated Proteins ◽  
Cancer Associated Thrombosis

Several studies have suggested a role for blood coagulation proteins in tumour progression. Herein, we discuss (1) the activation of the blood clotting cascade in the tumour microenvironment and its impact on primary tumour growth; (2) the intravascular activation of blood coagulation and its impact on tumour metastasis and cancer-associated thrombosis; and (3) antitumour therapies that target blood-coagulation-associated proteins. Expression levels of the clotting initiator protein TF (tissue factor) have been correlated with tumour cell aggressiveness. Simultaneous TF expression and PS (phosphatidylserine) exposure by tumour cells promote the extravascular activation of blood coagulation. The generation of blood coagulation enzymes in the tumour microenvironment may trigger the activation of PARs (protease-activated receptors). In particular, PAR1 and PAR2 have been associated with many aspects of tumour biology. The procoagulant activity of circulating tumour cells favours metastasis, whereas the release of TF-bearing MVs (microvesicles) into the circulation has been correlated with cancer-associated thrombosis. Given the role of coagulation proteins in tumour progression, it has been proposed that they could be targets for the development of new antitumour therapies.

scholarly journals A Complex Metabolic Network Confers Immunosuppressive Functions to Myeloid-Derived Suppressor Cells (MDSCs) within the Tumour Microenvironment

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2700
Author(s):  
Francesca Hofer ◽  
Gianna Di Sario ◽  
Chiara Musiu ◽  
Silvia Sartoris ◽  
Francesco De Sanctis ◽  
...  
Keyword(s):  
Metabolic Network ◽  
Cancer Progression ◽  
Immune Cells ◽  
Energy Demand ◽  
Tumour Progression ◽  
Suppressor Cells ◽  
Tumour Microenvironment ◽  
Metabolic Reprogramming ◽  
Myeloid Derived Suppressor Cells ◽  
Cell Proliferation And Differentiation

Myeloid-derived suppressor cells (MDSCs) constitute a plastic and heterogeneous cell population among immune cells within the tumour microenvironment (TME) that support cancer progression and resistance to therapy. During tumour progression, cancer cells modify their metabolism to sustain an increased energy demand to cope with uncontrolled cell proliferation and differentiation. This metabolic reprogramming of cancer establishes competition for nutrients between tumour cells and leukocytes and most importantly, among tumour-infiltrating immune cells. Thus, MDSCs that have emerged as one of the most decisive immune regulators of TME exhibit an increase in glycolysis and fatty acid metabolism and also an upregulation of enzymes that catabolise essential metabolites. This complex metabolic network is not only crucial for MDSC survival and accumulation in the TME but also for enhancing immunosuppressive functions toward immune effectors. In this review, we discuss recent progress in the field of MDSC-associated metabolic pathways that could facilitate therapeutic targeting of these cells during cancer progression.

scholarly journals Myeloid-Derived Suppressor Cells (MDSCs) in Haematology

2021 ◽  
Vol 11 (1) ◽  
pp. 187
Author(s):  
Nikoleta Bizymi ◽  
Helen A. Papadaki
Keyword(s):  
T Cell ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
T Cell Responses ◽  
Myeloid Derived Suppressor Cells ◽  
Cell Responses ◽  
Immature Myeloid Cells

Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells with immunomodulating properties, mainly acting by suppressing T-cell responses [...]

A Gene-Targeted Mouse Model for Bone Marrow Failure Syndrome.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4235-4235
Author(s):  
Masataka Kasai ◽  
Yuko Fukuda ◽  
Reiko Ishida
Keyword(s):  
Bone Marrow ◽  
Transcription Factors ◽  
Molecular Mechanisms ◽  
Bone Marrow Failure ◽  
Myeloid Cells ◽  
Pcr Analysis ◽  
Mrna Levels ◽  
Control Of Gene Expression ◽  
Wild Mice ◽  
Immature Myeloid Cells

Abstract Bone marrow failure is a disease syndrome characterized by dysfunction of bone marrow to produce mature blood cells. However, molecular mechanisms causing the disease syndromes remain remarkably obscure. We generated mice homozygous for an inactivating mutation of the Translin gene. Most of the aged mutant mice (Translin−/−) were found to exhibit progressive bone marrow dysfunction manifested by a reduction in immature myeloid cells and erythroblasts, and eventually developed marked splenomegaly, with up to 30-fold elevation in weight. Histological examination of enlarged spleens revealed extramedullary hematopoiesis, prominent expansion of the red pulp areas with an increase in the number of mature granulocytes and a marked lack of immature myeloid cells. Furthermore, these mice also featured complete loss of immature myeloid cells and erythroblasts in bone marrow. On the other hand, an increase in the number of reticulocytes (over 10 %) and unusual appearance of metamyelocytes and orthochromatic erythroblasts were seen in peripheral blood. A cascade of the lineage-restricted transcription factors is known to determine developmental decisions regarding hematopoiesis. How levels of transcription factors are translated into a decision to control lineage commitment is an intriguing question in hematopoiesis which remains to be explored. Therefore, we considered the bone marrow failure in aged Translin−/− might be due to decreased expression of the Ets family transcription factor PU.1 that has previously been suggested to be essential for myeloid development. However, quantitative RT-PCR analysis showed PU.1 mRNA to be expressed at equivalent levels in bone marrows of mutant and wild mice. In contrast, our data indicated a sharp reduction of the mRNA levels of the basic helix-loop-helix (bHLH) protein, E2A and its dimerization partner, TAL1, suggesting a contribution of E47/TAL heterodimer having distinctive DNA-binding properties for fine tune control of gene expression during hematopoiesis. In conclusion, the present studies demonstrated that expression levels of Translin are crucial to the bone marrow’s functional ability, and that our findings will shed light on the molecular events involved in bone marrow failure syndromes.

scholarly journals Investigating Radiotherapy Response in a Novel Syngeneic Model of Prostate Cancer

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2804
Author(s):  
Charles M. Haughey ◽  
Debayan Mukherjee ◽  
Rebecca E. Steele ◽  
Amy Popple ◽  
Lara Dura-Perez ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Suppressor Cells ◽  
Tumour Microenvironment ◽  
T Antigen ◽  
Receptor Expression ◽  
Sv40 Large T Antigen ◽  
Substantial Progress ◽  
A Cell ◽  
Syngeneic Model

The prostate cancer (PCa) field lacks clinically relevant, syngeneic mouse models which retain the tumour microenvironment observed in PCa patients. This study establishes a cell line from prostate tumour tissue derived from the Pten−/−/trp53−/− mouse, termed DVL3 which when subcutaneously implanted in immunocompetent C57BL/6 mice, forms tumours with distinct glandular morphology, strong cytokeratin 8 and androgen receptor expression, recapitulating high-risk localised human PCa. Compared to the commonly used TRAMP C1 model, generated with SV40 large T-antigen, DVL3 tumours are immunologically cold, with a lower proportion of CD8+ T-cells, and high proportion of immunosuppressive myeloid derived suppressor cells (MDSCs), thus resembling high-risk PCa. Furthermore, DVL3 tumours are responsive to fractionated RT, a standard treatment for localised and metastatic PCa, compared to the TRAMP C1 model. RNA-sequencing of irradiated DVL3 tumours identified upregulation of type-1 interferon and STING pathways, as well as transcripts associated with MDSCs. Upregulation of STING expression in tumour epithelium and the recruitment of MDSCs following irradiation was confirmed by immunohistochemistry. The DVL3 syngeneic model represents substantial progress in preclinical PCa modelling, displaying pathological, micro-environmental and treatment responses observed in molecular high-risk disease. Our study supports using this model for development and validation of treatments targeting PCa, especially novel immune therapeutic agents.

scholarly journals Immature myeloid cells directly contribute to skin tumor development by recruiting IL-17–producing CD4+ T cells

2015 ◽  
Vol 212 (3) ◽  
pp. 351-367 ◽  
Author(s):  
Myrna L. Ortiz ◽  
Vinit Kumar ◽  
Anna Martner ◽  
Sridevi Mony ◽  
Laxminarasimha Donthireddy ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Tumor Development ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Tumor Formation ◽  
Skin Tumor ◽  
Cellular Mechanisms ◽  
Direct Role ◽  
Immature Myeloid Cells

Evidence links chronic inflammation with cancer, but cellular mechanisms involved in this process remain unclear. We have demonstrated that in humans, inflammatory conditions that predispose to development of skin and colon tumors are associated with accumulation in tissues of CD33+S100A9+ cells, the phenotype typical for myeloid-derived suppressor cells in cancer or immature myeloid cells (IMCs) in tumor-free hosts. To identify the direct role of these cells in tumor development, we used S100A9 transgenic mice to create the conditions for topical accumulation of these cells in the skin in the absence of infection or tissue damage. These mice demonstrated accumulation of granulocytic IMCs in the skin upon topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA), resulting in a dramatic increase in the formation of papillomas during epidermal carcinogenesis. The effect of IMCs on tumorigenesis was not associated with immune suppression, but with CCL4 (chemokine [C-C motif] ligand 4)-mediated recruitment of IL-17–producing CD4+ T cells. This chemokine was released by activated IMCs. Elimination of CD4+ T cells or blockade of CCL4 or IL-17 abrogated the increase in tumor formation caused by myeloid cells. Thus, this study implicates accumulation of IMCs as an initial step in facilitation of tumor formation, followed by the recruitment of CD4+ T cells.

scholarly journals What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 5: Epigenetic Regulation of PD-L1

2021 ◽  
Vol 22 (22) ◽  
pp. 12314
Author(s):  
Andrea Palicelli ◽  
Stefania Croci ◽  
Alessandra Bisagni ◽  
Eleonora Zanetti ◽  
Dario De Biase ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Literature Review ◽  
Cell Lines ◽  
Systematic Literature Review ◽  
Epigenetic Regulation ◽  
Histone Deacetylase Inhibitors ◽  
Cpg Island ◽  
Transcriptional Level ◽  
Mrna Levels ◽  
Histone Modifiers

Epigenetic alterations (including DNA methylation or miRNAs) influence oncogene/oncosuppressor gene expression without changing the DNA sequence. Prostate cancer (PC) displays a complex genetic and epigenetic regulation of cell-growth pathways and tumor progression. We performed a systematic literature review (following PRISMA guidelines) focused on the epigenetic regulation of PD-L1 expression in PC. In PC cell lines, CpG island methylation of the CD274 promoter negatively regulated PD-L1 expression. Histone modifiers also influence the PD-L1 transcription rate: the deletion or silencing of the histone modifiers MLL3/MML1 can positively regulate PD-L1 expression. Epigenetic drugs (EDs) may be promising in reprogramming tumor cells, reversing epigenetic modifications, and cancer immune evasion. EDs promoting a chromatin-inactive transcriptional state (such as bromodomain or p300/CBP inhibitors) downregulated PD-L1, while EDs favoring a chromatin-active state (i.e., histone deacetylase inhibitors) increased PD-L1 expression. miRNAs can regulate PD-L1 at a post-transcriptional level. miR-195/miR-16 were negatively associated with PD-L1 expression and positively correlated to longer biochemical recurrence-free survival; they also enhanced the radiotherapy efficacy in PC cell lines. miR-197 and miR-200a-c positively correlated to PD-L1 mRNA levels and inversely correlated to the methylation of PD-L1 promoter in a large series. miR-570, miR-34a and miR-513 may also be involved in epigenetic regulation.

scholarly journals Systemic surfaceome profiling identifies target antigens for immune-based therapy in subtypes of advanced prostate cancer

2018 ◽  
Vol 115 (19) ◽  
pp. E4473-E4482 ◽  
Author(s):  
John K. Lee ◽  
Nathanael J. Bangayan ◽  
Timothy Chai ◽  
Bryan A. Smith ◽  
Tiffany E. Pariva ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Surface ◽  
Cell Lines ◽  
Treatment Resistance ◽  
Specific Cell ◽  
Surface Markers ◽  
Mrna Levels ◽  
Cell Surface Markers ◽  
Cell Surface Antigens ◽  
Cancer Subtypes

Prostate cancer is a heterogeneous disease composed of divergent molecular and histologic subtypes, including prostate adenocarcinoma (PrAd) and neuroendocrine prostate cancer (NEPC). While PrAd is the major histology in prostate cancer, NEPC can evolve from PrAd as a mechanism of treatment resistance that involves a transition from an epithelial to a neurosecretory cancer phenotype. Cell surface markers are often associated with specific cell lineages and differentiation states in normal development and cancer. Here, we show that PrAd and NEPC can be broadly discriminated by cell-surface profiles based on the analysis of prostate cancer gene expression datasets. To overcome a dependence on predictions of human cell-surface genes and an assumed correlation between mRNA levels and protein expression, we integrated transcriptomic and cell-surface proteomic data generated from a panel of prostate cancer cell lines to nominate cell-surface markers associated with these cancer subtypes. FXYD3 and CEACAM5 were validated as cell-surface antigens enriched in PrAd and NEPC, respectively. Given the lack of effective treatments for NEPC, CEACAM5 appeared to be a promising target for cell-based immunotherapy. As a proof of concept, engineered chimeric antigen receptor T cells targeting CEACAM5 induced antigen-specific cytotoxicity in NEPC cell lines. Our findings demonstrate that the surfaceomes of PrAd and NEPC reflect unique cancer differentiation states and broadly represent vulnerabilities amenable to therapeutic targeting.

APPICATION OF GALECTIN3 , A NOVEL IMMUNOSTAIN, IN PROSTATIC CARCINOMA TO ASSESS ITS PATTERN OF EXPRESSION AND FUTURE POTENTIAL- CONDUCTED AS A TOOL OF MINI RESEARCH PROJECT

2021 ◽  
pp. 33-36
Author(s):  
Sarbashis Hota ◽  
Tushar Kanti Das ◽  
Sneha Sneha ◽  
Anish Kumar Rakshit ◽  
Krishnendu Bikas Bag
Keyword(s):  
Prostate Cancer ◽  
Tumour Progression ◽  
Tertiary Care ◽  
Developed Countries ◽  
Tumour Microenvironment ◽  
Care Hospital ◽  
Grade Group ◽  
Cross Sectional ◽  
Thin Sections ◽  
Positive Expression

Carcinoma of prostate is the commonest type of cancer found in males of developed countries and is responsible for large number of cancer related deaths and signicant morbidity .Gleason’s grade and PSA level play pivotal role in decision making in the management of patients with prostate cancer. By modulating various aspects of tumour progression, Galectin 3 is emerging as a potential guardian of tumour microenvironment and studies indicate that it has important regulatory role in pathogenesis and progression of prostate cancer. An observational cross sectional study was undertaken in the department of pathology of a tertiary care hospital in East India, of 6 months duration. Twenty nine samples diagnosed as acinar adenocarcinoma of prostate were taken by systematic random sampling as per the inclusion-exclusion criteria from the received specimens in the department and immuno-histochemical examination was done on the selected samples using monoclonal antibody against Galectin3 after obtaining thin sections from formalin xed parafn embedded blocks and retrieval of antigen. The data was interpreted by light microscopy using a semi-quantitative method with respect to prexed parameters and statistical analysis was done using SPSS version 25. Based on the prexed cut off, 20.7% of total cases have shown positive expression of galectin3. Mainly the tumours with lower Gleason’s grade have shown positive expression of this marker (62.5% of grade group 1 and 16.6% of grade group 2). None of the cases belonging to grade group 3, 4 or 5 have shown even minimal positivity. Positive expression of galectin3 appeared to decrease with progression of Gleason’s grade and this association was found to be statistically signicant. However, no signicant association has been found between expression of this marker and percentage of the positive cores or the degree of maximum linear positivity.

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