Formation Of Microenvironments Research Articles

Glioma-Stem-Cell-Derived Exosomes Remodeled Glioma-Associated Macrophage via NEAT1/miR-125a/STAT3 Pathway

Glioblastoma (GBM), as the most common primary brain tumor, usually results in an extremely poor prognosis, in which glioma stem cells (GSCs) and their immunosuppressive microenvironment prominently intervene in the resistance to radiotherapy and chemotherapy that directly leads to tumor recurrence and shortened survival time. The specific mechanism through which exosomes generated from GSCs support the creation of an immunosuppressive microenvironment remains unknown, while it is acknowledged to be engaged in intercellular communication and the regulation of the glioma immunosuppressive microenvironment. The elevated expression of LncRNA-NEAT1 was found in glioma cells after radiotherapy, chemotherapy, and DNA damage stimulation, and NEAT1 could promote the malignant biological activities of GSCs. Emerging evidence suggests that lncRNAs may reply to external stimuli or DNA damage by playing a role in modulating different aspects of tumor biology. Our study demonstrated a promotive role of the carried NEAT1 by GSC-derived exosomes in the polarization of M2-like macrophages. Further experiments demonstrated the mediative role of miR-125a and its target gene STAT3 in NEAT1-induced polarization of M2-like macrophages that promote glioma progression. Our findings elucidate the mechanism by which GSCs influence the polarization of M2-like macrophages through exosomes, which may contribute to the formation of immunosuppressive microenvironments. Taken together, our study reveals the miR-125a-STAT3 pathway through which exosomal NEAT1 from treatment-resistant GSCs contributes to M2-like macrophage polarization, indicating the potential of exosomal NEAT1 for treating glioma.

Advancement in Cancer Vasculogenesis Modeling through 3D Bioprinting Technology.

Cancer vasculogenesis is a pivotal focus of cancer research and treatment given its critical role in tumor development, metastasis, and the formation of vasculogenic microenvironments. Traditional approaches to investigating cancer vasculogenesis face significant challenges in accurately modeling intricate microenvironments. Recent advancements in three-dimensional (3D) bioprinting technology present promising solutions to these challenges. This review provides an overview of cancer vasculogenesis and underscores the importance of precise modeling. It juxtaposes traditional techniques with 3D bioprinting technologies, elucidating the advantages of the latter in developing cancer vasculogenesis models. Furthermore, it explores applications in pathological investigations, preclinical medication screening for personalized treatment and cancer diagnostics, and envisages future prospects for 3D bioprinted cancer vasculogenesis models. Despite notable advancements, current 3D bioprinting techniques for cancer vasculogenesis modeling have several limitations. Nonetheless, by overcoming these challenges and with technological advances, 3D bioprinting exhibits immense potential for revolutionizing the understanding of cancer vasculogenesis and augmenting treatment modalities.

Targeting tumor-intrinsic SLC16A3 to enhance anti-PD-1 efficacy via tumor immune microenvironment reprogramming

Immunotherapy, especially immune checkpoint inhibitors, has revolutionized clinical practice within the last decade. However, primary and secondary resistance to immunotherapy is common in patients with diverse types of cancer. It is well-acknowledged that tumor cells can facilitate the formation of immunosuppressive microenvironments via metabolism reprogramming, and lactic acid, the metabolite of glycolysis, is a significant contributor. SLC16A3 (also named as MCT4) is a transporter mediating lactic acid efflux. In this study, we investigated the role of glycolysis in immunotherapy resistance and aimed to improve the immunotherapy effects via Slc16a3 inhibition. Bioinformatical analysis revealed that the expression of glycolysis-related genes correlated with less CD8+ T cell infiltration and increased myeloid-derived suppressor cells (MDSC) enrichment. We found that high glycolytic activity in tumor cells adversely affected the antitumor immune responses and efficacy of immunotherapy and radiotherapy. As the transporter of lactic acid, SLC16A3 is highly expressed in glycolytic B16–F10 (RRID: CVCL_0159) cells, as well as human non-small cell lung carcinoma. We validated that Slc16a3 expression in tumor cells negatively correlated with anti-PD-1 efficiency. Overexpression of Slc16a3 in tumor cells promoted lactic acid production and efflux, and reduced tumor response to anti-PD-1 inhibitors by inhibiting CD8+ T cell function. Genetic and pharmacological inhibition of Slc16a3 dramatically reduced the glycolytic activity and lactic acid production in tumor cells, and ameliorated the immunosuppressive tumor microenvironments (TMEs), leading to boosted antitumor effects via anti-PD-1 blockade. Our study therefore demonstrates that tumor cell-intrinsic SLC16A3 may be a potential target to reverse tumor resistance to immunotherapy.

Modulation of the pre-metastatic bone niche: molecular changes mediated by bone-homing prostate cancer extracellular vesicles.

Prostate cancer (PCa) is a leading male malignancy worldwide, often progressing to bone metastasis, with limited curative options. Extracellular vesicles (EVs) have emerged as key players in cancer communication and metastasis, promoting the formation of supportive microenvironments in distant sites. Our previous studies have highlighted the role of PCa EVs in modulating osteoblasts and facilitating tumor progression. However, the early pre-metastatic changes induced by PCa EVs within the bone microenvironment remain poorly understood. To investigate the early effects of repeated exposure to PCa EVs in vivo, mimicking EVs being shed from the primary tumor, PCa EVs isolated from cell line PC3MLuc2a were fluorescently labelled and repeatedly administered via tail vein injection to adult CD1 NuNu male mice for a period of 4weeks. In vivo imagining, histological analysis and gene expression profiling were performed to assess the impact of PCa EVs on the bone microenvironment. We demonstrate for the first time that PCa EVs home to both bone and lymph nodes following repeated exposures. Furthermore, the accumulation of EVs within the bone leads to distinct molecular changes indicative of disrupted bone homeostasis (e.g., changes to signaling pathways such as Paxillin p = 0.0163, Estrogen Receptor p = 0.0271, RHOA p = 0.0287, Ribonucleotide reductase p = 0.0307 and ERK/MAPK p = 0.0299). Changes in key regulators of these pathways were confirmed in vitro on human osteoblasts. In addition, our data compares the known gene signature of osteocytes and demonstrates a high proportion of overlap (52.2%), suggesting a potential role for this cell type in response to PCa EV exposure. No changes in bone histology or immunohistochemistry were detected, indicating that PCa EV mediated changes were induced at the molecular level. This study provides novel insights into the alterations induced by PCa EVs on the bone microenvironment. The observed molecular changes indicate changes in key pathways and suggest a role for osteocytes in these EV mediated early changes to bone. Further research to understand these early events may aid in the development of targeted interventions to disrupt the metastatic cascade in PCa.

Dissecting tumor microenvironment heterogeneity in syngeneic mouse models: insights on cancer-associated fibroblast phenotypes shaped by infiltrating T cells.

Murine syngeneic tumor models have been used extensively for cancer research for several decades and have been instrumental in driving the discovery and development of cancer immunotherapies. These tumor models are very simplistic cancer models, but recent reports have, however, indicated that the different inoculated cancer cell lines can lead to the formation of unique tumor microenvironments (TMEs). To gain more knowledge from studies based on syngeneic tumor models, it is essential to obtain an in-depth understanding of the cellular and molecular composition of the TME in the different models. Additionally, other parameters that are important for cancer progression, such as collagen content and mechanical tissue stiffness across syngeneic tumor models have not previously been reported. Here, we compare the TME of tumors derived from six common syngeneic tumor models. Using flow cytometry and transcriptomic analyses, we show that strikingly unique TMEs are formed by the different cancer cell lines. The differences are reflected as changes in abundance and phenotype of myeloid, lymphoid, and stromal cells in the tumors. Gene expression analyses support the different cellular composition of the TMEs and indicate that distinct immunosuppressive mechanisms are employed depending on the tumor model. Cancer-associated fibroblasts (CAFs) also acquire very different phenotypes across the tumor models. These differences include differential expression of genes encoding extracellular matrix (ECM) proteins, matrix metalloproteinases (MMPs), and immunosuppressive factors. The gene expression profiles suggest that CAFs can contribute to the formation of an immunosuppressive TME, and flow cytometry analyses show increased PD-L1 expression by CAFs in the immunogenic tumor models, MC38 and CT26. Comparison with CAF subsets identified in other studies shows that CAFs are skewed towards specific subsets depending on the model. In athymic mice lacking tumor-infiltrating cytotoxic T cells, CAFs express lower levels of PD-L1 and lower levels of fibroblast activation markers. Our data underscores that CAFs can be involved in the formation of an immunosuppressive TME.

The dominant genera of nitrogenase (nifH) affects soil biological nitrogen fixation along an elevational gradient in the Hengduan mountains

Biological nitrogen (N) fixation by diazotrophic microbes is an essential process for the N input. However, the patterns of biological N fixation and its biological or environmental mechanism along an elevational gradient in mountain ecosystems are not fully understood. In this study, a field experiment was conducted in the Hengduan Mountains to investigate the biological N fixation associated with the diversity and abundance of the nifH gene. Our results showed that both the abundance of the nifH gene and the biological N fixation displayed hump-shaped trends along an elevation gradient in the wet and dry seasons. However, the diversity of the nifH gene showed an inverse unimodal trend along an elevation gradient. We observed that biological N fixation was jointly associated with the abundance of the nifH gene, especially dominant genera, as well as soil chartacteristics. Among them, clay content played a preeminent role in the regulation of N fixation potentially through the formation of microaggregates and microenvironments. In general, our results revealed that biological N fixation was correlated with the abundance of microorganisms, especially dominant genera, and soil texture. These results highlighted the importance of dominant genera, which should be considered in the modeling and forecasting of N cycling under future environmental change.

Switching between C2+ Products and CH4 in CO2 Electrolysis by Tuning the Composition and Structure of Rare-Earth/Copper Catalysts.

Rational regulation of the reaction pathway to produce the desired products is one of the most significant challenges in the electrochemical CO2 reduction reaction (CO2RR). Herein, we designed a series of rare-earth Cu catalysts with mixed phases. It was found that the products could be switched from C2+ to CH4 by tuning the composition and structure of the catalysts. Particularly at the Cu/Sm atomic ratio of 9/1 (Cu9Sm1-Ox), the Faradaic efficiency (FE) for C2+ products (FEC2+) could reach 81% at 700 mA cm-2 with negligible CH4. However, the FE of CH4 (FECH4) was 65% at 500 mA cm-2 over Cu1Sm9-Ox (Cu/Sm = 1/9), and the FEC2+ was extremely low. Experiments and theoretical studies indicated that the stable CuSm2O4 phase existed in all the catalysts within the Cu/Sm range of 9/1 to 1/9. At a high Cu content, the catalyst was composed of CuSm2O4 and Cu phases. The small amount of Sm could enhance the binding strength of *CO and facilitate C-C coupling. Conversely, at a high Sm content, the catalyst was composed of CuSm2O4 and Sm2O3 phases. Sm could effectively stabilize bivalent Cu and enrich proton donors, lowering the reaction energy of *CO for deep hydrogenation to generate CH4. In both pathways, the stable CuSm2O4 phase could cooperate with the Cu or Sm2O3 phases, which induced the formation of different microenvironments to generate different products. This strategy also had commonality with other Cu-rare-earth (La, Pr, and Eu) catalysts to boost the CO2RR for C2+ or CH4 production.

Single-cell RNA sequencing deciphers transcriptional profiles of hepatocytes in mouse with hepatic alveolar echinococcosis

To investigate the cell composition and the transcriptional characteristics in microenvironments of hepatic tissues in mice at late stage of Echinococcus multilocularis infection at a single-cell level. Peri-lesion and paired distal hepatic specimens were collected from two BALB/c mice (6 to 8 weeks old) infected with E. multilocularis for single-cell RNA sequencing. The Seurat package in the R software was employed for quality control of data, multi-sample integration and correction of batch effects, and uniform manifold approximation and projection (UMAP) algorithm was used for cell clustering. Cell types were annotated using classical marker genes. Differentially expressed genes were screened in each cell type through differential gene expression analysis, and the biological roles of cells were predicted using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. A total of 43 710 cells from peri-lesion and distal hepatic tissues of E. multilocularis-infected mice were analyzed, and were classified into 11 cell types, including neutrophils, T cells, macrophages, granulocyte-monocyte progenitor cells, B cells, plasma cells, basophils, hepatic stellate cells, endothelial cells, hepatocytes, and platelets. T cells were the largest population of immune cells in the microenvironment of hepatic tissues, including five CD4+ T cell subsets, two CD8+ T cell subsets and phosphoantigen-reactive γδT cells. The proportions of CD4+ helper T cells and cytotoxic CD4+ T cells decreased and the proportion of T helper 2 (Th2) cells increased in peri-lesion tissues relative to distal hepatic tissues. In addition, the differentially expressed genes in Th2 cells were associated with negative regulation of the immune system, and the highly expressed genes in cytotoxic CD4+ T cells correlated with activation of the immune system. Single-cell RNA sequencing deciphers the cell composition and distribution in microenvironments of hepatic tissues from mice infected with E. multilocularis, and the increased proportion of Th2 cells in peri-lesion hepatic tissues may be associated with formation of immunosuppressive microenvironments.

An Enzyme-Loaded Metal-Organic Framework-Assisted Microfluidic Platform Enables Single-Cell Metabolite Analysis.

Colonization of cancer cells at secondary sites, a decisive step in tumor metastasis, is strongly dependent on the formation of metastatic microenvironments regulated by intrinsic single-cell metabolism traits. Herein, we report a single-cell microfluidic platform for high-throughput dynamic monitoring of tumor cell metabolites to evaluate tumor malignancy. This microfluidic device empowers efficient isolation of single cells (>99 %) in a squashed state similar to tumor extravasation, and employs enzyme-packaged metal-organic frameworks to catalyze tumor cell metabolites for visualization. The microfluidic evaluation was confirmed by in vivo assays, suggesting that the platform allowed predicting the tumorigenicity of captured tumor cells and screening metabolic inhibitors as anti-metastatic drugs. Furthermore, the platform efficiently detected various aggressive cancer cells in unprocessed whole blood samples with high sensitivity, showing potential for clinical application.

An Enzyme‐Loaded Metal–Organic Framework‐Assisted Microfluidic Platform Enables Single‐Cell Metabolite Analysis

AbstractColonization of cancer cells at secondary sites, a decisive step in tumor metastasis, is strongly dependent on the formation of metastatic microenvironments regulated by intrinsic single‐cell metabolism traits. Herein, we report a single‐cell microfluidic platform for high‐throughput dynamic monitoring of tumor cell metabolites to evaluate tumor malignancy. This microfluidic device empowers efficient isolation of single cells (>99 %) in a squashed state similar to tumor extravasation, and employs enzyme‐packaged metal–organic frameworks to catalyze tumor cell metabolites for visualization. The microfluidic evaluation was confirmed by in vivo assays, suggesting that the platform allowed predicting the tumorigenicity of captured tumor cells and screening metabolic inhibitors as anti‐metastatic drugs. Furthermore, the platform efficiently detected various aggressive cancer cells in unprocessed whole blood samples with high sensitivity, showing potential for clinical application.

Abstract 75: Impaired metastatic seeding underlies concomitant tumor resistance

Abstract Cancer metastasis, the spread of cancer cells from the primary tumor to distant organs, is responsible for poor overall survival of cancer patients even with advances in the development of targeted therapeutics. One of the reasons behind failure of current treatments is the continuous evolution of tumor cells and of their microenvironment at both the primary and distant sites, which leads to drug resistance. Primary tumor-derived signals such as secreted chemokines, cytokines, and growth factors can alter the host microenvironment at the metastatic site, leading to the recruitment of immune cells and to the formation of pre-metastatic microenvironments which promote metastasis. However, in some cases, primary tumor-derived signals have also been shown to have metastasis-suppressive effects, a phenomenon known as concomitant resistance. For example, unexpected increase in metastatic outgrowth upon surgical resection of a primary tumor has been reported for some breast cancer patients. Loss of concomitant resistance is a barrier to surgical intervention of primary tumor. This is currently being managed by chemotherapy and further identification of actionable mechanisms behind this phenomenon is necessary. The molecular mechanisms leading to concomitant resistance are poorly understood, and it remains poorly defined how this phenomenon evolves over time, during tumor progression. To investigate the effect of tumor progression on metastasis efficiency, non-tumor bearing (naïve) and tumor bearing mice were challenged with tail-vein injection of tumor cells and lung metastases were quantified. Our data indicate that primary tumors inhibit overt lung metastasis by impairing the ability of circulating tumor cells to seed in the lungs. Through time course studies, we found that early-stage (day 7 and 14) tumors impede early metastatic seeding, but later-stage tumors (day 28 and 35) do not. While adaptive immunity, involving T cells, can inhibit metastasis, results from depletion experiments suggest that the observed effect is T and B cell independent. Platelets can bind circulating tumor cells and recruit neutrophils at metastatic sites to facilitate seeding. We discovered that platelet activation and neutrophil recruitment to platelet-tumor cell clusters are impaired in tumor-bearing mice, suggesting that defects in these immune cell-tumor cell interactions might cause concomitant tumor resistance. Overall, our study uncovered that inefficient metastatic seeding mediates concomitant tumor resistance. Current and future work is directed towards identifying precise mechanisms by which platelets and neutrophils mediate concomitant tumor resistance, so that novel strategies could be developed to prevent metastasis. Citation Format: Akshita B. Bhatt, Manon Baures, Cecile Garcin, Myriam Labelle. Impaired metastatic seeding underlies concomitant tumor resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 75.

Abstract ED9-2: The contribution of the tumor microenvironment to cancer dormancy

Abstract In this seminar I will discuss how breast cancer DTCs modify the metastatic microenvironment to favor seeding and dormancy. In order to extravasate efficiently and form metastasis, cancer cells have to become migratory and coordinate both invasive and proliferative programs at distant organs. High-resolution lattice light-sheet with adaptive optics imaging in living cells revealed that DTCs extravasate from the blood vessels by forming actin-rich invadopodium protrusions. We have identified a population of breast cancer DTCs with pro-invasive and pro-dormancy capacities. These cells downregulate srGAP1, a GTPase regulator, favoring dissemination and dormancy at metastatic organs. Our findings describe a novel mechanism mediating the shift from a proliferative to an invasive/dormant phenotype in breast cancer cells in vivo. srGAP1 is a new regulator of dormancy that regulates the formation of dormancy-permissive microenvironments through increased secretion of TGFb2 and SMAD2 activation. Citation Format: Jose Javier Bravo-Cordero. The contribution of the tumor microenvironment to cancer dormancy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr ED9-2.

Maximizing biological discovery through global computational analyses of unbiased apex biotinylation data on chemokine receptors.

Chemokine receptors CCR2 and CCR5 shape inflammatory responses by driving monocyte recruitment to sites of injury. Unfortunately, through the same mechanism they contribute to the formation of onco-protective tumor microenvironments in cancer and tissue fibrosis in chronic inflammatory conditions. These associations motivated targeting CCR2 and CCR5 in nonalcoholic fatty liver disease and pancreatic cancer, among others.

Morphology and Size of Bacterial Colonies Control Anoxic Microenvironment Formation in Porous Media.

Bacterial metabolisms using electron acceptors other than oxygen (e.g., methanogenesis and fermentation) largely contribute to element cycling and natural contaminant attenuation/mobilization, even in well-oxygenated porous environments, such as shallow aquifers. This paradox is commonly explained by the occurrence of small-scale anoxic microenvironments generated by the coupling of bacterial respiration and dissolved oxygen (O2) transport by pore water. Such microenvironments allow facultative anaerobic bacteria to proliferate in oxic environments. Microenvironment dynamics are still poorly understood due to the challenge of directly observing biomass and O2 distributions at the microscale within an opaque sediment matrix. To overcome these limitations, we integrated a microfluidic device with transparent O2 planar optical sensors to measure the temporal behavior of dissolved O2 concentrations and biomass distributions with time-lapse videomicroscopy. Our results reveal that bacterial colony morphology, which is highly variable in flowing porous systems, controls the formation of anoxic microenvironments. We rationalize our observations through a colony-scale Damköhler number comparing dissolved O2 diffusion and a bacterial O2 uptake rate. Our Damköhler number enables us to predict the pore space fraction occupied by anoxic microenvironments in our system for a given bacterial organization.

Site-Specific Regulation of Sulfatase and Aromatase Pathways for Estrogen Production in Endometriosis.

Endometriosis is a highly prevalent gynecological disease characterized by lesions in different sites. Regulation of specific estrogen pathways may favor the formation of distinct microenvironments and the progression of endometriosis. However, no study has simultaneously evaluated the gene and protein regulation of the main estrogen-synthesizing enzymes in endometriosis. Thus, our goals were to study the relationship between gene and protein expression of aromatase (CYP19A1 or ARO), steroid sulfatase (STS), and hydroxysteroid 17-beta dehydrogenase (HSD17B1) in superficial (SUP), ovarian (OMA), and deep infiltrating (DIE) endometriotic lesion sites as well as in the eutopic endometrium of patients with (EE) and without (control) endometriosis in the same and large cohort of patients. The site-specific expression of these enzymes within different cells (glandular and stromal components) was also explored. The study included 108 patients surgically diagnosed with endometriosis who provided biopsies of EE and endometriotic lesions and 16 disease-free patients who collected normal endometrium tissue. Our results showed that CYP19A1 was detected in all endometriosis tissues and was in higher levels than in control. Unique patterns of the STS and HSD17B1 levels showed that they were most closely regulated in all tissues, with manifestation at greater levels in DIE compared to the other endometriotic lesion sites, OMA and SUP. Gene and protein expression of ARO, STS, and HSD17B1 occurred at different rates in endometriotic sites or EE. The distinctive levels of these estrogen-synthesizing enzymes in each endometriotic site support the hypothesis of a tissue microenvironment that can both influence and be influenced by the expression of different estrogenic pathways, locally affecting the availability of estrogen needed for maintenance and progression of endometriotic lesions.

Environmental inferences based on benthic foraminifera in surface sediments from the Beagle Channel (Argentina): A multiproxy approach

Micropaleontological analysis was performed on 22 samples of recent marine sediments from the Beagle Channel (Tierra del Fuego, Argentina) between 10 and 100 m of depth. The most important foraminifera found in the channel were Cibicidoides dispars (d'Orbigny), Buccella peruviana (d'Orbigny), Cibicides aknerianus (d'Orbigny), Cibicides fletcheri Galloway and Wissler, and Neoeponides bradyi (Le Calvez), which inhabit in clayey–sandy marine sediments. The observed variations in diversity and abundance revealed shallow marine conditions, low-energy, and low to moderate salinity, in the west sector and a deeper environment with normal marine conditions, high-energy, highly‑oxygenated and cold seawater in the east sector of the channel. The study area is a complex scenario with numerous landforms that lead to the formation of micro-environments in which patchy distribution of foraminifera was recognized. This study based on foraminifera and the sedimentological analysis supports the previous palynological information from the channel, which also shows an increase in number and diversity of dinocyst species reflecting the eastward changes of the marine environmental conditions due to the influence of the Atlantic.

Sustained AWT1 expression by Dupuytren's disease myofibroblasts promotes a proinflammatory milieu.

Palmar fibromatosis, also known as Dupuytren's disease (DD), is a common and heritable fibrosis of the hand. It is characterized by the formation of myofibroblastic nodules that can progress to palmar-digital contractures and permanent loss of dexterity. The presence of inflammatory cell infiltrate within these nodules has been interpreted to suggest a pathogenesis mediated by a proinflammatory microenvironment. However, the molecular mechanisms driving the formation of pro-fibrotic microenvironments in this and other fibroses remain unclear. To gain insights into this process, we have assessed the contributions of an alternatively spliced, multi-functional transcription factor, Wilms Tumor 1 (WT1), previously shown to be upregulated in primary myofibroblasts derived from DD tissues. Proinflammatory cytokine stimuli of DD myofibroblasts enhanced the expression of several distinct WT1 variants, the most sustained being a 5' truncated version of WT1, alternative WT1 (AWT1). Constitutive adenoviral expression of AWT1 in myofibroblasts derived from phenotypically non-fibrotic palmar fascia significantly induced the expression and secretion of proinflammatory cytokines, including some with potential as novel therapeutic targets. In summary, these data implicate roles for sustained AWT1 expression in DD as a transcriptional driver of a proinflammatory fascial milieu.

Chemokines in Type 1 Diabetes Mellitus.

BackgroundPrevious studies suggested that chemokines may play an important role in the formation and mediation of immune microenvironments of patients affected by Type 1 Diabetes Mellitus (T1DM). The aim of this study was to summarise available evidence on the associations of different chemokines with T1DM.MethodsFollowing PRISMA guidelines, we systematically searched in PubMed, Web of Science, Embase and Cochrane Library databases for studies on the associations of different chemokines with T1DM. The effect size of the associations were the standardized mean differences (SMDs) with corresponding 95% confidence intervals (CIs) of the chemokines concentrations, calculated as group differences between the T1DM patients and the controls. These were summarized using network meta-analysis, which was also used to rank the chemokines by surface under cumulative ranking curve (SUCRA) probabilities.ResultsA total of 32 original studies on the association of different chemokines with T1DM were identified. Fifteen different chemokine nodes were compared between 15,683 T1DM patients and 15,128 controls, and 6 different chemokine receptor nodes were compared between 463 T1DM patients and 460 controls. Circulating samples (blood, serum, and plasma) showed that concentrations of CCL5 and CXCL1 were significantly higher in the T1DM patients than in the controls (SMD of 3.13 and 1.50, respectively). On the other hand, no significant difference in chemokine receptors between T1DM and controls was observed. SUCRA probabilities showed that circulating CCL5 had the highest rank in T1DM among all the chemokines investigated.ConclusionThe results suggest that circulating CCL5 and CXCL1 may be promising novel biomarkers of T1DM. Future research should attempt to replicate these findings in longitudinal studies and explore potential mechanisms underlying this association.

The Role of Exosomes in Cancer Progression.

Early detection, characterization and monitoring of cancer are possible by using extracellular vesicles (EVs) isolated from non-invasively obtained liquid biopsy samples. They play a role in intercellular communication contributing to cell growth, differentiation and survival, thereby affecting the formation of tumor microenvironments and causing metastases. EVs were discovered more than seventy years ago. They have been tested recently as tools of drug delivery to treat cancer. Here we give a brief review on extracellular vesicles, exosomes, microvesicles and apoptotic bodies. Exosomes play an important role by carrying extracellular nucleic acids (DNA, RNA) in cell-to-cell communication causing tumor and metastasis development. We discuss the role of extracellular vesicles in the pathogenesis of cancer and their practical application in the early diagnosis, follow up, and next-generation treatment of cancer patients.

How Microgels Can Improve the Impact of Organ-on-Chip and Microfluidic Devices for 3D Culture: Compartmentalization, Single Cell Encapsulation and Control on Cell Fate.

The Organ-on-chip (OOC) devices represent the new frontier in biomedical research to produce micro-organoids and tissues for drug testing and regenerative medicine. The development of such miniaturized models requires the 3D culture of multiple cell types in a highly controlled microenvironment, opening new challenges in reproducing the extracellular matrix (ECM) experienced by cells in vivo. In this regard, cell-laden microgels (CLMs) represent a promising tool for 3D cell culturing and on-chip generation of micro-organs. The engineering of hydrogel matrix with properly balanced biochemical and biophysical cues enables the formation of tunable 3D cellular microenvironments and long-term in vitro cultures. This focused review provides an overview of the most recent applications of CLMs in microfluidic devices for organoids formation, highlighting microgels’ roles in OOC development as well as insights into future research.