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Tumor immunity represents a new avenue for cancer therapy. Immune checkpoint inhibitors have successfully improved outcomes in several tumor types. In addition, currently, immune cell-based therapy is also attracting significant attention. However, the clinical efficacy of these treatments requires further improvement. The mechanisms through which cancer cells escape the immune response must be identified and clarified. Cancer stem cells (CSCs) play a central role in multiple aspects of malignant tumors. CSCs can initiate tumors in partially immunocompromised mice, whereas non-CSCs fail to form tumors, suggesting that tumor initiation is a definitive function of CSCs. However, the fact that non-CSCs also initiate tumors in more highly immunocompromised mice suggests that the immune evasion property may be a more fundamental feature of CSCs rather than a tumor-initiating property. In this review, we summarize studies that have elucidated how CSCs evade tumor immunity and create an immunosuppressive milieu with a focus on CSC-specific characteristics and functions. These profound mechanisms provide important clues for the development of novel tumor immunotherapies., Highlights • Cancer stem cells (CSCs) play a central role in multiple aspects of malignant tumors. • Immune evasion is a fundamental feature of CSCs. • Immune evasion mechanisms must be precisely clarified to improve tumor immunotherapy. • CSCs are promising targets for tumor immunotherapy.

Background Abnormal construction of the extracellular matrix (ECM) is intimately linked with carcinogenesis and the development of solid tumours, especially hepatocellular carcinoma (HCC). As the major component of the ECM, collagen plays a pivotal role in carcinogenesis. P4HA2, the essential enzyme during collagen formation, becomes an important target in HCC treatment. Here, we tried to decipher whether aspirin (ASA), a classic anti-inflammatory drug, could improve the prognosis of HCC through targeting P4HA2. Methods Western blotting, qRT-PCR assay, immunofluorescence staining, luciferase reporter gene assay, and ChIP assay were applied to demonstrate the molecular mechanism of the regulation of P4HA2 expression by aspirin. A mouse xenograft model, cell viability assay, colony formation assay, and immunohistochemistry analysis were used to evaluate the anti-fibrosis effect of aspirin through targeting the NF-κB/P4HA2 axis and LMCD1-AS1/let-7g/P4HA2 axis in vitro and in vivo. The TCGA database was used to evaluate the correlation among P4HA2, let-7g, LMCD1-AS1 and overall survival of HCC patients. Findings In xenograft mice, aspirin was capable of targeting P4HA2 to decrease collagen deposition, resulting in the inhibition of liver tumour growth. TCGA database analysis revealed the close association between a higher P4HA2 concentration in HCC patients and shorter overall survival or a higher cancer stage and the pathological grade. Mechanistically, NF-κB can bind to the promoter of P4HA2 to activate its transcription. Moreover, lncRNA LMCD1-AS1 functions as a molecular sponge of let-7g to post-transcriptionally induce the target gene of let-7g, namely, P4HA2. Interpretation Our findings disclose the novel role and regulatory mechanism of aspirin in the suppression of HCC by disrupting abnormal collagen deposition. Funds 973 Program, National Natural Scientific Foundation of China, Fundamental Research Funds for the Central Universities, Project of Prevention and Control of Key Chronic Non-Infectious Diseases.

Visual Abstract, Highlights • Stat3, a major signaling molecule for proinflammatory cytokines including IL-6, was activated both in inflammatory cells and in SMC in the aortic walls of human AD and mouse AD model. • SMC-specific deletion of Socs3 enhanced Stat3 activation in SMC, induced moderate proinflammatory response in the aortic walls, and ameliorated AD in mice. • SmSocs3-KO aortas showed increases in fibroblasts, adventitial collagen fibers, and tensile strength of the aortic walls. • IL-6-stimulated SMC in culture secreted humoral factor(s) that promoted proliferative response of fibroblasts., Summary Aortic dissection (AD) is the acute destruction of aortic wall and is reportedly induced by inflammatory response. Here we investigated the role of smooth muscle Socs3 (a negative regulator of Janus kinases/signal transducer and activator of transcription signaling) in AD pathogenesis using a mouse model generated via β-aminopropionitrile and angiotensin II infusion. Socs3 deletion specifically in smooth muscle cells yielded a chronic inflammatory response of the aortic wall, which was associated with increased fibroblasts, reinforced aortic tensile strength, and less-severe tissue destruction. Although an acute inflammatory response is detrimental in AD, smooth muscle-regulated inflammatory response seemed protective against AD.

Pancreatic ductal adenocarcinoma (PDAC) shows remarkable propensity to metastasize. This predilection to escape from the primary tumor is driven by paracrine and autocrine mechanisms that guide cancer cells through a multi-step process concluding with colonization in distant tissues. Although cell-intrinsic features support the metastatic ability of cancer cells, permissive microenvironments within the primary organ and at sites of distant metastasis may be rate-limiting. Identification of cancer cell-extrinsic factors that regulate formation of these environments lend new therapeutic targets for intervening on the metastatic cascade. In addition, the bipolar, yet fundamental, role of the immune system in the metastatic process presents therapeutic opportunities. Herein, we review the current knowledge of the metastatic cascade in PDAC, and propose that genomically stable determinants of metastasis (e.g. the pro-metastatic niche and immune system) are actionable targets for preventing, containing, and treating metastasis in PDAC. Keywords: Inflammation, Cancer, Pancreatic ductal adenocarcinoma, Immunotherapy, Immune evasion, Treatment paradigms, T cells, Macrophages, Neutrophils, Tumor microenvironment, Immunosurveillance, Vaccines, Therapeutic resistance, Metastasis, Clinical trials

The composition and the stiffness of cardiac microenvironment change during development and/or in heart disease. Cardiomyocytes (CMs) and their progenitors sense these changes, which decides over the cell fate and can trigger CM (progenitor) proliferation, differentiation, de-differentiation or death. The field of mechanobiology has seen a constant increase in output that also includes a wealth of new studies specific to cardiac or cardiomyocyte mechanosensing. As a result, mechanosensing and transduction in the heart is increasingly being recognised as a main driver of regulating the heart formation and function. Recent work has for instance focused on measuring the molecular, physical and mechanical changes of the cellular environment - as well as intracellular contributors to the passive stiffness of the heart. On the other hand, a variety of new studies shed light into the molecular machinery that allow the cardiomyocytes to sense these properties. Here we want to discuss the recent work on this topic, but also specifically focus on how the different components are regulated at various stages during development, in health or disease in order to highlight changes that might contribute to disease progression and heart failure., Highlights • The stiffness of the heart changes during development or in disease. • These changes influence cardiomyocyte behaviour and function. • Various intra- and extracellular elements contribute to the stiffness. • The molecules and pathways that are sensing the stiffness are changing as well.

The cornea relies on its organised extracellular matrix for maintaining transparency and biomechanical strength. Studies have identified an elastic fibre system within the human posterior cornea, thought to allow for slight deformations in response to internal pressure fluctuations within the eye. However, the type of elastic fibres that exist within the cornea and their roles remain elusive. The aim of this study was to compare the distribution and organisation of the elastic fibres within the posterior peripheral mouse and human cornea, and elucidate how these fibres integrate with the trabecular meshwork, whilst characterising the distribution of their main likely components (fibrillin-1, elastin and type VI collagen) in different parts of the cornea and adjacent sclera. We identified key differences in the elastic fibre system between the human and mouse cornea. True elastic fibres (containing elastin) were identified within the human posterior peripheral cornea. Elastic fibres appeared to present as an extensive network throughout the mouse corneal stroma, but as fibrillin-rich microfibril bundles rather than true elastic fibres. However, tropoelastin staining indicated the possibility that true elastic fibres had yet to develop in the young mice studied. Differences were also apparent within the anatomy of the trabecular meshwork. The human trabecular meshwork appeared to insert between the corneal stroma and Descemet's membrane, with elastic fibres continuing into the stroma from the trabecular meshwork anterior to Descemet's membrane. Within the mouse cornea, no clear insertion point of the trabecular meshwork was seen, instead the elastic fibres within the trabecular meshwork continued into Descemet's membrane, with the trabecular meshwork joining posterior to Descemet's membrane., Highlights • True Elastic fibres (containing elastin) occur within the human posterior peripheral cornea. • A fibrillin-rich microfibril system was found throughout the mouse corneal stroma, with no apparent true elastic fibres. • Human trabecular meshwork inserts between the posterior corneal stroma and Descemet's membrane. • A continuity of elastic fibres was identified between cornea and trabecular meshwork in both species.

The role of tumor microenvironment in cancer progression is gaining significant attention. It is realized that cancer cells and the corresponding stroma co-evolve with time. Cancer cells recruit and transform the stromal cells, which in turn remodel the extra cellular matrix of the stroma. This complex interaction between the stroma and the cancer cells results in a dynamic feed-forward/feed-back loop with biochemical and biophysical cues that assist metastatic transition of the cancer cells. Although biochemistry has long been studied for the understanding of cancer progression, biophysical signaling is emerging as a critical paradigm determining cancer metastasis. In this mini review, we discuss the role of one of the biophysical cues, mostly the mechanical stiffness of tumor microenvironment, in cancer progression and its clinical implications., Graphical abstract Unlabelled Image

Hypoxia inducible factors (HIFs) are transcription factors that mediate the response of cells to hypoxia. HIFs have wide-ranging effects on metabolism, the tumor microenvironment (TME) and the extracellular matrix (ECM). Here we investigated the silencing effects of two of the three known isoforms, HIF-1α and HIF-2α, on collagen 1 (Col1) fibers, which form a major component of the ECM of tumors. Using a loss-of-function approach for HIF-1α or 2α or both HIF-1α and 2α, we identified a relationship between HIFs and Col1 fibers in MDA-MB-231 tumors. Tumors derived from MDA-MB-231 cells with HIF-1α or 2α or both HIF-1α and 2α silenced contained higher percent fiber volume and lower inter-fiber distance compared to tumors derived from empty vector MDA-MB-231 cells. Depending upon the type of silencing, we observed changes in Col1 degrading enzymes, and enzymes involved in Col1 synthesis and deposition. Additionally, a reduction in lysyl oxidase protein expression in HIF-down-regulated tumors suggests that more non-cross-linked fibers were present. Collectively these results identify the role of HIFs in modifying the ECM and the TME and provide new insights into the effects of hypoxia on the tumor ECM.

Reactive oxygen and nitrogen species (ROS/RNS) play an important role in the regulation of cardiac function. Increase in ROS/RNS concentration results in lipid and protein oxidation and is often associated with onset and/or progression of many cardiovascular disorders. However, interplay between lipid and protein modifications has not been simultaneously studied in detail so far. Biomolecule carbonylation is one of the most common biomarkers of oxidative stress. Using a dynamic model of nitroxidative stress we demonstrated rapid changes in biomolecule carbonylation in rat cardiomyocytes. Levels of carbonylated species increased as early as 15 min upon treatment with the peroxynitrite donor, 3-morpholinosydnonimine (SIN-1), and decreased to values close to control after 16 h. Total (lipids+proteins) vs. protein-specific carbonylation showed different dynamics, with a significant increase in protein-bound carbonyls at later time points. Treatment with SIN-1 in combination with inhibitors of proteasomal and autophagy/lysosomal degradation pathways allowed confirmation of a significant role of the proteasome in the degradation of carbonylated proteins, whereas lipid carbonylation increased in the presence of autophagy/lysosomal inhibitors. Electrophilic aldehydes and ketones formed by lipid peroxidation were identified and relatively quantified using LC-MS/MS. Molecular identity of reactive species was used for data-driven analysis of their protein targets. Combination of different enrichment strategies with LC-MS/MS analysis allowed identification of more than 167 unique proteins with 332 sites modified by electrophilic lipid peroxidation products. Gene ontology analysis of modified proteins demonstrated enrichment of several functional categories including proteins involved in cytoskeleton, extracellular matrix, ion channels and their regulation. Using calcium mobilization assays, the effect of nitroxidative stress on the activity of several ion channels was further confirmed., Graphical abstract fx1, Highlights • Different dynamics for lipid and protein carbonylation upon nitroxidative stress. • Shift of carbonyls from lipids to proteins within first 30 min. • Neutral and oxidized lipids increased in the presence of lysosomal inhibitors. • Electrophilic lipids identified and relatively quantified by LC-MS/MS. • Cytoskeleton, ECM and ion channel proteins are the main modification targets.

Objective Elastogenesis within the medial layer of the aortic wall involves a cascade of events orchestrated primarily by smooth muscle cells, including transcription of elastin and a cadre of elastin chaperone matricellular proteins, deposition and cross-linking of tropoelastin coacervates, and maturation of extracellular matrix fiber structures to form mechanically competent vascular tissue. Elastic fiber disruption is associated with aortic aneurysm; in aneurysmal disease a thin and weakened wall leads to a high risk of rupture if left untreated, and non-surgical treatments for small aortic aneurysms are currently limited. This study analyzed the effect of adipose-derived stromal cell secreted factors on each step of the smooth muscle cell elastogenesis cascade within a three-dimensional fibrin gel culture platform. Approach and results We demonstrate that adipose-derived stromal cell secreted factors induce an increase in smooth muscle cell transcription of tropoelastin, fibrillin-1, and chaperone proteins fibulin-5, lysyl oxidase, and lysyl oxidase-like 1, formation of extracellular elastic fibers, insoluble elastin and collagen protein fractions in dynamically-active 30-day constructs, and a mechanically competent matrix after 30 days in culture. Conclusion Our results reveal a potential avenue for an elastin-targeted small aortic aneurysm therapeutic, acting as a supplement to the currently employed passive monitoring strategy. Additionally, the elastogenesis analysis workflow explored here could guide future mechanistic studies of elastin formation, which in turn could lead to new non-surgical treatment strategies., Highlights • Stromal cells stimulate smooth muscle cells (SMC) using paracrine signals. • Stimulated SMC make RNA for both elastin and associated proteins. • After protein synthesis, new elastic fibers form that contain insoluble elastin. • Stromal cell products could promote elastin production in vivo.

The Rid protein family (PF14588, IPR006175) is divided into nine subfamilies, of which only the RidA subfamily has been characterized biochemically. RutC, the founding member of one subfamily, is encoded in the pyrimidine utilization (rut) operon that encodes a pathway that allows Escherichia coli to use uracil as a sole nitrogen source. Results reported herein demonstrate that RutC has 3-aminoacrylate deaminase activity and facilitates one of the reactions previously presumed to occur spontaneously in vivo. RutC was active with several enamine–imine substrates, showing similarities and differences in substrate specificity with the canonical member of the Rid superfamily, Salmonella enterica RidA. Under standard laboratory conditions, a Rut pathway lacking RutC generates sufficient nitrogen from uracil for growth of E. coli. These results support a revised model of the Rut pathway and provide evidence that Rid proteins may modulate metabolic fitness, rather than catalyzing essential functions.

Intracranial aneurysm (IA) accounts for 85% of Subarachnoid Hemorrhage (SAH) and is mainly caused due to the weakening of arterial wall. The structural integrity of the intracranial arteries is mainly influenced by the extracellular matrix (ECM) remodeling. The Proteoglycan Versican plays an important role in extracellular matrix assembly and plays a major role in the pathogenesis of IA. The linkage studies also indicated VCAN as a putative candidate gene for IA in the 5q22–31 region. Using a case–control study design, we tested the hypothesis whether the variants in VCAN gene, nonsynonymous variants in the coding region of Glycosaminoglycan α (GAG-α) and GAG-β and two reported SNPs involved in splicing rs251124 and rs173686 can increase the risk of aSAH among South Indian patients, either independently, or by interacting with other risk factors of the disease. We selected 200 radiologically confirmed aneurysmal cases and 250 ethnically, age and sex matched controls from the Dravidian Malayalam speaking population of South India. The present study reiterated the earlier association of rs251124 with intracranial aneurysm (P = 0.0002) and also found a novel association with rs2287926 (G428D) in exon 7 coding for GAG-α with intracranial aneurysm (P = 0.0015). Interestingly, both these SNPs contributed to higher risk for aneurysm in males. In-silico analysis predicted this SNP to have the highest functional relevance in the gene which might have a potentially altered regulatory role in transcription and splicing. Using meta-analysis with available literature rs251124 was found to be the strongest intracranial aneurysm marker for global ethnicities. This study with a novel functional SNP rs2287926 (G428D) further substantiates the potential role of VCAN in the pathogenesis of IA.