The link between chronic inflammation and cancer has long been suspected, due to the pioneering work of Rudolf Virchow over 150 years ago. Yet the causal relationship between inflammation and cancer ...was only deciphered in the past decade or so, using animal models of various cancers. Up to 20% of all human cancers result from chronic inflammation and persistent infections. Proinflammatory cytokines and tumor-infiltrating myeloid and immune cells play critical roles in almost every developmental stages of inflammation-induced cancers, from initiation, promotion, and progression to malignant metastasis. However, even in cancers with no preceding inflammation, inflammatory cells infiltrate tumor stroma and contribute to cancer development. Such "tumor-elicited inflammation" further emphasizes the importance of inflammation in different types of cancers, including that of the colon. In this review, we summarize our current knowledge of the function and induction mechanisms of inflammatory cytokines during colorectal cancer development, and hope to provide insight into the development of novel anticancer therapies by modulating tumor-elicited inflammation.
c-Jun-N-terminal kinase (JNK) is a mitogen-activated protein kinase family member that is activated by diverse stimuli, including cytokines (such as tumor necrosis factor and interleukin-1), reactive ...oxygen species (ROS), pathogens, toxins, drugs, endoplasmic reticulum stress, free fatty acids, and metabolic changes. Upon activation, JNK induces multiple biologic events through the transcription factor activator protein-1 and transcription-independent control of effector molecules. JNK isozymes regulate cell death and survival, differentiation, proliferation, ROS accumulation, metabolism, insulin signaling, and carcinogenesis in the liver. The biologic functions of JNK are isoform, cell type, and context dependent. Recent studies using genetically engineered mice showed that loss or hyperactivation of the JNK pathway contributes to the development of inflammation, fibrosis, cancer growth, and metabolic diseases that include obesity, hepatic steatosis, and insulin resistance. We review the functions and pathways of JNK in liver physiology and pathology and discuss findings from preclinical studies with JNK inhibitors.
Inflammation and autophagy are cellular defense mechanisms. When these processes are deregulated (deficient or overactivated) they produce pathologic effects, such as oxidative stress, metabolic ...impairments, and cell death. Unresolved inflammation and disrupted regulation of autophagy are common features of pancreatitis and pancreatic cancer. Furthermore, obesity, a risk factor for pancreatitis and pancreatic cancer, promotes inflammation and inhibits or deregulates autophagy, creating an environment that facilitates the induction and progression of pancreatic diseases. However, little is known about how inflammation, autophagy, and obesity interact to promote exocrine pancreatic disorders. We review the roles of inflammation and autophagy, and their deregulation by obesity, in pancreatic diseases. We discuss the connections among disordered pathways and important areas for future research.
Mitochondrial DNA (mtDNA) escaping stressed mitochondria provokes inflammation via cGAS-STING pathway activation and, when oxidized (Ox-mtDNA), it binds cytosolic NLRP3, thereby triggering ...inflammasome activation. However, it is unknown how and in which form Ox-mtDNA exits stressed mitochondria in non-apoptotic macrophages. We found that diverse NLRP3 inflammasome activators rapidly stimulated uniporter-mediated calcium uptake to open mitochondrial permeability transition pores (mPTP) and trigger VDAC oligomerization. This occurred independently of mtDNA or reactive oxygen species, which induce Ox-mtDNA generation. Within mitochondria, Ox-mtDNA was either repaired by DNA glycosylase OGG1 or cleaved by the endonuclease FEN1 to 500–650 bp fragments that exited mitochondria via mPTP- and VDAC-dependent channels to initiate cytosolic NLRP3 inflammasome activation. Ox-mtDNA fragments also activated cGAS-STING signaling and gave rise to pro-inflammatory extracellular DNA. Understanding this process will advance the development of potential treatments for chronic inflammatory diseases, exemplified by FEN1 inhibitors that suppressed interleukin-1β (IL-1β) production and mtDNA release in mice.
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•Ca2+ uptake via MCU triggers IMM mPTP opening to induce OMM VDAC oligomerization•Ox-mtDNA is repaired by OGG1 or cleaved by FEN1 to fragments that exit mitochondria•Cytosolic Ox-mtDNA activates NLRP3 inflammasome and cGAS-STING and escapes cells•mtOGG1 and FEN1 inhibitors suppress acute peritonitis and reduce circulating mtDNA
Ox-mtDNA enables NLRP3 inflammasome activation, but how Ox-mtDNA reaches the cytoplasm is unclear. In this issue of Immunity, Xian et al. show that Ox-mtDNA cleaved by FEN1 escapes mitochondria via mPTP and VDAC channels to activate NLRP3 inflammasome and STING.
Immunotherapy, Inflammation and Colorectal Cancer Lichtenstern, Charles Robert; Ngu, Rachael Katie; Shalapour, Shabnam ...
Cells (Basel, Switzerland),
03/2020, Letnik:
9, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Colorectal cancer (CRC) is the third most common cancer type, and third highest in mortality rates among cancer-related deaths in the United States. Originating from intestinal epithelial cells in ...the colon and rectum, that are impacted by numerous factors including genetics, environment and chronic, lingering inflammation, CRC can be a problematic malignancy to treat when detected at advanced stages. Chemotherapeutic agents serve as the historical first line of defense in the treatment of metastatic CRC. In recent years, however, combinational treatment with targeted therapies, such as vascular endothelial growth factor, or epidermal growth factor receptor inhibitors, has proven to be quite effective in patients with specific CRC subtypes. While scientific and clinical advances have uncovered promising new treatment options, the five-year survival rate for metastatic CRC is still low at about 14%. Current research into the efficacy of immunotherapy, particularly immune checkpoint inhibitor therapy (ICI) in mismatch repair deficient and microsatellite instability high (dMMR-MSI-H) CRC tumors have shown promising results, but its use in other CRC subtypes has been either unsuccessful, or not extensively explored. This Review will focus on the current status of immunotherapies, including ICI, vaccination and adoptive T cell therapy (ATC) in the treatment of CRC and its potential use, not only in dMMR-MSI-H CRC, but also in mismatch repair proficient and microsatellite instability low (pMMR-MSI-L).
Recent discoveries involving the cytokine interleukin (IL)-6 have originated from diverse disciplines, revealing roles in biological processes that are likewise varied. The most novel findings ...suggest a connection between inflammation and diseases, such as insulin resistance associated with diabetes mellitus and cancer, which had not or only weakly been appreciated previously. The IL-6 pathway is one of the mechanisms linking inflammation to these disease processes. In addition, new evidence points toward IL-6 as one of the mediators coordinating the interface between adaptive and innate immunity. Here, we review the evidence linking IL-6 to inflammatory diseases and cancer.
Chronic alcohol consumption is a leading risk factor for the development of hepatocellular carcinoma (HCC), which is associated with a marked increase in hepatic expression of pro-inflammatory IL-17A ...and its receptor IL-17RA.
Genetic deletion and pharmacological blocking were used to characterize the role of IL-17A/IL-17RA signaling in the pathogenesis of HCC in mouse models and human specimens.
We demonstrate that the global deletion of the Il-17ra gene suppressed HCC in alcohol-fed diethylnitrosamine-challenged Il-17ra–/– and major urinary protein-urokinase-type plasminogen activator/Il-17ra–/– mice compared with wild-type mice. When the cell-specific role of IL-17RA signaling was examined, the development of HCC was decreased in both alcohol-fed Il-17raΔMΦ and Il-17raΔHep mice devoid of IL-17RA in myeloid cells and hepatocytes, but not in Il-17raΔHSC mice (deficient in IL-17RA in hepatic stellate cells). Deletion of Il-17ra in myeloid cells ameliorated tumorigenesis via suppression of pro-tumorigenic/inflammatory and pro-fibrogenic responses in alcohol-fed Il-17raΔMΦ mice. Remarkably, despite a normal inflammatory response, alcohol-fed Il-17raΔHep mice developed the fewest tumors (compared with Il-17raΔMΦ mice), with reduced steatosis and fibrosis. Steatotic IL-17RA-deficient hepatocytes downregulated the expression of Cxcl1 and other chemokines, exhibited a striking defect in tumor necrosis factor (TNF)/TNF receptor 1-dependent caspase-2-SREBP1/2-DHCR7-mediated cholesterol synthesis, and upregulated the production of antioxidant vitamin D3. The pharmacological blocking of IL-17A/Th-17 cells using anti-IL-12/IL-23 antibodies suppressed the progression of HCC (by 70%) in alcohol-fed mice, indicating that targeting IL-17 signaling might provide novel strategies for the treatment of alcohol-induced HCC.
Overall, IL-17A is a tumor-promoting cytokine, which critically regulates alcohol-induced hepatic steatosis, inflammation, fibrosis, and HCC.
IL-17A is a tumor-promoting cytokine, which critically regulates inflammatory responses in macrophages (Kupffer cells and bone-marrow-derived monocytes) and cholesterol synthesis in steatotic hepatocytes in an experimental model of alcohol-induced HCC. Therefore, IL-17A may be a potential therapeutic target for patients with alcohol-induced HCC.
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•IL-17 promotes alcohol-induced hepatocellular carcinoma.•IL-17 regulates activation of macrophages.•IL-17 facilitates tumor necrosis factor/tumor necrosis factor receptor-mediated lipogenesis in alcohol-damaged hepatocytes.•IL-17 promotes lipogenesis via activation of caspase-2-SP1-SREBP1/2-DHCR7 pathway.•IL-17 signaling prevents TNFR1 exocytosis in steatotic hepatocytes.
Colitis-associated cancer (CAC) is the most serious complication of inflammatory bowel disease. Proinflammatory cytokines have been suggested to regulate preneoplastic growth during CAC ...tumorigenesis. Interleukin 6 (IL-6) is a multifunctional NF-κB-regulated cytokine that acts on epithelial and immune cells. Using genetic tools, we now demonstrate that IL-6 is a critical tumor promoter during early CAC tumorigenesis. In addition to enhancing proliferation of tumor-initiating cells, IL-6 produced by lamina propria myeloid cells protects normal and premalignant intestinal epithelial cells (IECs) from apoptosis. The proliferative and survival effects of IL-6 are largely mediated by the transcription factor Stat3, whose IEC-specific ablation has profound impact on CAC tumorigenesis. Thus, the NF-κB-IL-6-Stat3 cascade is an important regulator of the proliferation and survival of tumor-initiating IECs.
Summary
Among all the E2 ubiquitin‐conjugating enzymes, Ubc13, which heterodimerizes with Uev1a, specifically mediates lysine 63 (K63)‐linked protein polyubiquitylation, a process that does not lead ...to proteasomal degradation of its substrates. Instead, it plays a key role in signal transduction. Numerous roles of Lys63‐linked polyubiquitylation in immune responses have emerged, indicating the importance of this regulatory strategy. Here, we summarize some of the signaling pathways that depend on Lys63‐linked polyubiquitylation during innate and adaptive immune responses, with a focus on the underlying molecular mechanisms. In addition, we describe how Ubc13 itself is regulated and outline its function in transforming growth factor β signaling. We discuss the current progress in pharmacological targeting of Ubc13 in inflammatory and autoimmune diseases as well as cancer therapy.
The innate immune system relies on its capacity to rapidly detect invading pathogenic microbes as foreign and eliminate them. Indeed, Toll-like receptors are a class of membrane receptors that sense ...extracellular microbes and trigger anti-pathogen signalling cascades. Recently, intracellular microbial sensors have also been identified, including NOD-like receptors and the helicase-domain-containing antiviral proteins RIG-I and MDA5. Some of these cytoplasmic molecules sense microbial, as well as non-microbial, danger signals, but the mechanisms of recognition used by these sensors remain poorly understood. Nonetheless, it is apparent that these proteins are likely to have critical roles in health and disease.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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