Inflammation Carcinogenesis Research Articles

Inflammatory bowel disease biomarkers of human gut microbiota selected via different feature selection methods.

The tremendous boost in next generation sequencing and in the “omics” technologies makes it possible to characterize the human gut microbiome—the collective genomes of the microbial community that reside in our gastrointestinal tract. Although some of these microorganisms are considered to be essential regulators of our immune system, the alteration of the complexity and eubiotic state of microbiota might promote autoimmune and inflammatory disorders such as diabetes, rheumatoid arthritis, Inflammatory bowel diseases (IBD), obesity, and carcinogenesis. IBD, comprising Crohn’s disease and ulcerative colitis, is a gut-related, multifactorial disease with an unknown etiology. IBD presents defects in the detection and control of the gut microbiota, associated with unbalanced immune reactions, genetic mutations that confer susceptibility to the disease, and complex environmental conditions such as westernized lifestyle. Although some existing studies attempt to unveil the composition and functional capacity of the gut microbiome in relation to IBD diseases, a comprehensive picture of the gut microbiome in IBD patients is far from being complete. Due to the complexity of metagenomic studies, the applications of the state-of-the-art machine learning techniques became popular to address a wide range of questions in the field of metagenomic data analysis. In this regard, using IBD associated metagenomics dataset, this study utilizes both supervised and unsupervised machine learning algorithms, (i) to generate a classification model that aids IBD diagnosis, (ii) to discover IBD-associated biomarkers, (iii) to discover subgroups of IBD patients using k-means and hierarchical clustering approaches. To deal with the high dimensionality of features, we applied robust feature selection algorithms such as Conditional Mutual Information Maximization (CMIM), Fast Correlation Based Filter (FCBF), min redundancy max relevance (mRMR), Select K Best (SKB), Information Gain (IG) and Extreme Gradient Boosting (XGBoost). In our experiments with 100-fold Monte Carlo cross-validation (MCCV), XGBoost, IG, and SKB methods showed a considerable effect in terms of minimizing the microbiota used for the diagnosis of IBD and thus reducing the cost and time. We observed that compared to Decision Tree, Support Vector Machine, Logitboost, Adaboost, and stacking ensemble classifiers, our Random Forest classifier resulted in better performance measures for the classification of IBD. Our findings revealed potential microbiome-mediated mechanisms of IBD and these findings might be useful for the development of microbiome-based diagnostics.

Inflammatory bowel disease and carcinogenesis.

Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of cancer mortality worldwide. Colitis-associated colorectal cancer (CAC) is a subtype of CRC associated with inflammatory bowel disease (IBD). It is well known that individuals with IBD have a 2-3 times higher risk of developing CRC than those who do not, rendering CAC a major cause of death in this group. Although the etiology and pathogenesis of CAC are incompletely understood, animal models of chronic inflammation and human cohort data indicate that changes in the intestinal environment, including host response dysregulation and gut microbiota perturbations, may contribute to the development of CAC. Genomic alterations are a hallmark of CAC, with patterns that are distinct from those in sporadic CRC. The discovery of the biological changes that underlie the development of CAC is ongoing; however, current data suggest that chronic inflammation in IBD increases the risk of developing CAC. Therefore, a deeper understanding of the precise mechanisms by which inflammation triggers genetic alterations and disrupts intestinal homeostasis may provide insight into novel therapeutic strategies for the prevention of CAC.

Colitis and Colorectal Carcinogenesis: The Focus on Isolated Lymphoid Follicles.

Gut-associated lymphoid tissue is one of the most diverse and complex immune compartments in the human body. The subepithelial compartment of the gut consists of immune cells of innate and adaptive immunity, non-hematopoietic mesenchymal cells, and stem cells of different origins, and is organized into secondary (and even tertiary) lymphoid organs, such as Peyer’s patches, cryptopatches, and isolated lymphoid follicles. The function of isolated lymphoid follicles is multifaceted; they play a role in the development and regeneration of the large intestine and the maintenance of (immune) homeostasis. Isolated lymphoid follicles are also extensively associated with the epithelium and its conventional and non-conventional immune cells; hence, they can also function as a starting point or maintainer of pathological processes such as inflammatory bowel diseases or colorectal carcinogenesis. These relationships can significantly affect both physiological and pathological processes of the intestines. We aim to provide an overview of the latest knowledge of isolated lymphoid follicles in colonic inflammation and colorectal carcinogenesis. Further studies of these lymphoid organs will likely lead to an extended understanding of how immune responses are initiated and controlled within the large intestine, along with the possibility of creating novel mucosal vaccinations and ways to treat inflammatory bowel disease or colorectal cancer.

Galectins, Aspects in Cardiovascular Diseases

The Galectins are proteins that belongs to Lectines family, ancient group that includes 15 types of Galectines, each with an specific role. Are involved in inflammatory processes, carcinogenesis, heart diseases, morbidity and mortality related to cardiovascular diseases being still in the first place worldwide. It is important to establish a link between Galectins (Galectin-3) and the process of heart failure, atherosclerosis, heart fibrosis. This review is done to determine the diagnostic performance of Galectin-3 parameters, total cardiac enzymes and their correlation.

Association of Diabetes Mellitus and Alcohol Abuse with Cancer: Molecular Mechanisms and Clinical Significance.

Diabetes mellitus (DM), one of the metabolic diseases which is characterized by sustained hyperglycemia, is a life-threatening disease. The global prevalence of DM is on the rise, mainly in low- and middle-income countries. Diabetes is a major cause of blindness, heart attacks, kidney failure, stroke, and lower limb amputation. Type 2 diabetes mellitus (T2DM) is a form of diabetes that is characterized by high blood sugar and insulin resistance. T2DM can be prevented or delayed by a healthy diet, regular physical activity, maintaining normal body weight, and avoiding alcohol and tobacco use. Ethanol and its metabolites can cause differentiation defects in stem cells and promote inflammatory injury and carcinogenesis in several tissues. Recent studies have suggested that diabetes can be treated, and its consequences can be avoided or delayed with proper management. DM has a greater risk for several cancers, such as breast, colorectal, endometrial, pancreatic, gallbladder, renal, and liver cancer. The incidence of cancer is significantly higher in patients with DM than in those without DM. In addition to DM, alcohol abuse is also a risk factor for many cancers. We present a review of the recent studies investigating the association of both DM and alcohol abuse with cancer incidence.

Fisetin Protects HaCaT Human Keratinocytes from Fine Particulate Matter (PM2.5)-Induced Oxidative Stress and Apoptosis by Inhibiting the Endoplasmic Reticulum Stress Response.

Fine particulate matter (PM2.5) originates from the combustion of coal and is found in the exhaust of fumes of diesel vehicles. PM2.5 readily penetrates the skin via the aryl hydrocarbon receptor, causing skin senescence, inflammatory skin diseases, DNA damage, and carcinogenesis. In this study, we investigated whether fisetin, a bioactive flavonoid, prevents PM2.5-induced apoptosis in HaCaT human keratinocytes. The results demonstrated that fisetin significantly downregulated PM2.5-induced apoptosis at concentrations below 10 μM. Fisetin strongly inhibited the production of reactive oxygen species (ROS) and the expression of pro-apoptotic proteins. The PM2.5-induced apoptosis was associated with the induction of the endoplasmic reticulum (ER) stress response, mediated via the protein kinase R-like ER kinase (PERK)–eukaryotic initiation factor 2α (eIF2α)–activating transcription factor 4 (ATF4)–CCAAT-enhancer-binding protein (C/EBP) homologous protein (CHOP) axis. Additionally, the cytosolic Ca2+ levels were markedly increased following exposure to PM2.5. However, fisetin inhibited the expression of ER stress-related proteins, including 78 kDa glucose-regulated protein (GRP78), phospho-eIF2α, ATF4, and CHOP, and reduced the cytosolic Ca2+ levels. These data suggest that fisetin inhibits PM2.5-induced apoptosis by inhibiting the ER stress response and production of ROS.

Autoimmunity Profiles as Prognostic Indicators in Patients with Colorectal Cancer versus Those with Cancer at Other Sites: A Prospective Study.

Simple SummaryThe clinical utility of tumor-associated autoantibodies (TAABs) detected in patient sera with different types of cancer has not yet been established. Their possible use in early cancer detection, oncological follow-up, and patient prognosis is highly desirable. We developed a prospective study to investigate the role of TAABs in a five-year survival analysis in different types of cancer patients. Overall, overproduction of TAABs is associated with advanced oncological disease, the presence of metastasis, and poorer prognosis of cancer patients. There is evidence that more intensive follow-up programs provide different results for colorectal cancer than other cancers, because more intensive follow-up improves survival and is cost-effective in colorectal cancer. It is necessary to emphasize that there are many important aspects of follow-up in addition to detection of recurrence, and this must lead to proposals to change the way follow-up care is delivered.Colorectal cancer represents a paradigmatic model of inflammatory carcinogenesis accompanied by the production of several kinds of tumor-associated autoantibodies (TAABs). The specific aim of this study is to define the clinical impact of the presence of non-specific circulating TAABs in a cohort of cancer patients and to establish whether significant differences were present between colorectal cancer and cancers at other sites. For this aim a prospective study was developed and a five-year survival analysis performed. Indirect immunofluorescence on rat tissues for non-organ specific autoantibodies (NOSAs: liver-kidney-stomach), on rat colon substrates (colon-related autoantibodies, CAAs) and on HEp-2 cell lines was performed. NOSA positivity was more frequent in patients with colorectal cancer than in those with cancer at other sites. Survival analysis demonstrated a significantly worse prognosis in cancer patients positive for TAABs. CAA positivity is a predictor of survival, independently from the presence of comorbidities, and HEp-2 reactivity was a strong predictor of survival in a stepwise Cox-regression model, including stage at diagnosis. Overall overproduction of TAABs is associated with advanced oncological disease, the presence of metastasis, and poorer prognosis of cancer patients.

Moringa oleifera leaves alleviated inflammation through downregulation of IL-2, IL-6, and TNF-α in a colitis-associated colorectal cancer model

New chemopreventive alternatives are needed due to the rising worldwide incidence of colorectal cancer. The objective was to evaluate the chemopreventive activity of Moringa oleifera leaves (MO) in a colitis-associated colon carcinogenesis model. We hypothesized that MO contain bioactive compounds capable of modulating the expression of genes involved in the inflammatory response and carcinogenesis. Forty-eight male mice (CD-1) were divided into six groups; 1: Healthy control; 2: Positive control induced with azoxymethane (AOM, 10 mg/Kg body weight, intraperitoneal injection) and three cycles of dextran sodium sulfate (DSS, 1.5% in drinking water); groups 3, 4, and 5 were induced with AOM/DSS and supplemented with 5%, 10%, and 20% of MO, respectively; group 6: had no disease induction and supplemented with 20% of MO. Mice were treated for 12 weeks and euthanized. Significant differences (p < 0.05) were found for the moringa-administered groups in morphological and histopathological parameters compared to the AOM/DSS control. A decrease in myeloperoxidase activity (~50%) and lipid peroxidation (1.9–3.1 times) were found in groups with 10% and 20% of MO compared to the AOM/DSS control (p < 0.05). The group supplemented with 10% MO showed a significant increase (~3 times) in butyrate and propionate in fecal and cecal content. Groups supplemented with 10%, and 20% MO showed a reduction in proinflammatory cytokines in serum (MCP-1, IL-6, TNF-α) compared to the AOM/DSS control. Treatment with 10% MO induced differential expression of 65 genes in colon tissue such as IL-2, IL-6, TNF, IL-1ß, and INF-γ. MO downregulated proinflammatory mediators showing chemopreventive properties against inflammatory response and colon carcinogenesis.

Emerging Roles of Metallothioneins in Beta Cell Pathophysiology: Beyond and Above Metal Homeostasis and Antioxidant Response.

Simple SummaryDefective insulin secretion by pancreatic beta cells is key for the development of type 2 diabetes but the precise mechanisms involved are poorly understood. Metallothioneins are metal binding proteins whose precise biological roles have not been fully characterized. Available evidence indicated that Metallothioneins are protective cellular effectors involved in heavy metal detoxification, metal ion homeostasis and antioxidant defense. This concept has however been challenged by emerging evidence in different medical research fields revealing novel negative roles of Metallothioneins, including in the context of diabetes. In this review, we gather and analyze the available knowledge regarding the complex roles of Metallothioneins in pancreatic beta cell biology and insulin secretion. We comprehensively analyze the evidence showing positive effects of Metallothioneins on beta cell function and survival as well as the emerging evidence revealing negative effects and discuss the possible underlying mechanisms. We expose in parallel findings from other medical research fields and underscore unsettled questions. Then, we propose some future research directions to improve knowledge in the field.Metallothioneins (MTs) are low molecular weight, cysteine-rich, metal-binding proteins whose precise biological roles have not been fully characterized. Existing evidence implicated MTs in heavy metal detoxification, metal ion homeostasis and antioxidant defense. MTs were thus categorized as protective effectors that contribute to cellular homeostasis and survival. This view has, however, been challenged by emerging evidence in different medical fields revealing novel pathophysiological roles of MTs, including inflammatory bowel disease, neurodegenerative disorders, carcinogenesis and diabetes. In the present focused review, we discuss the evidence for the role of MTs in pancreatic beta-cell biology and insulin secretion. We highlight the pattern of specific isoforms of MT gene expression in rodents and human beta-cells. We then discuss the mechanisms involved in the regulation of MTs in islets under physiological and pathological conditions, particularly type 2 diabetes, and analyze the evidence revealing adaptive and negative roles of MTs in beta-cells and the potential mechanisms involved. Finally, we underscore the unsettled questions in the field and propose some future research directions.

COLON SPECIFIC ROLE FOR SELENOPROTEIN P IN COLITIS AND COLITIS-ASSOCIATED CARCINOMA

Abstract Selenium (Se) is an essential trace element incorporated into selenoproteins (SEPs), which provide a broad scope of antioxidant functions. Se status inversely correlates with inflammatory bowel disease (IBD) severity, and animal models have shown that Se deficiency worsens colitis and colitis-associated cancer (CAC). One of the most highly expressed and functionally critical SEPs is Selenoprotein P (SEPP1/SELENOP). SELENOP serves two known roles: 1) distributing Se throughout the organism, and 2) acting as a lipid peroxidase. SELENOP is also markedly reduced in IBD. Global SELENOP reduction augmented experimental CAC. SELENOP is primarily produced in the liver for tissue distribution through the plasma; however, liver-specific SELENOP deletion failed to modify CAC, thus implicating epithelial SELENOP as a primary disease modifier. As the roles of intestinal epithelial SELENOP in colitis and CAC remain unknown, we investigated these roles using the Vil-CreERT2 driver to inducibly delete intestinal epithelial SELENOP in AOM/DSS inflammatory carcinogenesis models. First, Selenop deletion was confirmed in intestinal epithelial cells of tamoxifen-induced Vil-CreERT2; Selenopfl/fl mice (ΔIEC). Epithelial-specific SELENOP loss promoted tumor initiation, as evidenced by greater tumor multiplicity visible by colonoscopy in ΔIEC mice. Upon sacrifice, ΔIEC mice demonstrated increased colon tumor number and size. Additionally, ΔIEC colon tumors displayed greater apoptosis (cleaved caspase-3), DNA damage (pγH2AX), and dysplasia severity. Overall, these results are consistent with our model that epithelial SELENOP loss promotes tumor formation through increased intratumoral oxidative stress and resultant genomic instability. To further investigate SELENOP’s contributions in pure epithelial cultures, we determined that both CACO2 cells and human colonoids produce SELENOP in a sodium selenite-dependent fashion; furthermore, polarized CACO2 cells preferentially secrete SELENOP basolaterally, suggesting a local extracellular role for SELENOP in the immediate colonic epithelial microenvironment. Also, SELENOP knockdown in human intestinal organoids derived from ulcerative colitis (UC) patients increased oxidative stress, increased sensitivity to H2O2 treatment, and reduced organoid growth, implicating SELENOP in modulating the epithelial ROS-protective response. RNA-seq analysis from the PROTECT cohort revealed reduced SELENOP expression in pediatric UC biopsies that inversely correlated with disease activity and S100A8 (calprotectin) levels. Lastly, SELENOP RNA in situ hybridization of adult UC/Crohn’s Disease and CAC TMAs demonstrated decreased epithelial transcript in IBD and stage-dependent reductions in CAC. These data collectively indicate critical roles for SELENOP in epithelial and colonic microenvironment antioxidant defenses in IBD.

Lung carcinomas induced by NNK and LPS.

Cigarette smoking is the major culprit of chronic lung diseases and the most dominant risk factor for the development of both lung cancer and chronic obstructive pulmonary disease (COPD). In addition, chronic inflammation has been shown to increase the risk of lung cancer and COPD in clinical and epidemiological studies. For pulmonary disease-related research, mice are the most commonly used model system. Multiple lung cancer mouse models driven by targeted genetic alterations are used to evaluate the critical roles of oncogenes and tumor suppressor genes. These models are useful in addressing lung tumorigenesis associated with specific genetic changes, but they are not able to provide a global insight into cigarette smoke-induced carcinogenesis. To fill this knowledge gap, we developed a lung cancer model by treating mice with cigarette smoke carcinogen nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) with/without repeated lipopolysaccharides (LPS) exposure in order to determine the role of chronic inflammation in lung tumorigenesis. Notably, combined LPS/NNK treatment increased tumor number, tumor incidence, and tumor area compared to NNK treatment alone. Therefore, this model offers a feasible approach to investigate lung cancer development on a more global level, determine the role of inflammation in carcinogenesis, and provide a tool for evaluating chemoprevention and immunotherapy.

Colonic Epithelial-Derived Selenoprotein P Is the Source for Antioxidant-Mediated Protection in Colitis-Associated Cancer

Patients with inflammatory bowel disease (IBD) demonstrate nutritional selenium deficiencies and are at greater risk of developing colon cancer. Previously, we determined that global reduction of the secreted antioxidant selenium-containing protein, selenoprotein P (SELENOP), substantially increased tumor development in an experimental colitis-associated cancer (CAC) model. We next sought to delineate tissue-specific contributions of SELENOP to intestinal inflammatory carcinogenesis and define clinical context. Selenop floxed mice crossed with Cre driver lines to delete Selenop from the liver, myeloid lineages, or intestinal epithelium were placed on an azoxymethane/dextran sodium sulfate experimental CAC protocol. SELENOP loss was assessed in human ulcerative colitis (UC) organoids, and expression was queried in human and adult UC samples. Although large sources of SELENOP, both liver- and myeloid-specific Selenop deletion failed to modify azoxymethane/dextran sodium sulfate-mediated tumorigenesis. Instead, epithelial-specific deletion increased CAC tumorigenesis, likely due to elevated oxidative stress with a resulting increase in genomic instability and augmented tumor initiation. SELENOP was down-regulated in UC colon biopsies and levels were inversely correlated with endoscopic disease severity and tissue S100A8 (calprotectin) gene expression. Although global selenium status is typically assessed by measuring liver-derived plasma SELENOP levels, our results indicate that the peripheral SELENOP pool is dispensable for CAC. Colonic epithelial SELENOP is the main contributor to local antioxidant capabilities. Thus, colonic SELENOP is the most informative means to assess selenium levels and activity in IBD patients and may serve as a novel biomarker for UC disease severity and identify patients most predisposed to CAC development.

Modulatory effects of gut microbiome in cancer immunotherapy: A novel paradigm for blockade of immune checkpoint inhibitors.

The human gastrointestinal (GI) tract harbors gut microbiome, which plays a crucial role in preserving homeostasis at the intestinal host‐microbial interface. Conversely, specific gut microbiota may be altered during various pathological conditions and produce a number of toxic compounds and oncoproteins, in turn, to induce both inflammatory response and carcinogenesis. Recently, promising findings have been documented toward the implementation of certain intestinal microbiome in the next era of cancer biology and cancer immunotherapy. Notably, intestinal microbiota can cooperate with immune checkpoint inhibitors (ICIs) of its host, especially in enhancing the efficacy of programmed death 1 (PD‐1) protein and its ligand programmed death ligand 1 (PD‐L1) blockade therapy for cancer. Herein, we review the dual function of gut microbiota in triggering GI cancers, its association with host immunity and its beneficial functions in modulation of cancer immunotherapy responses. Furthermore, we consider the significance of gut microbiota as a potential biomarker for predicting the efficacy of cancer immunotherapy. Finally, we summarize the relevant limitations that affect the effectiveness and clinical applications of gut microbiome in response to immunotherapy.

β-Carotene: Preventive Role for Type 2 Diabetes Mellitus and Obesity: A Review.

Carotenoids are vital antioxidants for plants and animals. They protect cells from oxidative events and act against the inflammatory process and carcinogenesis. Among the most abundant carotenoids in human and foods is β-carotene. This carotenoid has the highest level of provitamin A activity, as it splits into two molecules of retinol through the actions of the cytosolic enzymes: β-carotene-15,15′-monooxygenase (β-carotene-15,15′-oxygenase 1) and β-carotene-9′,10′-dioxygenase (β-carotene-9′,10′-oxygenase 2). The literature supports the idea that β-carotene acts against type 2 diabetes mellitus, cardiovascular diseases, obesity, and metabolic syndrome. Due to the many processes involved in β-carotene biosynthesis and metabolic function, little is known about such components, since many mechanisms have not yet been fully elucidated. Therefore, our study concisely described the relationships between the consumption of carotenoids, with emphasis on β-carotene, and obesity and type 2 diabetes mellitus and its associated parameters in order to understand the preventive role of carotenoids better and encourage their consumption.

Transcriptomic analysis of tobacco-flavored E-cigarette and menthol-flavored E-cigarette exposure in the human middle ear

Electronic cigarettes (e-cigarettes) are the most widely used electronic nicotine delivery systems and are designed to imitate smoking and aid in smoking cessation. Although the number of e-cigarette users is increasing rapidly, especially among young adults and adolescents, the potential health impacts and biologic effects of e-cigarettes still need to be elucidated. Our previous study demonstrated the cytotoxic effects of electronic liquids (e-liquids) in a human middle ear epithelial cell (HMEEC-1) line, which were affected by the manufacturer and flavoring agents regardless of the presence of nicotine. In this study, we aimed to evaluate the gene expression profile and identify potential molecular modulator genes and pathways in HMEEC-1 exposed to two different e-liquids (tobacco- and menthol-flavored). HMEEC-1 was exposed to e-liquids, and RNA sequencing, functional analysis, and pathway analysis were conducted to identify the resultant transcriptomic changes. A total of 843 genes were differentially expressed following exposure to the tobacco-flavored e-liquid, among which 262 genes were upregulated and 581 were downregulated. Upon exposure to the menthol-flavored e-liquid, a total of 589 genes were differentially expressed, among which 228 genes were upregulated and 361 were downregulated. Among the signaling pathways associated with the differentially expressed genes mediated by tobacco-flavored e-liquid exposure, several key molecular genes were identified, including IL6 (interleukin 6), PTGS2 (prostaglandin-endoperoxide synthase 2), CXCL8 (C-X-C motif chemokine ligand 8), JUN (Jun proto-oncogene), FOS (Fos proto-oncogene), and TP53 (tumor protein 53). Under menthol-flavored e-liquid treatment, MMP9 (matrix metallopeptidase 9), PTGS2 (prostaglandin-endoperoxide synthase 2), MYC (MYC proto-oncogene, bHLH transcription factor), HMOX1 (heme oxygenase 1), NOS3 (nitric oxide synthase 3), and CAV1 (caveolin 1) were predicted as key genes. In addition, we identified related cellular processes, including inflammatory responses, oxidative stress and carcinogenesis, under exposure to tobacco- and menthol-flavored e-liquids. We identified differentially expressed genes and related cellular processes and gene signaling pathways after e-cigarette exposure in human middle ear cells. These findings may provide useful evidence for understanding the effect of e-cigarette exposure.

The Toxicity of Carcinogenic Metals to the Brain

Metal toxicity is often associated with inflammatory diseases and carcinogenesis. Various metal compounds have the capacity to induce DNA damage and elicit epigenetic changes that contribute to cell transformation and cancer. Understanding the altered pathways elicited by these metals and metal compounds aid in the preventative care as well as establishment of therapy regimens. As the ambient environment becomes contaminated with these toxic metals, studies have also demonstrated a growing capacity of metals designated as carcinogens to also exhibit neurotoxicity. The brain is often thought as a protected organ within the confines of the skull and protected from foreign substances by the blood brain barrier. Unfortunately, carcinogenic metals exist as compounds conferring their ability to enter the brain and accumulate, and in many instances they do so by destroying the blood brain barrier. The presence and accumulation of these pernicious compounds activates pathways that alter neurochemistry that support cognitive and motor function.

C3 Drives Inflammatory Skin Carcinogenesis Independently of C5

Nonmelanoma skin cancer such as cutaneous squamous cell carcinoma (cSCC) is the most common form of cancer and can occur as a consequence of DNA damage to the epithelium by UVR or chemical carcinogens. There is growing evidence that the complement system is involved in cancer immune surveillance; however, its role in cSCC remains unclear. Here, we show that complement genes are expressed in tissue from patients with cSCC, and C3 activation fragments are present in cSCC biopsies, indicating complement activation. Using a range of complement-deficient mice in a two-stage mouse model of chemically-induced cSCC, where a subclinical dose of 7,12-dimethylbenz[a]anthracene causes oncogenic mutations in epithelial cells and 12-O-tetradecanoylphorbol-13-acetate promotes the outgrowth of these cells, we found that C3-deficient mice displayed a significantly reduced tumor burden, whereas an opposite phenotype was observed in mice lacking C5aR1, C5aR2, and C3a receptor. In addition, in mice unable to form the membrane attack complex, the tumor progression was unaltered. C3 deficiency did not affect the cancer response to 7,12-dimethylbenz[a]anthracene treatment alone but reduced the epidermal hyperplasia during 12-O-tetradecanoylphorbol-13-acetate–induced inflammation. Collectively, these data indicate that C3 drives tumorigenesis during chronic skin inflammation, independently of the downstream generation of C5a or membrane attack complex.

New Study: Helicobacter Species as a Potential Zoonotic Infectious Carcinogen : A Review

In 1983 two Australian doctors discovered a spiral bacterium in the human stomach which was called Campylobacter pylori (or pyloridis) to be re-named (Helicobacter pylori) in 1990. Carried by half the global population it was first believed exclusive to Human causing chronic gastritis, peptic and duodenal ulcer, gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. This discovery revolutionized peptic ulcer treatment with antibiotics instead of surgery. H.pylori is the only bacterial agent classified as Class 1 carcinogen. In 1997 genetic advances allowed genome sequencing and detailed research particularly on genomic pathogenesis. Genome printing methods revealed that H.pylori was transmitted from domesticated animals to pre-stone-age man probably of African ancestry. New non-pylori Helicobacter species were found in farm, small, wild, and non-human primate animals. Some cause chronic gastritis and vomiting, occasionally lymphocytic gastric tissue proliferation and cancer. Some animal and avian species are contagious to human, sometimes sharing genomic similarities with H.pylori. There are currently about 35 Helicobacter species. In pathogenic strains, certain genes function as virulence factors making proteins responsible for chronic inflammatory reactions and carcinogenesis in variable degrees. This is called (genomic polymorphism), it create diverse species and strains with variable degrees of pathogenicity. Genomic heterogeneity is the result of Helicobacter adaptation in various environmental, geographic, and host circumstances. Helicobacter strains with diverse virulence may exist in different ethnic and geographic groups. Both H.pylori in human and non-pylori species in animal may co-exist mixed in one host. Sheep is believed the reservoir for H.pylori and H.canis.

The role of toll-like receptor 9 (TLR9) in Epstein-Barr virus-associated gastric cancer

Abstract Epstein-Barr virus-associated gastric carcinoma (EBVaGC) is the most common malignancy caused by EBV infection. Toll-like receptors (TLRs) as major components of innate immune system are crucial in the development of inflammatory processes and carcinogenesis. The aim of our study was to evaluate tissue and serum level of TLR9 in EBV-positive and EBV-negative gastric cancer patients. The study involved 30 EBV(+) and 30 EBV(-) patients. EBV DNA was detected in fresh frozen tumor tissue. In serum samples TLR9 level, transforming growth factor β (TGFβ), interleukin 10 (IL-10) and antibodies against EBV were detected using ELISA tests. TLR9 level was also measured in homogenate of tumour tissue. TLR9 level was statistically lower in EBV(+) patients both in serum and tissue, with statistically higher level in tissue than in serum. Lower level of TLR9 was accompanied by higher level of Epstein-Barr virus capsid antigen (EBVCA), Epstein-Barr virus nuclear antigen (EBNA) and early antigen (EA). A lower level of TLR9 was detected in patients with poorly differentiated cancer (G3) and greater lymph nodes involvement (N3-N4). Lower level of TLR9 in patients with EA may point to TLR9 role in reactivation of EBV infection.

IL-37 suppresses hepatocellular carcinoma development through T cell activation and angiogenesis suppression

Abstract IL-37, a relatively newly identified IL-1 family cytokine, has been shown to play an important immune regulatory role in inflammatory diseases, autoimmune diseases and carcinogenesis. IL-37 has been demonstrated to recruiting NK cells, stimulating CD4+ T cells, as well as inhibiting tumor angiogenesis to suppress tumor growth in various tumor models. In this current study, we found that IL-37 could suppress hepatocellular carcinoma (HCC) development in murine orthotopic HCC model and DEN-induced HCC model. Further study revealed that IL-37 could enhance the T cell killing capacity. This anti-tumor effect was fully abrogated in NOD-SCID mice. Furthermore, IL-37 could inhibit tumor angiogenesis in murine HCC model. In vitro study revealed that IL-37 treatment directly promoted HUVECs migration and tubule formation capacity, indicating IL-37 is a pro-angiogenic factor. However, the supernatant from IL-37 over-expression HCC cell line promoted HUVECs apoptosis and impaired the migration and tubule formation capacity of HUVECs. Microarray data suggested IL-37 affected the pro- and anti-angiogenic factors expression pattern from tumor cells. The pro-angiogenic factors ANGPT1, CYP1B1, FN1, MMP2, MCAM, PIK3CG were downregulated by IL-37, while the anti-angiogenic factor ANGPT1 was upregulated. These results indicated IL-37 could affect angiogenesis in both direct and indirect ways. Overall, our results demonstrated that IL-37 could suppress HCC development through T cell activation and angiogenesis suppression.