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Nutrients Sep 2021Approximately 4% of cancers worldwide are caused by alcohol consumption. Drinking alcohol increases the risk of several cancer types, including cancers of the upper... (Review)
Review
Approximately 4% of cancers worldwide are caused by alcohol consumption. Drinking alcohol increases the risk of several cancer types, including cancers of the upper aerodigestive tract, liver, colorectum, and breast. In this review, we summarise the epidemiological evidence on alcohol and cancer risk and the mechanistic evidence of alcohol-mediated carcinogenesis. There are several mechanistic pathways by which the consumption of alcohol, as ethanol, is known to cause cancer, though some are still not fully understood. Ethanol's metabolite acetaldehyde can cause DNA damage and block DNA synthesis and repair, whilst both ethanol and acetaldehyde can disrupt DNA methylation. Ethanol can also induce inflammation and oxidative stress leading to lipid peroxidation and further DNA damage. One-carbon metabolism and folate levels are also impaired by ethanol. Other known mechanisms are discussed. Further understanding of the carcinogenic properties of alcohol and its metabolites will inform future research, but there is already a need for comprehensive alcohol control and cancer prevention strategies to reduce the burden of cancer attributable to alcohol.
Topics: Acetaldehyde; Alcohol Drinking; Alcohol-Induced Disorders; Carcinogenesis; DNA Damage; DNA Methylation; Ethanol; Humans; Neoplasms
PubMed: 34579050
DOI: 10.3390/nu13093173 -
Cellular and Molecular Life Sciences :... Apr 2022Bile acids are soluble derivatives of cholesterol produced in the liver that subsequently undergo bacterial transformation yielding a diverse array of metabolites. The... (Review)
Review
Bile acids are soluble derivatives of cholesterol produced in the liver that subsequently undergo bacterial transformation yielding a diverse array of metabolites. The bulk of bile acid synthesis takes place in the liver yielding primary bile acids; however, other tissues have also the capacity to generate bile acids (e.g. ovaries). Hepatic bile acids are then transported to bile and are subsequently released into the intestines. In the large intestine, a fraction of primary bile acids is converted to secondary bile acids by gut bacteria. The majority of the intestinal bile acids undergo reuptake and return to the liver. A small fraction of secondary and primary bile acids remains in the circulation and exert receptor-mediated and pure chemical effects (e.g. acidic bile in oesophageal cancer) on cancer cells. In this review, we assess how changes to bile acid biosynthesis, bile acid flux and local bile acid concentration modulate the behavior of different cancers. Here, we present in-depth the involvement of bile acids in oesophageal, gastric, hepatocellular, pancreatic, colorectal, breast, prostate, ovarian cancer. Previous studies often used bile acids in supraphysiological concentration, sometimes in concentrations 1000 times higher than the highest reported tissue or serum concentrations likely eliciting unspecific effects, a practice that we advocate against in this review. Furthermore, we show that, although bile acids were classically considered as pro-carcinogenic agents (e.g. oesophageal cancer), the dogma that switch, as lower concentrations of bile acids that correspond to their serum or tissue reference concentration possess anticancer activity in a subset of cancers. Differences in the response of cancers to bile acids lie in the differential expression of bile acid receptors between cancers (e.g. FXR vs. TGR5). UDCA, a bile acid that is sold as a generic medication against cholestasis or biliary surge, and its conjugates were identified with almost purely anticancer features suggesting a possibility for drug repurposing. Taken together, bile acids were considered as tumor inducers or tumor promoter molecules; nevertheless, in certain cancers, like breast cancer, bile acids in their reference concentrations may act as tumor suppressors suggesting a Janus-faced nature of bile acids in carcinogenesis.
Topics: Bile Acids and Salts; Carcinogenesis; Esophageal Neoplasms; Humans; Liver; Male
PubMed: 35429253
DOI: 10.1007/s00018-022-04278-2 -
International Journal of Molecular... Jun 2019Transforming growth factor β (TGF-β) is a secreted cytokine that regulates cell proliferation, migration, and the differentiation of a plethora of different cell... (Review)
Review
Transforming growth factor β (TGF-β) is a secreted cytokine that regulates cell proliferation, migration, and the differentiation of a plethora of different cell types. Consistent with these findings, TGF-β plays a key role in controlling embryogenic development, inflammation, and tissue repair, as well as in maintaining adult tissue homeostasis. TGF-β elicits a broad range of context-dependent cellular responses, and consequently, alterations in TGF-β signaling have been implicated in many diseases, including cancer. During the early stages of tumorigenesis, TGF-β acts as a tumor suppressor by inducing cytostasis and the apoptosis of normal and premalignant cells. However, at later stages, when cancer cells have acquired oncogenic mutations and/or have lost tumor suppressor gene function, cells are resistant to TGF-β-induced growth arrest, and TGF-β functions as a tumor promotor by stimulating tumor cells to undergo the so-called epithelial-mesenchymal transition (EMT). The latter leads to metastasis and chemotherapy resistance. TGF-β further supports cancer growth and progression by activating tumor angiogenesis and cancer-associated fibroblasts and enabling the tumor to evade inhibitory immune responses. In this review, we will consider the role of TGF-β signaling in cell cycle arrest, apoptosis, EMT and cancer cell metastasis. In particular, we will highlight recent insights into the multistep and dynamically controlled process of TGF-β-induced EMT and the functions of miRNAs and long noncoding RNAs in this process. Finally, we will discuss how these new mechanistic insights might be exploited to develop novel therapeutic interventions.
Topics: Animals; Carcinogenesis; Epithelial-Mesenchymal Transition; Humans; Immune Evasion; Neoplasm Metastasis; Signal Transduction; Transforming Growth Factor beta
PubMed: 31195692
DOI: 10.3390/ijms20112767 -
Toxicological Sciences : An Official... Oct 2018
Review
Topics: Animals; Biological Evolution; Carcinogenesis; Gene-Environment Interaction; Humans; Neoplasms
PubMed: 30629266
DOI: 10.1093/toxsci/kfy184 -
Seminars in Cancer Biology Dec 2015Cancer immune evasion is a major stumbling block in designing effective anticancer therapeutic strategies. Although considerable progress has been made in understanding... (Review)
Review
Cancer immune evasion is a major stumbling block in designing effective anticancer therapeutic strategies. Although considerable progress has been made in understanding how cancers evade destructive immunity, measures to counteract tumor escape have not kept pace. There are a number of factors that contribute to tumor persistence despite having a normal host immune system. Immune editing is one of the key aspects why tumors evade surveillance causing the tumors to lie dormant in patients for years through "equilibrium" and "senescence" before re-emerging. In addition, tumors exploit several immunological processes such as targeting the regulatory T cell function or their secretions, antigen presentation, modifying the production of immune suppressive mediators, tolerance and immune deviation. Besides these, tumor heterogeneity and metastasis also play a critical role in tumor growth. A number of potential targets like promoting Th1, NK cell, γδ T cell responses, inhibiting Treg functionality, induction of IL-12, use of drugs including phytochemicals have been designed to counter tumor progression with much success. Some natural agents and phytochemicals merit further study. For example, use of certain key polysaccharide components from mushrooms and plants have shown to possess therapeutic impact on tumor-imposed genetic instability, anti-growth signaling, replicative immortality, dysregulated metabolism etc. In this review, we will discuss the advances made toward understanding the basis of cancer immune evasion and summarize the efficacy of various therapeutic measures and targets that have been developed or are being investigated to enhance tumor rejection.
Topics: Antigen Presentation; Carcinogenesis; Humans; Immune Evasion; Immune Tolerance; Neoplasms; Phytochemicals; T-Lymphocytes, Regulatory; Tumor Escape
PubMed: 25818339
DOI: 10.1016/j.semcancer.2015.03.004 -
International Journal of Molecular... Oct 2018The immense diversity of extracellular matrix (ECM) proteins confers distinct biochemical and biophysical properties that influence cell phenotype. The ECM is highly... (Review)
Review
The immense diversity of extracellular matrix (ECM) proteins confers distinct biochemical and biophysical properties that influence cell phenotype. The ECM is highly dynamic as it is constantly deposited, remodelled, and degraded during development until maturity to maintain tissue homeostasis. The ECM's composition and organization are spatiotemporally regulated to control cell behaviour and differentiation, but dysregulation of ECM dynamics leads to the development of diseases such as cancer. The chemical cues presented by the ECM have been appreciated as key drivers for both development and cancer progression. However, the mechanical forces present due to the ECM have been largely ignored but recently recognized to play critical roles in disease progression and malignant cell behaviour. Here, we review the ways in which biophysical forces of the microenvironment influence biochemical regulation and cell phenotype during key stages of human development and cancer progression.
Topics: Animals; Carcinogenesis; Epithelial-Mesenchymal Transition; Extracellular Matrix; Humans; Tumor Microenvironment
PubMed: 30287763
DOI: 10.3390/ijms19103028 -
Journal of Hematology & Oncology Feb 2022RNA modification plays a crucial role in many biological functions, and its abnormal regulation is associated with the progression of cancer. Among them, N-methyladenine... (Review)
Review
RNA modification plays a crucial role in many biological functions, and its abnormal regulation is associated with the progression of cancer. Among them, N-methyladenine (mA) is the most abundant RNA modification. Methyltransferase-like 14 (METTL14) is the central component of the mA methylated transferase complex, which is involved in the dynamic reversible process of mA modification. METTL14 acts as both an oncogene and tumor suppressor gene to regulate the occurrence and development of various cancers. The abnormal mA level induced by METTL14 is related to tumorigenesis, proliferation, metastasis, and invasion. To date, the molecular mechanism of METTL14 in various malignant tumors has not been fully studied. In this paper, we systematically summarize the latest research progress on METTL14 as a new biomarker for cancer diagnosis and its biological function in human tumors and discuss its potential clinical application. This study aims to provide new ideas for targeted therapy and improved prognoses in cancer.
Topics: Adenine; Animals; Carcinogenesis; Gene Expression Regulation, Neoplastic; Humans; Methylation; Methyltransferases; Neoplasms; Prognosis; RNA
PubMed: 35115038
DOI: 10.1186/s13045-022-01231-5 -
Nature Cancer Sep 2021Pseudouridine is the most frequent epitranscriptomic modification. However, its cellular functions remain largely unknown. Here, we show that pseudouridine synthase 7...
Pseudouridine is the most frequent epitranscriptomic modification. However, its cellular functions remain largely unknown. Here, we show that pseudouridine synthase 7 (PUS7) is highly expressed in glioblastoma versus normal brain tissues, and high PUS7 expression levels are associated with worse survival in patients with glioblastoma. PUS7 expression and catalytic activity are required for glioblastoma stem cell (GSC) tumorigenesis. Mechanistically, we identify PUS7 targets in GSCs through small RNA pseudouridine sequencing and show that pseudouridylation of PUS7-regulated transfer RNA is critical for codon-specific translational control of key regulators of GSCs. Moreover, we identify chemical inhibitors for PUS7 and show that these compounds prevent PUS7-mediated pseudouridine modification, suppress tumorigenesis and extend the life span of tumor-bearing mice. Overall, we identify an epitranscriptomic regulatory mechanism in glioblastoma and provide preclinical evidence of a potential therapeutic strategy for glioblastoma.
Topics: Animals; Carcinogenesis; Cell Transformation, Neoplastic; Glioblastoma; Humans; Intramolecular Transferases; Mice; Pseudouridine; RNA, Transfer
PubMed: 35121864
DOI: 10.1038/s43018-021-00238-0 -
Seminars in Cancer Biology Nov 2021Lung cancer has the second highest incidence and highest mortality compared to all other cancers. Polycyclic aromatic hydrocarbon (PAH) molecules belong to a class of... (Review)
Review
Lung cancer has the second highest incidence and highest mortality compared to all other cancers. Polycyclic aromatic hydrocarbon (PAH) molecules belong to a class of compounds that are present in tobacco smoke, diesel exhausts, smoked foods, as well as particulate matter (PM). PAH-derived reactive metabolites are significant contributors to lung cancer development. The formation of these reactive metabolites entails metabolism of the parent PAHs by cytochrome P4501A1/1B1 (CYP1A1/1B1) and epoxide hydrolase enzymes. These reactive metabolites then react with DNA to form DNA adducts, which contribute to key gene mutations, such as the tumor suppressor gene, p53 and are linked to pulmonary carcinogenesis. PAH exposure also leads to upregulation of CYP1A1 transcription by binding to the aryl hydrocarbon receptor (AHR) and eliciting transcription of the CYP1A1 promoter, which comprises specific xenobiotic-responsive element (XREs). While hepatic and pulmonary CYP1A1/1B1 metabolize PAHs to DNA-reactive metabolites, the hepatic CYP1A2, however, may protect against lung tumor development by suppressing both liver and lung CYP1A1 enzymes. Further analysis of these enzymes has shown that PAH-exposure also induces sustained transcription of CYP1A1, which is independent of the persistence of the parent PAH. CYP1A2 enzyme plays an important role in the sustained induction of hepatic CYP1A1. PAH exposure may further contribute to pulmonary carcinogenesis by producing epigenetic alterations. DNA methylation, histone modification, long interspersed nuclear element (LINE-1) activation, and non-coding RNA, specifically microRNA (miRNA) alterations may all be induced by PAH exposure. The relationship between PAH-induced enzymatic reactive metabolite formation and epigenetic alterations is a key area of research that warrants further exploration. Investigation into the potential interplay between these two mechanisms may lead to further understanding of the mechanisms of PAH carcinogenesis. These mechanisms will be crucial for the development of effective targeted therapies and early diagnostic tools.
Topics: Animals; Carcinogenesis; Humans; Lung Neoplasms; Polycyclic Aromatic Hydrocarbons
PubMed: 34242741
DOI: 10.1016/j.semcancer.2021.07.001 -
Carcinogenesis Sep 2020Many metals are essential for living organisms, but at higher doses they may be toxic and carcinogenic. Metal exposure occurs mainly in occupational settings and... (Review)
Review
Many metals are essential for living organisms, but at higher doses they may be toxic and carcinogenic. Metal exposure occurs mainly in occupational settings and environmental contaminations in drinking water, air pollution and foods, which can result in serious health problems such as cancer. Arsenic (As), beryllium (Be), cadmium (Cd), chromium (Cr) and nickel (Ni) are classified as Group 1 carcinogens by the International Agency for Research on Cancer. This review provides a comprehensive summary of current concepts of the molecular mechanisms of metal-induced carcinogenesis and focusing on a variety of pathways, including genotoxicity, mutagenesis, oxidative stress, epigenetic modifications such as DNA methylation, histone post-translational modification and alteration in microRNA regulation, competition with essential metal ions and cancer-related signaling pathways. This review takes a broader perspective and aims to assist in guiding future research with respect to the prevention and therapy of metal exposure in human diseases including cancer.
Topics: Animals; Carcinogenesis; Carcinogens; Environmental Exposure; Humans; Metals; Neoplasms
PubMed: 32674145
DOI: 10.1093/carcin/bgaa076