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Nature Reviews. Clinical Oncology Jan 2022The MYC proto-oncogenes encode a family of transcription factors that are among the most commonly activated oncoproteins in human neoplasias. Indeed, MYC aberrations or... (Review)
Review
The MYC proto-oncogenes encode a family of transcription factors that are among the most commonly activated oncoproteins in human neoplasias. Indeed, MYC aberrations or upregulation of MYC-related pathways by alternate mechanisms occur in the vast majority of cancers. MYC proteins are master regulators of cellular programmes. Thus, cancers with MYC activation elicit many of the hallmarks of cancer required for autonomous neoplastic growth. In preclinical models, MYC inactivation can result in sustained tumour regression, a phenomenon that has been attributed to oncogene addiction. Many therapeutic agents that directly target MYC are under development; however, to date, their clinical efficacy remains to be demonstrated. In the past few years, studies have demonstrated that MYC signalling can enable tumour cells to dysregulate their microenvironment and evade the host immune response. Herein, we discuss how MYC pathways not only dictate cancer cell pathophysiology but also suppress the host immune response against that cancer. We also propose that therapies targeting the MYC pathway will be key to reversing cancerous growth and restoring antitumour immune responses in patients with MYC-driven cancers.
Topics: Genes, myc; Humans; Immune Evasion; Neoplasms; Oncogenes
PubMed: 34508258
DOI: 10.1038/s41571-021-00549-2 -
Lung Cancer (Amsterdam, Netherlands) Mar 2021Lung cancer is the most common cause of cancer mortality worldwide and, while tobacco smoke remains the primary cause, there is increasing concern that vaping and... (Review)
Review
OBJECTIVES
Lung cancer is the most common cause of cancer mortality worldwide and, while tobacco smoke remains the primary cause, there is increasing concern that vaping and E-cigarette use may also increase lung cancer risk. This review concentrates on the current data, scholarship and active foci of research regarding potential cancer risk and oncogenic mechanisms of vaping and lung cancer.
MATERIALS AND METHODS
We performed a literature review of current and historical publications on lung cancer oncogenesis, vaping device/e-liquid contents and daughter products, molecular oncogenic mechanisms and the fundamental, potentially oncogenic, effects of electronic cigarette smoke/e-liquid products.
RESULTS
E-cigarette devices and vaping fluids demonstrably contain a series of both definite and probable oncogens including nicotine derivatives (e.g. nitrosnornicotine, nitrosamine ketone), polycyclic aromatic hydrocarbons, heavy metals (including organometal compounds) and aldehydes/other complex organic compounds. These arise both as constituents of the e-liquid (with many aldehydes and other complex organics used as flavourings) and as a result of pyrolysis/complex organic reactions in the electronic cigarette device (including unequivocal carcinogens such as formaldehyde - formed from pyrolysis of glycerol). Various studies demonstrate in vitro transforming and cytotoxic activity of these derivatives. E-cigarette device use has been significantly increasing - particularly amongst the younger cohort and non-smokers; thus, this is an area of significant concern for the future.
CONCLUSION
Although research remains somewhat equivocal, there is clear reason for concern regarding the potential oncogenicity of E-Cigarettes/E-Liquids with a strong basic and molecular science basis. Given lag times (extrapolating from tobacco smoke data) of perhaps 20 years, this may have significant future public health implications. Thus, the authors feel further study in this field is strongly warranted and consideration should be made for tighter control and regulation of these products.
Topics: Electronic Nicotine Delivery Systems; Humans; Lung Neoplasms; Nicotine; Oncogenes; Vaping
PubMed: 33429159
DOI: 10.1016/j.lungcan.2020.12.030 -
International Journal of Cancer May 2020Smoking is indisputably linked to lung cancer, yet only a small fraction of smokers develops this disease. Although previously tobacco-derived carcinogens and enzyme... (Review)
Review
Smoking is indisputably linked to lung cancer, yet only a small fraction of smokers develops this disease. Although previously tobacco-derived carcinogens and enzyme polymorphisms have been identified to increase the risk for smokers, recent epidemiological data suggest even sex-specificity as a new and additional factor. Obviously, women have a higher risk to develop lung cancer upon smoking than men. Overall, the odds ratio to develop lung cancer was almost three times greater for women than for men, DNA adduct levels were higher among females than in males and mutations in the tumor suppressor gene p53 and the proto-oncogene K-RAS were more frequently found in women than in men. A growing number of studies suggest that the interaction between tobacco carcinogens and endogenous and exogenous sex steroids may be important. Women taking hormone replacement therapy (HRT) or oral contraceptives experienced to have an increased lung cancer incidence. Epidemiologic data on HRT show a significant association between both a younger median age at lung cancer diagnosis and a shorter median survival time. Another clue is the significantly higher number of lung cancer diagnosed women who are largely premenopausal in comparison to diagnosed men in the same age or women with shorter menstrual cycles. Finally, the Coronary Drug Project (men who received estrogen preparations to reduce future cardiac events) was stopped when increased lung cancer mortality was observed in the estrogen therapy group. The present review provides a short overview and discussion on lung cancer risk and the impact thereon of sex.
Topics: Carcinogens; Female; Hormone Replacement Therapy; Humans; Incidence; Lung Neoplasms; Male; Proto-Oncogene Mas; Proto-Oncogenes; Risk Factors; Sex Factors; United States
PubMed: 31583690
DOI: 10.1002/ijc.32716 -
Food and Chemical Toxicology : An... Jul 2022Tobacco and tobacco smoke contain a complex mixture of over 9500 chemical compounds, many of which have been recognized as hazardous to human health by regulatory... (Review)
Review
Tobacco and tobacco smoke contain a complex mixture of over 9500 chemical compounds, many of which have been recognized as hazardous to human health by regulatory agencies. In 2012, the U.S. Food and Drug Administration established a list of harmful and potentially harmful constituents in unburned tobacco and tobacco smoke, 79 of which are considered as carcinogens. Over the past 10 years, with advancing analytical technology, significant amounts of new data have been published, increasing our understanding of levels of carcinogens in tobacco products. The International Agency for Research on Cancer (IARC) has released 35 monographs since 2012, with an increasing number of compounds in unburned tobacco and tobacco smoke classified as carcinogens. In this paper, we provide an updated list of IARC-classified carcinogens in unburned tobacco and tobacco mainstream smoke. A total of 83 carcinogens has been identified - 37 in unburned tobacco and 80 in tobacco smoke - with their occurrence levels reported since 2012. No clear decreasing trends were observed for any of these carcinogens in recent years. Surveillance of the levels of tobacco carcinogens as well as regulatory actions are needed to ensure control of their levels so that potential reduced risks of cancer and other diseases may be achieved.
Topics: Carcinogens; Humans; Smoke; Nicotiana; Tobacco Products; Tobacco Smoke Pollution
PubMed: 35643228
DOI: 10.1016/j.fct.2022.113179 -
Oncogene Apr 2021More than 25 years of research and preclinical validation have defined EphA2 receptor tyrosine kinase as a promising molecular target for clinical translation in cancer... (Review)
Review
More than 25 years of research and preclinical validation have defined EphA2 receptor tyrosine kinase as a promising molecular target for clinical translation in cancer treatment. Molecular, genetic, biochemical, and pharmacological targeting strategies have been extensively tested in vitro and in vivo, and drugs like dasatinib, initially designed to target SRC family kinases, have been found to also target EphA2 activity. Other small molecules, therapeutic targeting antibodies, and peptide-drug conjugates are being tested, and more recently, approaches harnessing antitumor immunity against EphA2-expressing cancer cells have emerged as a promising strategy. This review will summarize preclinical studies supporting the oncogenic role of EphA2 in breast cancer, lung cancer, glioblastoma, and melanoma, while delineating the differing roles of canonical and noncanonical EphA2 signaling in each setting. This review also summarizes completed and ongoing clinical trials, highlighting the promise and challenges of targeting EphA2 in cancer.
Topics: Humans; Neoplasms; Oncogenes; Receptor, EphA2
PubMed: 33686241
DOI: 10.1038/s41388-021-01714-8 -
Nature Reviews. Cancer Apr 2024Extrachromosomal DNA (ecDNA) has recently been recognized as a major contributor to cancer pathogenesis that is identified in most cancer types and is associated with... (Review)
Review
Extrachromosomal DNA (ecDNA) has recently been recognized as a major contributor to cancer pathogenesis that is identified in most cancer types and is associated with poor outcomes. When it was discovered over 60 years ago, ecDNA was considered to be rare, and its impact on tumour biology was not well understood. The application of modern imaging and computational techniques has yielded powerful new insights into the importance of ecDNA in cancer. The non-chromosomal inheritance of ecDNA during cell division results in high oncogene copy number, intra-tumoural genetic heterogeneity and rapid tumour evolution that contributes to treatment resistance and shorter patient survival. In addition, the circular architecture of ecDNA results in altered patterns of gene regulation that drive elevated oncogene expression, potentially enabling the remodelling of tumour genomes. The generation of clusters of ecDNAs, termed ecDNA hubs, results in interactions between enhancers and promoters in trans, yielding a new paradigm in oncogenic transcription. In this Review, we highlight the rapid advancements in ecDNA research, providing new insights into ecDNA biogenesis, maintenance and transcription and its role in promoting tumour heterogeneity. To conclude, we delve into a set of unanswered questions whose answers will pave the way for the development of ecDNA targeted therapeutic approaches.
Topics: Humans; Neoplasms; Oncogenes; DNA
PubMed: 38409389
DOI: 10.1038/s41568-024-00669-8 -
Toxicological Sciences : An Official... May 2015Excessive exposure to polycyclic aromatic hydrocarbons (PAHs) often results in lung cancer, a disease with the highest cancer mortality in the United States. After entry... (Review)
Review
Excessive exposure to polycyclic aromatic hydrocarbons (PAHs) often results in lung cancer, a disease with the highest cancer mortality in the United States. After entry into the lung, PAHs induce phase I metabolic enzymes such as cytochrome P450 (CYP) monooxygenases, i.e. CYP1A1/2 and 1B1, and phase II enzymes such as glutathione S-transferases, UDP glucuronyl transferases, NADPH quinone oxidoreductases (NQOs), aldo-keto reductases (AKRs), and epoxide hydrolases (EHs), via the aryl hydrocarbon receptor (AhR)-dependent and independent pathways. Humans can also be exposed to PAHs through diet, via consumption of charcoal broiled foods. Metabolism of PAHs through the CYP1A1/1B1/EH pathway, CYP peroxidase pathway, and AKR pathway leads to the formation of the active carcinogens diol-epoxides, radical cations, and o-quinones. These reactive metabolites produce DNA adducts, resulting in DNA mutations, alteration of gene expression profiles, and tumorigenesis. Mutations in xenobiotic metabolic enzymes, as well as polymorphisms of tumor suppressor genes (e.g. p53) and/or genes involved in gene expression (e.g. X-ray repair cross-complementing proteins), are associated with lung cancer susceptibility in human populations from different ethnicities, gender, and age groups. Although various metabolic activation/inactivation pathways, AhR signaling, and genetic susceptibilities contribute to lung cancer, the precise points at which PAHs induce tumor initiation remain unknown. The goal of this review is to provide a current state-of-the-science of the mechanisms of human lung carcinogenesis mediated by PAHs, the experimental approaches used to study this complex class of compounds, and future directions for research of these compounds.
Topics: Activation, Metabolic; Carcinogens; Cytochrome P-450 Enzyme System; Humans; Lung Neoplasms; Polycyclic Aromatic Hydrocarbons
PubMed: 25911656
DOI: 10.1093/toxsci/kfv040 -
Cancer Discovery Nov 2020is the most frequently mutated oncogene in cancer, yet there is little understanding of how specific KRAS amino acid changes affect tumor initiation, progression, or...
is the most frequently mutated oncogene in cancer, yet there is little understanding of how specific KRAS amino acid changes affect tumor initiation, progression, or therapy response. Using high-fidelity CRISPR-based engineering, we created an allelic series of new mutant mice, reflecting codon 12 and 13 mutations that are highly prevalent in lung (KRAS), pancreas (KRAS), and colon (KRAS) cancers. Induction of each allele in either the murine colon or pancreas revealed striking quantitative and qualitative differences between KRAS mutants in driving the early stages of transformation. Furthermore, using pancreatic organoid models, we show that KRAS mutants are sensitive to EGFR inhibition, whereas KRAS-mutant organoids are selectively responsive to covalent G12C inhibitors only when EGFR is suppressed. Together, these new mouse strains provide an ideal platform for investigating KRAS biology and for developing preclinical precision oncology models of KRAS-mutant pancreas, colon, and lung cancers. SIGNIFICANCE: KRAS is the most frequently mutated oncogene. Here, we describe new preclinical models that mimic tissue-selective KRAS mutations and show that each mutation has distinct cellular consequences and carries differential sensitivity to targeted therapeutic agents...
Topics: Alleles; Cell Line, Tumor; Humans; Oncogenes; Phenotype; Proto-Oncogene Proteins p21(ras)
PubMed: 32792368
DOI: 10.1158/2159-8290.CD-20-0442 -
Chemico-biological Interactions May 2021Current regulatory cancer risk assessment principles and practices assume a linear dose-response relationship-the linear no-threshold (LNT) model-that theoretically... (Review)
Review
Current regulatory cancer risk assessment principles and practices assume a linear dose-response relationship-the linear no-threshold (LNT) model-that theoretically estimates cancer risks occurring following low doses of carcinogens by linearly extrapolating downward from experimentally determined risks at high doses. The two-year rodent bioassays serve as experimental vehicles to determine the high-dose cancer risks in animals and then to predict, by extrapolation, the number of carcinogen-induced tumors (tumor incidence) that will arise during the lifespans of humans who are exposed to environmental carcinogens at doses typically orders of magnitude below those applied in the rodent assays. An integrated toxicological analysis is conducted herein to reconsider an alternative and once-promising approach, tumor latency, for estimating carcinogen-induced cancer risks at low doses. Tumor latency measures time-to-tumor following exposure to a carcinogen, instead of tumor incidence. Evidence for and against the concept of carcinogen-induced tumor latency is presented, discussed, and then examined with respect to its relationship to dose, dose rates, and the dose-related concepts of initiation, tumor promotion, tumor regression, tumor incidence, and hormesis. Considerable experimental evidence indicates: (1) tumor latency (time-to-tumor) is inversely related to the dose of carcinogens and (2) lower doses of carcinogens display quantifiably discrete latency thresholds below which the promotion and, consequently, the progression and growth of tumors are delayed or prevented during a normal lifespan. Besides reconciling well with the concept of tumor promotion, such latency thresholds also reconcile favorably with the existence of thresholds for tumor incidence, the stochastic processes of tumor initiation, and the compensatory repair mechanisms of hormesis. Most importantly, this analysis and the arguments presented herein provide sound theoretical, experimental, and mechanistic rationales for rethinking the foundational premises of low-dose linearity and updating the current practices of cancer risk assessment to include the concept of carcinogen thresholds.
Topics: Animals; Carcinogenicity Tests; Carcinogens; Dose-Response Relationship, Drug; Hormesis; Humans; Incidence; Neoplasms; Risk Assessment; Toxicity Tests, Chronic
PubMed: 33823170
DOI: 10.1016/j.cbi.2021.109464 -
Nature Reviews. Drug Discovery Jun 2022Immune checkpoint inhibitors (ICIs) have revolutionized the clinical management of multiple tumours. However, only a few patients respond to ICIs, which has generated... (Review)
Review
Immune checkpoint inhibitors (ICIs) have revolutionized the clinical management of multiple tumours. However, only a few patients respond to ICIs, which has generated considerable interest in the identification of resistance mechanisms. One such mechanism reflects the ability of various oncogenic pathways, as well as stress response pathways required for the survival of transformed cells (a situation commonly referred to as 'non-oncogene addiction'), to support tumour progression not only by providing malignant cells with survival and/or proliferation advantages, but also by establishing immunologically 'cold' tumour microenvironments (TMEs). Thus, both oncogene and non-oncogene addiction stand out as promising targets to robustly inflame the TME and potentially enable superior responses to ICIs.
Topics: Humans; Immune Checkpoint Inhibitors; Immunotherapy; Neoplasms; Oncogenes; Tumor Microenvironment
PubMed: 35292771
DOI: 10.1038/s41573-022-00415-5