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Cell Reports Nov 2023Somatic copy number gains are pervasive across cancer types, yet their roles in oncogenesis are insufficiently evaluated. This inadequacy is partly due to copy gains...
Somatic copy number gains are pervasive across cancer types, yet their roles in oncogenesis are insufficiently evaluated. This inadequacy is partly due to copy gains spanning large chromosomal regions, obscuring causal loci. Here, we employed organoid modeling to evaluate candidate oncogenic loci identified via integrative computational analysis of extreme copy gains overlapping with extreme expression dysregulation in The Cancer Genome Atlas. Subsets of "outlier" candidates were contextually screened as tissue-specific cDNA lentiviral libraries within cognate esophagus, oral cavity, colon, stomach, pancreas, and lung organoids bearing initial oncogenic mutations. Iterative analysis nominated the kinase DYRK2 at 12q15 as an amplified head and neck squamous carcinoma oncogene in p53 oral mucosal organoids. Similarly, FGF3, amplified at 11q13 in 41% of esophageal squamous carcinomas, promoted p53 esophageal organoid growth reversible by small molecule and soluble receptor antagonism of FGFRs. Our studies establish organoid-based contextual screening of candidate genomic drivers, enabling functional evaluation during early tumorigenesis.
Topics: Humans; Tumor Suppressor Protein p53; Oncogenes; Cell Transformation, Neoplastic; Neoplasms; Carcinogenesis; Gene Amplification
PubMed: 37922313
DOI: 10.1016/j.celrep.2023.113355 -
Scientific Reports Sep 2023E-cigarettes are now very popular in the world. Compared to traditional cigarettes, e-cigarettes are often considered safer and healthier. However, their safety remains...
E-cigarettes are now very popular in the world. Compared to traditional cigarettes, e-cigarettes are often considered safer and healthier. However, their safety remains controversial and requires further research and regulation. In this study, we aimed to understand the possible hazards to humans of four compounds (formaldehyde, acetaldehyde, acrolein, and acetone) and seven heavy metals (arsenic, cadmium, manganese, lead, copper, nickel, and chromium) contained in e-cigarette liquids and aerosols and perform a health risk assessment. We searched PubMed, CNKI, and other databases for relevant literature to obtain data on organic compounds and heavy metals in e-cigarette liquids and aerosols, and conducted acute, chronic, and carcinogenic risk assessments of various chemicals by different exposure routes. This study showed that exposure to four organic compounds and seven heavy metals in e-cigarette aerosols and e-liquids can cause varying levels of health risks in humans through different routes, with the inhalation route posing a higher overall risk than dermal exposure and oral intake. Various chemicals at high exposure doses can produce health risks beyond the acceptable range. E-cigarette designers must improve their products by changing the composition of the e-liquid and controlling the power of the device to reduce the health effects on humans.
Topics: Humans; Carcinogens; Electronic Nicotine Delivery Systems; Carcinogenesis; Metals, Heavy; Arsenic
PubMed: 37749131
DOI: 10.1038/s41598-023-43112-y -
Environmental Research Aug 2023Glyphosate is a broad-spectrum and one of the most widely used herbicides in the world, which has led to its high environmental dissemination. In 2015, the International... (Review)
Review
Glyphosate is a broad-spectrum and one of the most widely used herbicides in the world, which has led to its high environmental dissemination. In 2015, the International Agency for Research on Cancer stated that glyphosate was a probable human carcinogen. Since then, several studies have provided new data about the environmental exposure of glyphosate and its consequences on human health. Thus, the carcinogenic effects of glyphosate are still under debate. This work aimed to review glyphosate occurrence and exposure since 2015 up to date, considering studies associated with either environmental or occupational exposure and the epidemiological assessment of cancer risk in humans. These articles showed that herbicide residues were detectable in all spheres of the earth and studies on the population showed an increase in the concentration of glyphosate in biofluids, both in the general population and in the occupationally exposed population. However, the epidemiological studies under review provided limited evidence for the carcinogenicity of glyphosate, which was consistent with the International Agency for Research on Cancer classification as a probable carcinogen.
Topics: Humans; Environmental Exposure; Occupational Exposure; Carcinogens; Herbicides; Neoplasms; Glyphosate
PubMed: 37209985
DOI: 10.1016/j.envres.2023.116201 -
ELife Oct 2023Activation of the Wnt pathway lies at the core of many human cancers. Wnt and macropinocytosis are often active in the same processes, and understanding how Wnt...
Activation of the Wnt pathway lies at the core of many human cancers. Wnt and macropinocytosis are often active in the same processes, and understanding how Wnt signaling and membrane trafficking cooperate should improve our understanding of embryonic development and cancer. Here, we show that a macropinocytosis activator, the tumor promoter phorbol 12-myristate 13-acetate (PMA), enhances Wnt signaling. Experiments using the embryo as an in vivo model showed marked cooperation between the PMA phorbol ester and Wnt signaling, which was blocked by inhibitors of macropinocytosis, Rac1 activity, and lysosome acidification. Human colorectal cancer tissue arrays and xenografts in mice showed a correlation of cancer progression with increased macropinocytosis/multivesicular body/lysosome markers and decreased GSK3 levels. The crosstalk between canonical Wnt, focal adhesions, lysosomes, and macropinocytosis suggests possible therapeutic targets for cancer progression in Wnt-driven cancers.
Topics: Female; Pregnancy; Humans; Animals; Mice; Carcinogens; Wnt Signaling Pathway; Glycogen Synthase Kinase 3; Phorbol Esters; Esters; Neoplasms
PubMed: 37902809
DOI: 10.7554/eLife.89141 -
Journal of Thoracic Oncology : Official... Jun 2024Alterations in the highly actionable lung cancer oncogenes, EGFR, ALK, and ROS1, occur across the age spectrum. Pregnancy and plans for motherhood consequently overlap... (Review)
Review
INTRODUCTION
Alterations in the highly actionable lung cancer oncogenes, EGFR, ALK, and ROS1, occur across the age spectrum. Pregnancy and plans for motherhood consequently overlap with diagnoses of advanced oncogene-driven NSCLC. Guidelines for cytotoxic agents and pregnancy are well established. Nevertheless, accessible data on targeted lung cancer therapy during pregnancy or egg retrieval has not been collated previously, nor have the issues of reproduction in the setting of specific oncogene-addicted advanced NSCLC been widely discussed.
METHODS
We performed a narrative review of ex vivo placenta perfusion studies, pharmacologic characteristics, mutagenicity, animal embryo-fetal development studies, and case reports of pathways to motherhood, pregnancies, and egg retrieval while on EGFR-, ALK-, or ROS1-targeted therapy.
RESULTS
EGFR inhibitors may reduce female fertility while on therapy owing to decrease in corpora lutea. Odds of pregnancy in women on EGFR and ALK inhibitors may be reduced owing to potential increase in postimplantation loss found in animals. Crizotinib and entrectinib exhibit in vitro mutagenic potential. Several effects on human pregnancies have been noted; however, 11 EGFR and ALK tyrosine kinase inhibitor-exposed infants have been documented free of substantial adverse health effects by ages 4 months to 2 years. Successful gestational surrogacy has been reported in two women treated with crizotinib. Adoption and termination approaches have also been undertaken by some patients.
CONCLUSIONS
Reproduction may not be out of reach for some patients with advanced NSCLC. Additional explorations of the impact and optimal timing of targeted therapy in egg capture and pregnancy are needed. Wider scientific and societal discussion about the issues of reproduction in advanced NSCLC is warranted.
Topics: Humans; Female; Pregnancy; Lung Neoplasms; Oncogenes; Fertility; Animals
PubMed: 38185202
DOI: 10.1016/j.jtho.2024.01.003 -
Journal of Translational Medicine Sep 2023Colorectal cancer (CRC) has become a global health problem which has almost highest morbidity and mortality in all types of cancers. This study aimed to uncover the...
Colorectal cancer (CRC) has become a global health problem which has almost highest morbidity and mortality in all types of cancers. This study aimed to uncover the biological functions and underlying mechanism of MCM8 in the development and progression of CRC. The expression level of MCM8 was found to be upregulated in CRC tissues and significantly associated with tumor grade and patients' survival. Knocking down MCM8 expression in CRC cells could restrain cell growth and cell motility while promoting cell apoptosis in vitro, as well as inhibit tumor growth in xenograft mice model. Based on the RNA screening performing on CRC cells with or without MCM8 knockdown and the following IPA analysis, CHSY1 was identified as a potential target of MCM8 in CRC, whose expression was also found to be higher in tumor tissues than in normal tissues. Moreover, it was demonstrated that MCM8 may regulate the expression of CHSY1 through affecting its NEDD4-mediated ubiquitination, both of which synergistically execute tumor promotion effects on CRC. In conclusion, the outcomes of our study showed the first evidence that MCM8 act as a tumor promotor in CRC, and may be a promising therapeutic target of CRC treatment.
Topics: Humans; Animals; Mice; Apoptosis; Carcinogens; Cell Cycle; Cell Movement; Disease Models, Animal; Colorectal Neoplasms; Minichromosome Maintenance Proteins
PubMed: 37710286
DOI: 10.1186/s12967-023-04084-9 -
The Journal of Clinical Investigation Oct 2023Carcinogen exposure is strongly associated with enhanced cancer immunogenicity. Increased tumor mutational burden and resulting neoantigen generation have been proposed...
Carcinogen exposure is strongly associated with enhanced cancer immunogenicity. Increased tumor mutational burden and resulting neoantigen generation have been proposed to link carcinogen exposure and cancer immunogenicity. However, the neoantigen-independent immunological impact of carcinogen exposure on cancer is unknown. Here, we demonstrate that chemical carcinogen-exposed cancer cells fail to establish an immunosuppressive tumor microenvironment (TME), resulting in their T cell-mediated rejection in vivo. A chemical carcinogen-treated breast cancer cell clone that lacked any additional coding region mutations (i.e., neoantigen) was rejected in mice in a T cell-dependent manner. Strikingly, the coinjection of carcinogen- and control-treated cancer cells prevented this rejection, suggesting that the loss of immunosuppressive TME was the dominant cause of rejection. Reduced M-CSF expression by carcinogen-treated cancer cells significantly suppressed tumor-associated macrophages (TAMs) and resulted in the loss of an immunosuppressive TME. Single-cell analysis of human lung cancers revealed a significant reduction in the immunosuppressive TAMs in former smokers compared with individuals who had never smoked. These findings demonstrate that carcinogen exposure impairs the development of an immunosuppressive TME and indicate a novel link between carcinogens and cancer immunogenicity.
Topics: Humans; Animals; Mice; Carcinogens; Tumor Microenvironment; T-Lymphocytes; Lung Neoplasms; Biomarkers, Tumor; Immunotherapy
PubMed: 37843274
DOI: 10.1172/JCI166494 -
Aging Dec 2023Type X collagen (COL10) is a homologous trimeric non-fibrillar collagen found in the extracellular matrix of human tissues, and it exhibits a distinctive white...
BACKGROUND
Type X collagen (COL10) is a homologous trimeric non-fibrillar collagen found in the extracellular matrix of human tissues, and it exhibits a distinctive white appearance. Type X collagen α1 chain (COL10A1) is a specific cleaved fragment of type X collagen. However, the expression, prognostic significance, clinicopathological attributes and immune-related associations of COL10A1 in prostate cancer as well as in pan-cancer contexts remain poorly understood.
METHODS
Using bioinformatic analysis of data from the most recent databases (TCGA, GTEx and GEO databases), we have extensively elucidated the role played by COL10A1 in terms of its expression patterns, prognostic implications, and immune efficacy across a pan-cancer spectrum. Subsequently, the biological functions of COL10A1 in prostate cancer were elucidated by experimental validation.
RESULTS
Our findings have confirmed that COL10A1 was highly expressed in most cancers and was associated with poorer prognosis in cancer patients. Immune correlation analysis of COL10A1 in various cancers showed its significant correlation with Tumor mutational burden (TMB), microsatellite instability (MSI) and immune cell infiltration. In addition, knockdown of COL10A1 in prostate cancer resulted in a substantial reduction in the proliferation, migration, and invasive potential of prostate cancer cells.
CONCLUSION
Our pan-cancer analysis of COL10A1 gene provided novel insights into its pivotal role in cancer initiation, progression, and therapeutic implications, underscoring its potential significance in prognosis and immunotherapeutic interventions for cancer, particularly prostate cancer.
Topics: Humans; Male; Collagen Type X; Oncogenes; Prognosis; Prostate; Prostatic Neoplasms
PubMed: 38147021
DOI: 10.18632/aging.205337 -
Molecular Cancer Nov 2023Recent studies have uncovered various physiological functions of CDK5 in many nonneuronal tissues. Upregulation of CDK5 and/or its activator p35 in neurons promotes... (Review)
Review
Recent studies have uncovered various physiological functions of CDK5 in many nonneuronal tissues. Upregulation of CDK5 and/or its activator p35 in neurons promotes healthy neuronal functions, but their overexpression in nonneuronal tissues is causally linked to cancer of many origins. This review focuses on the molecular mechanisms by which CDK5 recruits diverse tissue-specific substrates to elicit distinct phenotypes in sixteen different human cancers. The emerging theme suggests that CDK5's role as an oncogene or anti-oncogene depends upon its subcellular localization. CDK5 mostly acts as an oncogene, but in gastric cancer, it is a tumor suppressor due to its unique nuclear localization. This indicates that CDK5's access to certain nuclear substrates converts it into an anti-oncogenic kinase. While acting as a bonafide oncogene, CDK5 also activates a few cancer-suppressive pathways in some cancers, presumably due to the mislocalization of nuclear substrates in the cytoplasm. Therefore, directing CDK5 to the nucleus or exporting tumor-suppressive nuclear substrates to the cytoplasm may be promising approaches to combat CDK5-induced oncogenicity, analogous to neurotoxicity triggered by nuclear CDK5. Furthermore, while p35 overexpression is oncogenic, hyperactivation of CDK5 by inducing p25 formation results in apoptosis, which could be exploited to selectively kill cancer cells by dialing up CDK5 activity, instead of inhibiting it. CDK5 thus acts as a molecular rheostat, with different activity levels eliciting distinct functional outcomes. Finally, as CDK5's role is defined by its substrates, targeting them individually or in conjunction with CDK5 should create potentially valuable new clinical opportunities.
Topics: Humans; Nerve Tissue Proteins; Apoptosis; Oncogenes; Cytoplasm; Genes, Tumor Suppressor; Cyclin-Dependent Kinase 5
PubMed: 37993880
DOI: 10.1186/s12943-023-01895-8 -
Comptes Rendus Biologies Sep 2023Replication stress is an alteration in the progression of replication forks caused by a variety of events of endogenous or exogenous origin. In precancerous lesions,... (Review)
Review
Replication stress is an alteration in the progression of replication forks caused by a variety of events of endogenous or exogenous origin. In precancerous lesions, this stress is exacerbated by the deregulation of oncogenic pathways, which notably disrupts the coordination between replication and transcription, and leads to genetic instability and cancer development. It is now well established that transcription can interfere with genome replication in different ways, such as head-on collisions between polymerases, accumulation of positive DNA supercoils or formation of R-loops. These structures form during transcription when nascent RNA reanneals with DNA behind the RNA polymerase, forming a stable DNA:RNA hybrid. In this review, we discuss how these different cotranscriptional processes disrupt the progression of replication forks and how they contribute to genetic instability in cancer cells.
Topics: Transcription, Genetic; R-Loop Structures; DNA Replication; DNA; Oncogenes; RNA; Neoplasms
PubMed: 37779381
DOI: 10.5802/crbiol.123