Initiation Of Carcinogenesis Research Articles

A Crosstalk Between Dual-Specific Phosphatases and Dual-Specific Protein Kinases Can Be A Potential Therapeutic Target for Anti-cancer Therapy.

While protein tyrosine kinases (PTKs) play an initiative role in growth factor-mediated cellular processes, protein tyrosine phosphatases (PTPs) negatively regulates these processes, acting as tumor suppressors. Besides selective tyrosine dephosphorylation of PTKs via PTPs may affect oncogenic pathways during carcinogenesis. The PTP family contains a group of dual-specificity phosphatases (DUSPs) that regulate the activity of Mitogen-activated protein kinases (MAPKs), which are key effectors in the control of cell growth, proliferation and survival. Abnormal MAPK signaling is critical for initiation and progression stages of carcinogenesis. Since depletion of DUSP-MAPK phosphatases (MKPs) can reduce tumorigenicity, altering MAPK signaling by DUSP-MKP inhibitors could be a novel strategy in anti-cancer therapy. Moreover, Cdc25A is, a DUSP and a key regulator of the cell cycle, promotes cell cycle progression by dephosphorylating and activating cyclin-dependent kinases (CDK). Cdc25A-CDK pathway is a novel mechanism in carcinogenesis. Besides the mammalian target of rapamycin (mTOR) kinase inhibitors or mammalian target of rapamycin complex 1 (mTORC1) inhibition in combination with the dual phosphatidylinositol 3 kinase (PI3K)/mTOR or AKT kinase inhibitors are more effective in inhibiting the phosphorylation of eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and cap-dependent translation. Dual targeting of the Akt and mTOR signaling pathways regulates cellular growth, proliferation and survival. Like the Cdc2-like kinases (CLK), dual-specific tyrosine phosphorylation-regulated kinases (DYRKs) are essential for the regulation of cell fate. The crosstalk between dual-specific phosphatases and dual- specific protein kinases is a novel drug target for anti-cancer therapy. Therefore, the focus of this chapter involves protein kinase modules, critical biochemical checkpoints of cancer therapy and the synergistic effects of protein kinases and anti-cancer molecules.

Role of Bacterial Flora in Oral Cancer- An Insight

The human body contains about 1014 bacteria which usually colonise different parts of the body. The bacterial flora is important for a person’s health as well as normal functioning of tissue and organ systems. Bacteria are single celled organisms and are found on almost all surfaces of human body. They act in synergy with host immune mechanism and provide protection against various undesirable foreign invasions, especially in the oral cavity, where they exist in a diversified form which survive in a symbiotic relationship with the host. When there is a disturbance in this equilibrium due to various factors like trauma or tobacco smoking, betel nut chewing and alcohol intake, which makes the mucous membrane more permeable to invading microorganisms, these commensal bacterial species can become virulent and give rise to oral diseases ranging from dental caries to oral carcinoma. The effects of these bacteria can be either direct or indirect initiation of chronic inflammation, formation of procarcinogens that contribute to the development of oral carcinoma. This article focuses on the role of oral bacterial flora in initiation and progression of oral carcinogenesis. Various bacterial and fungal species associated with oral carcinoma and predominant bacterial species in oral cavity and oropharyngeal region along with measures to prevent their adverse effects are described.

Immuno-hormonal network in postmenopausal women: disturbance in breast cancer patients.

IntroductionAntibodies to estradiol and progesterone (Es and Pg) modulated their blood serum concentration and biological effects in immunized animals. Antibodies to membrane steroid receptors acted as hormone agonists or antagonists in cell cultures.Material and methodsHere we studied the levels of Es and Pg, idiotypic immunoglobulin (Ig) A1 and anti-idiotypic IgG2 specific to Es and Pg in the serum of postmenopausal women (82 healthy donors and 443 breast cancer patients).ResultsIt was found that individual high ratios of Pg/Es (> 4), IgA-Pg1/IgA-Es1 (> 1) and IgG-Pg2/IgG-Es2 (> 1) were associated with low breast cancer risk (OR = 0.4-0.5). High ratios of IgA-Pg1/IgA-Es1 and IgG-Pg2/IgG-Es2 were associated with a high Pg/Es ratio in healthy women but not in breast cancer patients. The levels of idiotypic IgA to benzo[a]pyrene correlated significantly with IgA-Es1 and IgA-Pg1 levels in both compared groups. IgA-Pg1/IgA-Es1 ratio correlated with IgG-Pg2/IgG-Es2 only in healthy women but not in breast cancer patients.ConclusionsThe normal immune-hormonal balance supports the real adaptation of the organism to environmental carcinogens and inhibits the initiation and promotion of carcinogenesis. The disturbance between certain elements of this network (immune-hormonal disbalance) could stimulate carcinogenesis. Further studies of immune-hormonal interaction could be helpful for understanding the pathogenesis of other carcinogen-induced steroid-dependent diseases in humans.

Involvement of Oral Microbiota in the Gut Microbiota of Colorectal Cancer

Background: The oral microbiota is reportedly associated with the gut microbiota and influences colorectal cancer (CRC) progression; however, the details remain unclear. Methods: This study included 52 patients diagnosed with CRC and 51 healthy controls. Saliva and stool samples were collected, and microbiota were evaluated using 16S rRNA analysis and next-generation sequencing. Comparative analysis was performed on both groups. Findings: Linear discriminant analysis Effect Size (LEfSe) revealed indigenous oral bacteria, such as Peptostreptococcus, Streptococcus, and Solobacterium spp., were present at a significantly higher relative abundance in CRC patients compared with controls, consistent for both saliva and stool. LEfSe was also performed after the CRC patients were divided into early stage (Stage I, II; n = 26; 50%) and advanced stage (Stage III, IV; n = 26;, 50%) disease. S. moorei was present at a significantly higher relative abundance in the advanced-stage group compared with the early-stage group, again consistent for both saliva and stool. Interpretation: Among the bacterial species whose relative abundance was significantly higher in CRC patients, P. stomatis, S. anginosus, S. koreensis and S. moorei were apparently supplied from the oral cavity, suggesting indigenous oral bacteria may have promoted initiation of CRC carcinogenesis. Furthermore, S. moorei may influence CRC progression. Funding Statement: This research was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (19K10361)(15H05045). Declaration of Interests: All authors declare no interests. Ethics Approval Statement: The study was conducted in accordance with the “Declaration of Helsinki.” The study protocols were approved by the ethics committee of Kagoshima University. Informed consent was obtained from all the study participants.

Patient Stratification of Clear Cell Renal Cell Carcinoma Using the Global Transcription Factor Activity Landscape Derived From RNA-Seq Data.

Clear cell renal cell carcinoma represents the most common type of kidney cancer. Precision medicine approach to ccRCC requires an accurate stratification of patients that can predict prognosis and guide therapeutic decision. Transcription factors are implicated in the initiation and progression of human carcinogenesis. However, no comprehensive analysis of transcription factor activity has been proposed so far to realize patient stratification. Here we propose a novel approach to determine the subtypes of ccRCC patients based on global transcription factor activity landscape. Using the TCGA cohort dataset, we identified different subtypes that have distinct up-regulated biomarkers and altered biological pathways. More important, this subtype information can be used to predict the overall survival of ccRCC patients. Our results suggest that transcription factor activity can be harnessed to perform patient stratification.

Hepatocyte-specific NRF2 activation controls fibrogenesis and carcinogenesis in steatohepatitis

In chronic liver diseases, inflammation induces oxidative stress and thus may contribute to the progression of liver injury, fibrosis, and carcinogenesis. The KEAP1/NRF2 axis is a major regulator of cellular redox balance. In the present study, we investigated whether the KEAP1/NRF2 system is involved in liver disease progression in humans and mice. The clinical relevance of oxidative stress was investigated by liver RNA sequencing in a well-characterized cohort of patients with non-alcoholic fatty liver disease (n= 63) and correlated with histological and clinical parameters. For functional analysis, hepatocyte-specific Nemo knockout (NEMOΔhepa) mice were crossed with hepatocyte-specific Keap1 knockout (KEAP1Δhepa) mice. Immunohistochemical analysis of human liver sections showed increased oxidative stress and high NRF2 expression in patients with chronic liver disease. RNA sequencing of liver samples in a human pediatric NAFLD cohort revealed a significant increase of NRF2 activation correlating with the grade of inflammation, but not with the grade of steatosis, which could be confirmed in a second adult NASH cohort. In mice, microarray analysis revealed that Keap1 deletion induces NRF2 target genes involved in glutathione metabolism and xenobiotic stress (e.g., Nqo1). Furthermore, deficiency of one of the most important antioxidants, glutathione (GSH), in NEMOΔhepa livers was rescued after deleting Keap1. As a consequence, NEMOΔhepa/KEAP1Δhepa livers showed reduced apoptosis compared to NEMOΔhepa livers as well as a dramatic downregulation of genes involved in cell cycle regulation and DNA replication. Consequently, NEMOΔhepa/KEAP1Δhepa compared to NEMOΔhepa livers displayed decreased fibrogenesis, lower tumor incidence, reduced tumor number, and decreased tumor size. NRF2 activation in patients with non-alcoholic steatohepatitis correlates with the grade of inflammation, but not steatosis. Functional analysis in mice demonstrated that NRF2 activation in chronic liver disease is protective by ameliorating fibrogenesis, initiation and progression of hepatocellular carcinogenesis. The KEAP1 (Kelch-like ECH-associated protein-1)/NRF2 (erythroid 2-related factor 2) axis has a major role in regulating cellular redox balance. Herein, we show that NRF2 activity correlates with the grade of inflammation in patients with non-alcoholic steatohepatitis. Functional studies in mice actually show that NRF2 activation, resulting from KEAP1 deletion, protects against fibrosis and cancer.

Restraint stress abates the antioxidant potential of melatonin on dimethyl benz (a) anthracene (DMBA) induced carcinogenesis.

Free radical involvement in initiation, promotion and progression of carcinogenesis, implicates that scavengers of free radicals may act as inhibitors in the carcinogenic process. Melatonin, an antioxidant was used in the present study to evaluate its effectiveness on skin carcinogenesis induced by DMBA both with and without chronic restraint stress (CRS). Fifty Swiss albino young male rats were divided into five groups of 10 rats each as controls, topical DMB alone, Pre CRS-DMBA, melatonin DMBA and Pre-CRS-DMBA-melatonin treated groups. After 18 weeks blood was collected along with liver and skin samples. These were used for antioxidant enzyme assay, DNA damage and fluorescent spectra analysis. Melatonin showed antioxidant potential in combatting DMBA induced skin carcinogenesis measured by free radical scavenging enzymes and in vivo antioxidant status, DNA damage. Sensitive detection of the DMBA induced micro biochemical changes was possible by fluorescent spectroscopy from the transformed ratio of fluorescent intensity (F1 530 nm/630 nm) otherwise found constant for normal tissues. By melatonin treatment this ratio was similar to control values. The decreased antioxidant biochemical parameters depicting oxidative stress were comparable to comet assay and fluorescent studies, endorsing the chemo-preventive efficacy of melatonin against skin carcinogenesis caused by DMBA. CRS pre-exposure diminished the chemo-preventive/antioxidant ability of melatonin and the results were same as DMBA alone treatment, showing stress affected both cancer development and chemoprevention. CRS decreased the antioxidant potential of melatonin. Hence, managing stress could be perceived in cancer chemoprevention. Further studies focusing on stress reduction are needed.

Protective effect of Matricaria chamomilla extract against 1,2-dimethylhydrazine-induced colorectal cancer in mice.

Background Colorectal cancer (CRC) is a major public health problem, with almost 1.8 million newly diagnosed cases and about 881,000 deaths annually. Chamomile (Matricaria chamomilla) is a well-documented medicinal herb that possesses anti-inflammatory and anti-carcinogenic properties. This study aimed to unravel the effect of aqueous chamomile extract against 1,2-dimethylhydrazine(DMH)-induced CRC in mice. Methods Male Balb/c mice received a weekly intraperitoneal injection of DMH (20 mg/kg body weight) for 12 weeks. Chamomile extract (150 mg/kg body weight/5 days/week p.o.) was administered at the initiation and post-initiation stages of carcinogenesis. Polyps count, histopathological analysis, real-time polymerase chain reaction (RT-PCR) analysis of Wnt signaling genes, ELISA of cyclooxygenase-2 (COX-2), and enzyme assay for inducible nitric oxide synthase (iNOS) were performed. Results Chamomile extract modulated the Wnt pathway in colonic tissues, where it significantly downregulated Wnt5a, β-catenin, T cell factor (Tcf4), lymphoid enhancer factor 1 (Lef1), c-Myc and Cyclin D1 expression levels, while it upregulated adenomatous polyposis coli (APC) and glycogen synthase kinase (GSK3β) expression levels. This extract significantly reduced COX-2 levels and iNOS activities. Polyps count and histopathological analysis provided supportive evidence for the biochemical and molecular analyses. Conclusions Chamomile can act as a potent dietary chemopreventive agent against DMH-induced CRC.

Dual Effects of Non-Coding RNAs (ncRNAs) in Cancer Stem Cell Biology.

The identification of cancer stem cells (CSCs) as initiators of carcinogenesis has revolutionized the era of cancer research and our perception for the disease treatment options. Additional CSC features, including self-renewal and migratory and invasive capabilities, have further justified these cells as putative diagnostic, prognostic, and therapeutic targets. Given the CSC plasticity, the identification of CSC-related biomarkers has been a serious burden in CSC characterization and therapeutic targeting. Over the past decades, a compelling amount of evidence has demonstrated critical regulatory functions of non-coding RNAs (ncRNAs) on the exclusive features of CSCs. We now know that ncRNAs may interfere with signaling pathways, vital for CSC phenotype maintenance, such as Notch, Wnt, and Hedgehog. Here, we discuss the multifaceted contribution of microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), as representative ncRNA classes, in sustaining the CSC-like traits, as well as the underlying molecular mechanisms of their action in various CSC types. We further discuss the use of CSC-related ncRNAs as putative biomarkers of high diagnostic, prognostic, and therapeutic value.

Abstract 3828: Tumor promoting effects of sulforaphane on diethylnitrosamine-induced murine hepatocarcinogenesis

Abstract Nuclear factor erythroid 2-related factor 2 (NRF2) is a key transcription factor involved in protection against initiation of carcinogenesis in normal cells. Notably, recent studies have demonstrated that mutation of the gene encoding this transcription factor causes its overactivation in various types of human malignancies. The aberrant activation of NRF2 is considered to accelerate the proliferation and progression of cancer cells. However, the exact function of NRF2 in the stage of pre-malignancy remains still largely unresolved. The differential effects of NRF2 on multi-stage carcinogenesis have raised a concern about the validity of NRF2 activators for chemoprevention. In the present study, a well-known NRF2 activating chemopreventive phytochemical, sulforaphane (SFN), was daily injected intraperitonally (25 mg/kg) for 3 months to male C57BL/6 mice at 6 months after single intraperitoneal administration of a hepatocarcinogen, diethylnitrosamine (DEN). The relative fold changes of liver weight, tumor growth, and the number and the size of hepatomas measured at 9 months after DEN administration were significantly higher in SFN-treated mice than that in vehicle-treated mice. Moreover, the expression of NRF2, its target protein NAD(P)H:quinone oxidoreductase 1 (NQO1), and the cell proliferation marker proliferating cell nuclear antigen (PCNA) and the DNA damage marker gamma-histone 2A family member X (γH2AX) was markedly elevated in SFN-treated mice compared with that in vehicle-treated mice as assessed by the Western blot assay. Immunohistochemistry and Immunofluorescence staining data further verified higher expression of NRF2 and PCNA in SFN-treated mice. These results suggest that once HCC is initiated, SFN stimulates the progression of DEN-induced HCC via activation of NRF2, rather than exerting a cancer chemopreventive effect. RNA sequencing analysis with liver tumors from DEN-treated mice revealed the B-raf V637E mutation (4/7). We speculate that mutation of B-raf proto-oncogene may contribute, at least in part, to activation of oncogenic NRF2 in DEN-induced murine carcinogenesis. The effects of SFN on DEN-induced mutation spectrum is under investigation. This study was supported by the Global Core Research Center (GCRC) Grant (No. 2011-003-0001) from the National Research Foundation (NRF) of Republic of Korea. Citation Format: Jie Zheng, Do-Hee Kim, Xi Zhu Fang, Seong Hoon Kim, Soma Saeidi, Su-Jung Kim, Young-Joon Surh. Tumor promoting effects of sulforaphane on diethylnitrosamine-induced murine hepatocarcinogenesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3828.

Abstract B31: YAP1-induced cervical carcinogenesis challenges the HPV dogma

Abstract Aims: HPV infections are common in women but only rarely cause cervical cancer, suggesting that individual genetic susceptibility may play a critical role in the establishment of persistent HPV infection and development of cervical cancer. The molecular mechanisms underlying cervical cancer development remain unclear. Although our previous in vitro studies have shown that YAP1 plays a role in the malignant transformation of cervical epithelial cells, whether YAP1 contributes to the cervical carcinogenesis in vivo is unknown. This study aims to determine whether YAP1, alone or interacting with HPV, contributes to cervical carcinogenesis in vivo. Methods: Cellular and transgenic mouse models were developed to evaluate the role of YAP1 in cervical carcinogenesis. Results: Keratin-14 promoter-driven expression of constitutively active YAP1 (YAPS127A) in mouse cervical epithelial cells induced invasive cervical cancer, suggesting that hyperactivation of YAP1 is sufficient to induce cervical cancer development. Cervical epithelial cell-specific HPV and YAP1 double knockin mouse models showed that HPV synergizes with YAP1 to promote the initiation and progression of cervical carcinogenesis. Our mechanistic studies demonstrated that hyperactivation of YAP1 in cervical epithelium not only increased the putative HPV receptor molecules and cellular susceptibility to HPV infection, but also disrupted the host cell innate immune system, resulting in failure of HPV viral recognition, suppression of type I IFN production, inhibition of the IFNRs/JAKs/STATs pathway, and blockage of production of antiviral interferon-stimulated genes. Conclusion: Our results indicated that the YAP1 oncogene plays a central role in cervical cancer development. The synergism between hyperactivated YAP1 and high-risk HPV may be a key driver of cervical cancer initiation and progression. Our finding challenges the dogma that HPV is a necessary agent for the development of cervical cancer, uncovers a novel mechanism for the cervical carcinogenesis, and provides new targets for developing strategies to improve prevention and treatment of cervical cancer. Note: This abstract was not presented at the conference. Citation Format: Cheng Wang. YAP1-induced cervical carcinogenesis challenges the HPV dogma [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr B31.

Suppression of Membranous LRP5 Recycling, Wnt/β-Catenin Signaling, and Colon Carcinogenesis by 15-LOX-1 Peroxidation of Linoleic Acid in PI3P

APC mutation activation of Wnt/β-catenin drives initiation of colorectal carcinogenesis (CRC). Additional factors potentiate β-catenin activation to promote CRC. Western diets are enriched in linoleic acid (LA); LA-enriched diets promote chemically induced CRC in rodents. 15-Lipoxygenase-1 (15-LOX-1), the main LA-metabolizing enzyme, is transcriptionally silenced during CRC. Whether LA and 15-LOX-1 affect Wnt/β-catenin signaling is unclear. We report that high dietary LA promotes CRC in mice treated with azoxymethane or with an intestinally targeted Apc mutation (ApcΔ580) by upregulating Wnt receptor LRP5 protein expression and β-catenin activation. 15-LOX-1 transgenic expression in mouse intestinal epithelial cells suppresses LRP5 protein expression, β-catenin activation, and CRC. 15-LOX-1 peroxidation of LA in phosphatidylinositol-3-phosphates (PI3P_LA) leads to PI3P_13-HODE formation, which decreases PI3P binding to SNX17 and LRP5 and inhibits LRP5 recycling from endosomes to the plasma membrane, thereby increasing LRP5 lysosomal degradation. This regulatory mechanism of LRP5/Wnt/β-catenin signaling could be therapeutically targeted to suppress CRC.

Induction of Biosynthetic Genes Related to Rosmarinic Acid in Plant Callus Culture and Antiproliferative Activity Against Breast Cancer Cell Line.

Rosmarinic acid is considered as one of the most important secondary metabolites in medicinal plants especially of family Lamiaceae. Rosmarinic acid can prevent both the tumor initiation and promotion stages of carcinogenesis. The aim of current study was to evaluate the antiproliferative effects of Hyssopus officinalis and Thymus vulgaris callus crude extracts contained rosmarinic acid on breast cancer cells with correlation to phenylpropanoid biosynthetic pathway genes expression. Calli of both plants were maintained on Murashige and Skoog medium supplemented with kinetin and 2,4-D. Rosmarinic acid was determined spectrophotometrically in both seed-germinated plants (control) and callus tissues. Transcriptional profiling of rosmarinic acid pathway genes was performed with RT-PCR system. The human breast cancer cell line MCF-7 was treated with different levels of crude extracts at different time intervals in order to show their effects on the cell proliferation using a cell viability colorimetric assay (MTT). The results showed a significant increase of rosmarinic acid content up to 6.5% in callus compared to control. The transcriptional profile of the selected rosmarinic acid genes in callus tissues indicated significant effects on the rosmarinic acid content in both genotypes. T. vulgaris (90 μg mL-1) and H. officinalis (150 μg mL-1) callus extracts had exhibited highest reduction in the cell MCF-7 viability after 48 h of exposure. It was concluded that rosmarinic acid production increased in callus tissue, showed the higher gene expression levels and remarkably inhibited growth of human breast cancer cell line.

Genomic and transcriptomic profiling of carcinogenesis in patients with familial adenomatous polyposis

ObjectiveFamilial adenomatous polyposis (FAP) is characterised by the development of hundreds to thousands of adenomas at different evolutionary stages in the colon and rectum that will inevitably progress to adenocarcinomas...

Persistent SARS-CoV-2 infection and the risk for cancer

The current SARS-CoV-2 has put significant strain on healthcare services worldwide due to acute COVID-19. However, the potential long-term effects of this infection haven’t been extensively discussed.We hypothesize that SARS-CoV-2 may be able to cause persistent infection in some individuals, and should this be the case, that in a few years we may see a rise in cancer incidence due to carcinogenic effects of this coronavirus.Non-retroviral RNA viruses such as Coronaviridae have been shown to cause persistent infection in hosts. Empirical evidence of viral genomic material shedding weeks after apparent clinical and laboratorial resolution of COVID-19 may be an indirect proof for persistent viral infection. Furthermore, tropism towards certain immune-privileged territories may facilitate immune evasion by this virus.Structural homology with SARS-CoV-1 indicates that SARS-CoV-2 may be able to directly impair pRb and p53, which are key gatekeepers with tumor suppressor functions. Additionally, COVID-19 features preeminent inflammatory response with marked oxidative stress, which acts as both as initiator and promotor of carcinogenesis.Should there be a carcinogenic risk associated with SARS-CoV-2, the implications for public health are plenty, as infected patients should be closely watched during long periods of follow-up.Additional investigation to establish or exclude the possibility for persistent infection is paramount to identify and prevent possible complications in the future.

Procarcinogen Activation and Mutational Signatures Model the Initiation of Carcinogenesis in Human Urothelial Tissues In Vitro

Disparity between genome-wide mutations in bladder and other cancers where smoking is a risk factor raises questions about carcinogenesis in different epithelia. To develop an experimental model of bladder carcinogenesis, we clonally expanded in vitro differentiated normal human urothelial (NHU) cells following exposure to an exemplar procarcinogen and used whole-genome DNA sequencing to derive mutational signatures. Benzo[a]pyrene (BaP) was activated by endogenous cytochrome P450 (cytochrome P450 family 1 subfamily A member 1 [CYP1A1]) to create genomically modified NHU cells. Comparison with the Catalogue of Somatic Mutations in Cancer (COSMIC) showed that mutations induced by BaP in NHU cells were similar to smoking-associated signatures in bladder and other cancers, including single- and doublet-base substitution signatures characterised by C > A transversions (COSMIC_SBS4 and COSMIC_DBS2, respectively), and an insertion/deletion signature of C deletions in homopolymer regions (COSMIC ID3). Our study provides the first direct evidence that BaP is activated locally in the urothelium, initiating the well-described smoking-associated mutational signatures. An absence of other common bladder cancer (BLCA)-associated genomic signatures points strongly to other primary causes of BLCA, which the new experimental approach described here is well placed to investigate. Mutational signatures ignore whether genes are affected, but tissue-specific drivers (KMT2D, KMT2C, and CDKN1A) were significantly overmutated in this model, providing insight on the emergent selection pressures. Patient summaryIn a carefully controlled laboratory setting, we exposed normal human urothelial tissues to a procarcinogen (benzo[a]pyrene) found in cigarette smoke. We show that the urothelial tissues activated the carcinogen and led to mutations forming across the genome in a characteristic pattern. This particular “mutational signature” is found in bladder tumours and other smoking-induced cancers (eg, lung); however, our study highlights that there are other unknown mutational processes in bladder cancer that is not the direct result of smoke carcinogens, and this will require further investigation.

The Dual Function of Aryl Hydrocarbon Receptor in Bladder Carcinogenesis.

Although Aryl hydrocarbon receptor (AhR) may be critical to several types of cancers, the function of AhR for carcinogenesis of bladder cancer (BC) is still inconclusive. We, therefore, sought to examine the involvement of AhR in bladder carcinogenesis. We examined the AhR expression of human BC and N-butyl-N-(4-hydroxybutyl)-induced bladder carcinogenesis in AhR-deficient mice. There was a significantly higher expression of AhR in non-muscle-invasive BC compared to normal tissue and muscle-invasive BC (MIBC). The incidence of MIBC in AhR-deficient mice (87.5%) was significantly higher than wild-type mice (9.5%, p<0.01). In cell invasion assay, the induction of AhR signaling resulted in attenuation of BC cell invasiveness and proliferation. These results suggest that AhR may be essential for the initiation of carcinogenesis and attenuated the invasion of BC cells; this signaling may have a dual function in bladder carcinogenesis.

Betel quid-associated cancer: Prevention strategies and targeted treatment.

Betel quid (BQ) and areca nut use are at risk of cancer. This review includes the latest evidence of carcinogenesis caused by BQ exposure, suggests possible prevention strategies. We conducted a systematic literature search in the PubMed and Web of Science databases to identify relevant articles published in the past 10 years according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. Arecoline N-oxide, a metabolite of areca nut, is likely an initiator in carcinogenesis and is detoxified by N-acetylcysteine. Oral potentially malignant disorder and reactive oxygen species involved in carcinogenesis pathways may be treatable using antioxidants. Screening programs conducted by trained physicians are useful for identifying patients with early stages of oral cancer in high-risk groups. Anti-inflammatory medications may be used as chemopreventive agents in the disease-free stage after surgery. The association between survival and tumor somatic mutations in patients who chew BQ should be addressed in cancer studies. Current evidence on the natural course from BQ exposure to cancer occurrence and development provides information for developing primary, secondary, and tertiary prevention strategies against BQ-associated cancer at clinical or translational levels.

Current and Novel Therapies Against Helminthic Infections: The Potential of Antioxidants Combined with Drugs.

Infections caused by Schistosoma haematobium and Opisthorchis viverrini are classified as Group 1 biological carcinogen and it has been postulated that parasites produce oxysterol and estrogen-like metabolites that might be considered as initiators of infection-associated carcinogenesis. Chemotherapy for these helminthic infections relies on a single drug, praziquantel, (PZQ) that mainly targets the parasite. Additionally, PZQ has some major drawbacks as inefficacy against juvenile form and alone it is not capable to counteract pathologies associated to infections or prevent carcinogenesis. There is an urgent need to develop novel therapeutic approaches that not only target the parasite but also improve the pathologies associated to infection, and ultimately, counteract or/and prevent the carcinogenesis processes. Repurposing the drug in combination of compounds with different modes of action is a promising strategy to find novel therapeutics approaches against these helminthic infections and its pathologies. Here, we emphasized that using antioxidants either alone or combined with anthelmintic drugs could ameliorate tissue damage, infection-associated complications, moreover, could prevent the development of cancer associated to infections. Hence, antioxidants represent a potential adjuvant approach during treatment to reduce morbidity and mortality. Despite the success of some strategies, there is a long way to go to implement novel therapies for schistosomiasis.

Bacterial signatures and their inflammatory potentials associated with prostate cancer.

Chronic inflammation can create a microenvironment that can contribute to the formation of prostate pathologies. Far less well understood is the origin of inflammation in the prostate. One potential source is microbial infections of the prostate. This review summarizes recent findings regarding the presence of bacteria in the prostate and the dysbiosis of bacterial populations in the urinary tract and the gastrointestinal tract related to prostate cancer, thereby focusing on next-generation sequencing (NGS)-generated data. The current limitations regarding NGS-based detection methods and other difficulties in the quest for a microbial etiology for prostate cancer are discussed. We then focus on a few bacterial species, including Cutibacterium acnes and Escherichia coli that are often NGS-detected in prostatic tissue specimens, and discuss their possible contribution as initiator or enhancer of prostate inflammation and prostate carcinogenesis.