Promotion Of Carcinogenesis Research Articles

Ecosystemic Approach to Understanding Gut Microbiome-Mediated Prevention of Colorectal Cancer.

Humans and their associated microorganisms coexist in complex symbiotic relationships. Continuously advancing research is demonstrating the crucial role of host-associated microbiota in the pathophysiology and etiology of disease and in mediating the prevention thereof. As an exemplar, the gut microbiota, especially colonic bacteria, have been extensively studied in colorectal cancer (CRC), and the growing body of evidence establishes new oncomicrobes and their oncometabolites associated with the initiation and promotion of carcinogenesis. Herein, we discuss the importance of approaching the gut microbiome as an ecosystem rather than an assortment of individual factors, especially in the context of cancer prevention. Furthermore, we argue that a dietary pattern effectively drives multiple nodes of the gut microbial ecosystem toward disease- or health-promoting qualities. In the modern circumstances of excessive consumption of ultraprocessed and animal-based foods and concomitant escalation of chronic disease burden worldwide, we focus on whole food-derived dietary fiber as a key to establishing a health-promoting eubiosis in the gut.

Endogenous nitroso compounds (NOC) from dietary source: Plausible promoters of oral carcinogenesis in non-smokers and non-alcoholics

Goal of the perspectiveEndogenous nitroso compounds (NOCs) from food sources contribute to oral carcinogenesis in non-smokers and non-alcoholics. Research in this field may lead to improved preventative and intervention methods for treating oral cancer in those who are not exposed to conventional risk factors like alcoholism and smoking. DiscussionThe intricate interplay between endogenous nitroso compounds, oral microbiota, and the host's immune response presents a complex landscape in understanding the promotion of oral carcinogenesis in non-smokers and non-alcoholics. Insights gained from these research efforts hold the potential to comprehensively understand the mechanisms through which NOCs contribute to oral carcinogenesis. Identification of specific molecular and cellular pathways through which NOCs from dietary sources contribute to oral carcinogenesis are crucial to establish the role of Endogenous NOCs. ConclusionThe field of study on endogenous NOCs derived from diet and their potential impact on oral carcinogenesis in individuals who do not smoke or drink is a dynamic and constantly changing one. In-depth research is vital to create specialized/customised prevention and treatment plans for this category of oral cancer.

Histone modification-linked prognostic model for ovarian cancer reveals LBX2 as a novel growth promoter.

Ovarian cancer (OC) is a deadly disease with limited treatment options and poor overall survival rates. This study aimed to investigate the role of histone modification-related genes in predicting the prognosis of OC patients. Transcriptome data from multiple cohorts, including bulk RNA-Seq data and single-cell scRNA-Seq data, were collected. Gene set enrichment analysis was used to identify enriched gene sets in the histone modification pathway. Differentially expressed genes (DEGs) between histone modification-high and histone modification-low groups were identified using Lasso regression. A prognostic model was constructed using five selected prognostic genes from the DEGs in the TCGA-OV cohort. The study found enrichment of gene sets in the histone modification pathway and identified five prognostic genes associated with OC prognosis. The constructed risk score model based on histone modification-related genes was correlated with immune infiltration of T cells and M1 macrophages. Mutations are more prevalent in the high-risk group compared to the low-risk group. Several drugs were screened against the model genes. Through invitro experiments, we confirmed the expression patterns of the model genes. LBX2 facilitates the proliferation of OC. Histone modification-related genes have the potential to serve as biomarkers for predicting OC prognosis. Targeting these genes may lead to the development of more effective therapies for OC. Additionally, LBX2 represents a novel cell proliferation promoter in OC carcinogenesis.

Effect of Low-Dose Alcohol Consumption on Chronic Liver Disease.

Although alcohol is one of the most important etiologic agents in the development of chronic liver disease worldwide, also recognized as a promoter of carcinogenesis, several studies have shown a beneficial effect of moderate consumption in terms of reduced cardiovascular morbidity and mortality. Whether this benefit is also present in patients with liver disease due to other causes (viral, metabolic, and others) is still debated. Although there is no clear evidence emerging from guidelines and scientific literature, total abstention from drinking is usually prescribed in clinical practice. In this review, we highlight the results of the most recent evidence on this controversial topic, in order to understand the effect of mild alcohol use in this category of individuals. The quantification of alcohol intake, the composition of the tested populations, and the discrepancy between different works in relation to the outcomes represent important limitations emerging from the scientific literature. In patients with NAFLD, a beneficial effect is demonstrated only in a few works. Even if there is limited evidence in patients affected by chronic viral hepatitis, a clear deleterious effect of drinking in determining disease progression in a dose-dependent manner emerges. Poor data are available about more uncommon pathologies such as hemochromatosis. Overall, based on available data, it is not possible to establish a safe threshold for alcohol intake in patients with liver disease.

Passive Smoking–Induced Mutagenesis as a Promoter of Lung Carcinogenesis

IntroductionThe International Agency for Research on Cancer has classified passive smoking (PS) or secondhand smoke exposure as a group 1 carcinogen linked to lung cancer. However, in contrast to active smoking, the mutagenic properties of PS remain unclear. MethodsA consecutive cohort of 564 lung adenocarcinoma samples from female never-smokers, who provided detailed information about their exposure to PS during adolescence and in their thirties through a questionnaire, was prepared. Of these, all 291 cases for whom frozen tumor tissues were available were subjected to whole exome sequencing to estimate tumor mutational burden, and the top 84 cases who were exposed daily, or not, to PS during adolescence, in their thirties or in both periods, were further subjected to whole genome sequencing. ResultsA modest yet statistically significant increase in tumor mutational burden was observed in the group exposed to PS compared with the group not exposed to PS (median values = 1.44 versus 1.29 per megabase, respectively; p = 0.020). Instead of inducing driver oncogene mutations, PS-induced substantial subclonal mutations exhibiting APOBEC-type signatures, including SMAD4 and ADGRG6 hotspot mutations. A polymorphic APOBEC3A/3B allele-specific to the Asian population that leads to up-regulated expression of APOBEC3A accentuated the mutational load in individuals exposed daily to PS during adolescence. ConclusionsThis study reveals that PS–induced mutagenesis can promote lung carcinogenesis. The APOBEC3A/3B polymorphism may serve as a biomarker for identifying passive nonsmoking individuals at high risk of developing lung cancer.

Epidemiology of gallbladder cancer in India 2018–2023

ABSTRACT India is a high-incidence area for gallbladder cancer (GBC), contributing approximately 10% of the global GBC burden. Within the country, the incidence is notably high in North, North-East, Central, and Eastern regions, whereas it is less common in South and West India. The incidence has been steadily rising in both genders. Patients often present with advanced disease, which carries a dismal prognosis. Unlike the West, GBC in India typically affects younger patients in their fifth and sixth decades of life. Gallstones are present in 80% of Indian GBC patients, increasing the vulnerability of the gallbladder to mucosal injury. However, the incidence of GBC is disproportionate to the prevalence of gallstones in the country. Additional cofactors such as older age, lower socioeconomic status, chronic Salmonella typhi infection, Helicobacter pylori infection, exposure to pollutants, heavy metals, chemicals, adulterated mustard oil, and smoking in patients with gallstones have been identified as promoters of carcinogenesis. These risk factors act additively, resulting in a higher incidence of GBC and accelerating its development. Environmental risk factors, including soil and water contamination by industrial wastes, agricultural effluents, and human sewage, have also been identified as putative risk factors. The combination of a toxic environment, a vulnerable gallbladder, and a susceptible host plays a key role in the pathogenesis of GBC in India. Large multicentric comprehensive studies are required to assess the attributable risk of each identified putative risk factor. This will aid in formulating cost-effective national strategies to prevent GBC-related mortality in the country. Meanwhile, maintaining a high index of suspicion to detect incidental GBC and improving access to health-care facilities for appropriate management of gallstones will help reduce GBC-related mortality.

In Vivo Anti-Hepatocellular Carcinoma Effects of the Chloroform Root Extract of Clausena excavata Burm.

Liver cancer is the most common cancer among males in Africa. The disease has a poor prognosis and its treatment is associated with toxicity and resistance. For this reason, numerous herbal combinations are being subjected to anticancer screening to circumvent the shortcomings of the conventional anticancer drugs. In the current study, the in vivo anti-cancer effects of the chloroform root extract of the herb, Clausena excavata Burm were investigated. Liver cancer was induced in mice by a single intraperitoneal injection of diethylnitrosamine (DEN) followed by oral administration of the promoter of carcinogenesis, 2-aminoacetyl fluorine that was mixed with the mice feed. The cytotoxicity of the root extract of C. excavata on liver cancer cells was investigated using liver enzyme, histology, DNA fragmentation and caspases assays. Real time qPCR was conducted to evaluate the effect of the extract on apoptotic genes. The findings revealed that the extract of C. excavata significantly decreased the progression of hepatocarcinogenesis and the toxicity-induced production of the liver enzymes, alanine and aspartate aminotransferases. The histological analyses of the liver tissues revealed evidence of apoptotic cell death. The extract also provoked significant (p < .05) expressions of caspase 9 protein and gene as well as other apoptotic genes (P53, P27, Apaf-1, cytochrome C, bax and bid). Therefore, we postulate that the chloroform root extract of C. excavata induces apoptosis of liver cancer in mice.

Salivary Oxidative Stress Assessment in Tobacco Users with and without Potentially Malignant Disorders and Micronuclei Estimation using Fluorescent Microscopy

Abstract Background: Consumption of tobacco in either smoking or nonsmoking form produces free radicals, contributing to an increased risk of oral cancer as a result of oxidative stress. Biochemical changes in antioxidant enzymes are responsible for tobacco-associated oral carcinogenesis. Due to the production of reactive oxygen species and oxidative stress, the promotion of carcinogenesis occurs in the cells. Oral potentially malignant disorders (OPMDs) is an assembly of benign lesions with morphologically altered clinical or histopathological tissue that has a greater than normal risk of transforming into malignant lesions after diagnosis at a later date. Micronuclei are the goal site for early genotoxic events and are involved in carcinogenic events. Micronuclei in exfoliated cells are useful biomarkers in assessing cytogenetic damage. Early detection will help to devise appropriate treatment plans, thereby improving patient survival rates. Aim and Objectives: To estimate the salivary superoxide dismutase (SOD) levels and the expression of micronuclei in exfoliated buccal cells of tobacco users before the onset of tobacco-induced oral lesions and correlating the same with patients with OPMDs to determine if this can be useful in predicting early malignant potential in subjects with habitual tobacco usage. Materials and Methods: The study included three groups. Group I – Tobacco users with OPMD (n = 50), Group II – Tobacco users without OPMD (n = 50), and Group III – Healthy controls (n = 50). Sandwich enzyme-linked immunosorbent assay was done for saliva samples for quantification of salivary SOD. Exfoliated buccal cells were smeared and stained with acridine orange stain and viewed under a fluorescent microscope for micronuclei estimation. Results: The study showed a significant difference in salivary SOD levels and increased micronuclei expression among tobacco users than healthy controls. Conclusion: Our study results revealed a gradual and steady decrease of SOD levels and increased micronuclei expression from healthy control to tobacco users without lesions and tobacco users with lesion, and this can be used as an effective noninvasive early diagnostic biomarker in assessing malignant progression in tobacco users. Furthermore, the evaluation of micronuclei estimation can serve as a simple, quick, and noninvasive chair-side procedure for regular oral cancer screening in patients with tobacco usage.

Carcinogenesis promotion in oral squamous cell carcinoma: KDM4A complex-mediated gene transcriptional suppression by LEF1.

Oral squamous cell carcinoma (OSCC) is the most prevalent cancer of the mouth, characterised by rapid progression and poor prognosis. Hence, an urgent need exists for the development of predictive targets for early diagnosis, prognosis determination, and clinical therapy. Dysregulation of lymphoid enhancer-binding factor 1 (LEF1), an important transcription factor involved in the Wnt-β-catenin pathway, contributes to the poor prognosis of OSCC. Herein, we aimed to explore the correlation between LEF1 and histone lysine demethylase 4 A (KDM4A). Results show that the KDM4A complex is recruited by LEF1 and specifically binds the LATS2 promoter region, thereby inhibiting its expression, and consequently promoting cell proliferation and impeding apoptosis in OSCC. We also established NOD/SCID mouse xenograft models using CAL-27 cells to conduct an in vivo analysis of the roles of LEF1 and KDM4A in tumour growth, and our findings show that cells stably suppressing LEF1 or KDM4A have markedly decreased tumour-initiating capacity. Overall, the results of this study demonstrate that LEF1 plays a pivotal role in OSCC development and has potential to serve as a target for early diagnosis and treatment of OSCC.

Farnesoid X receptor activation inhibits pancreatic carcinogenesis

Farnesoid X receptor (FXR), a member of the nuclear receptor superfamily that controls bile acid (BA) homeostasis, has also been proposed as a tumor suppressor for breast and liver cancer. However, its role in pancreatic ductal adenocarcinoma (PDAC) tumorigenesis remains controversial. We recently found that FXR attenuates acinar cell autophagy in chronic pancreatitis resulting in reduced autophagy and promotion of pancreatic carcinogenesis. Feeding Kras-p48-Cre (KC) mice with the BA chenodeoxycholic acid (CDCA), an FXR agonist, attenuated pancreatic intraepithelial neoplasia (PanIN) progression, reduced cell proliferation, neoplastic cells and autophagic activity, and increased acinar cells, elevated pro-inflammatory cytokines and chemokines, with a compensatory increase in the anti-inflammatory response. Surprisingly, FXR-deficient KC mice did not show any response to CDCA, suggesting that CDCA attenuates PanIN progression and decelerate tumorigenesis in KC mice through activating pancreatic FXR. FXR is activated in pancreatic cancer cell lines in response to CDCA in vitro. FXR levels were highly increased in adjuvant and neoadjuvant PDAC tissue compared to healthy pancreatic tissue, indicating that FXR is expressed and potentially activated in human PDAC. These results suggest that BA exposure activates inflammation and suppresses autophagy in KC mice, resulting in reduced PanIN lesion progression. These data suggest that activation of pancreatic FXR has a protective role by reducing the growth of pre-cancerous PDAC lesions in response to CDCA and possibly other FXR agonists.

The Effect of Xanthohumol Derivatives on Apoptosis Induction in Canine Lymphoma and Leukemia Cell Lines.

Xanthohumol is a cancer chemopreventive agent that can interfere with the initiation, promotion, and progression phase of carcinogenesis via a variety of inhibitory mechanisms. Xanthohumol was reported as an effective agent against leukemia/lymphoma cells. In the present study, we investigated the effect of xanthohumol and its natural and semisynthetic derivatives against various canine leukemia/lymphoma cell lines. Xanthohumol, three hops minor prenylflavonoids (xanthohumol C, xanthohumol D, α,β-dihydroxanthohumol) and four derivatives obtained by biotransformation (xanthohumol 4'-O-β-D-(4‴-O-methyl)-glucopyranoside) as well as by chemical modification (1″,2″-dihydroxanthohumol K, 2,3-dehydroisoxanthohumol, (Z)-6,4'-dihydroxy-4-methoxy-7-prenylaurone) were tested for their antiproliferative and pro-apoptotic activities against the following canine leukemia/lymphoma cell lines: CLBL-1 (B-cell lymphoma), CLB70 (B-cell leukemia), and GL-1 (B-cell leukemia). The compounds were tested at a final concentration range of 0.1-30 µM for 48 h. All eight of the tested flavonoids exerted concentration-dependent cytotoxicity in the selected canine lymphoma/leukemia cell lines. Three compounds markedly decreased the viability of all cell lines with IC50 in the range of 0.5 to 8 μM. Double-staining of the treated cells with AnnexinV and propidium iodide revealed that the dying cells were mostly in the late apoptosis stage. ROS production and changes in mitochondrial potential were detected. Western blot analysis showed a decreased expression of Bcl-2. Canine lymphoma and leukemia cell lines are sensitive to xanthohumol derivatives, and the compounds acted through an apoptotic cell-death mechanism. These compounds, either used alone or in combination with other therapies, may be useful for the treatment of canine leukemia/lymphoma.

Pivotal role of AKR1B1 in pathogenesis of colitis associated colorectal carcinogenesis

Identifying the target linking inflammation and oxidative stress to aggravate the disease progression will help to prevent colitis associated carcinogenesis. Since AKR1B1 overexpression is observed in inflammatory diseases and various cancers, we have investigated the role of AKR1B1 in colitis-associated colon carcinogenesis with the aid of epalrestat and its potent analogue NARI-29 (investigational molecule) as pharmacological probes. A TNF-α inducible NF-κB reporter cell line (GloResponse™ NF-κB-RE-luc2P HEK293) and dextran sodium sulfate (DSS) and 1,2 dimethyl hydrazine (DMH))-induced mouse model was used to investigate our hypothesis in vitro and in vivo. Clinically, an increased expression of AKR1B1 was observed in patients with ulcerative colitis. Our in vitro and in vivo findings suggest that the AKR1B1 modulated inflammation and ROS generation for the progression of colitis to colon cancer. AKR1B1 overexpression was observed in DSS+DMH-treated mice colons. Moreover, we could observe histopathological changes like immune cell infiltration, aberrant crypt foci, and tumour formation in DC groups. Mechanistically, we have witnessed modulation of the IKK/IκB/NF-κB and Akt/FOXO-3a/DR axis, increased inflammatory cytokines, increased expression of proliferative markers, Ki-67 and PCNA, and accumulation of β-catenin in the colon epithelium. However, pharmacological inhibition of AKR1B1 using NARI-29 or EPS has reversed the clinical, histopathological, and molecular alterations induced by DSS+DMH, confirming the obvious role of AKR1B1 in the promotion of colitis-associated carcinogenesis. In conclusion, our findings suggest that AKR1B1 targeted therapy could be a promising strategy for preventing CA-CRC and NARI-29 could be developed as a potent AKR1B1 inhibitor.

Helicobacter pylori promotes colorectal carcinogenesis by deregulating intestinal immunity and inducing a mucus-degrading microbiota signature

ObjectiveHelicobacter pylori infection is the most prevalent bacterial infection worldwide. Besides being the most important risk factor for gastric cancer development, epidemiological data show that infected individuals harbour a nearly...

Dairy Proteins Protect against Dimethylhydrazine-Induced Intestinal Cancers in Rats

The impact of different dietary protein sources (whey, casein, soybean, red meat) on the incidence, burden and mass index of intestinal tumors induced by dimethylhydrazine in male Sprague-Dawley rats was assessed. A purified diet (based on AIN-76A) with a fat concentration of 20 g/100 g and other proteins substituted for casein (20 g/100 g) was used. Whey and casein diets were more protective against the development of intestinal tumors than were the red meat or soybean diets, as evidenced by a reduced incidence of rats affected (P = 0.15), fewer tumors per treatment group (burden, P < 0.005), and a reduced pooled area of tumors (tumor mass index) that formed (P = 0.39). Intracellular concentration of glutathione, an antioxidant and anticarcinogenic tripeptide, measured in liver, was greatest in whey protein- and casein-fed rats and lowest in soybean-fed animals (P < 0.001). For other tissues (spleen, colon, tumor) the differences were not significant, although the whey-fed animals had the highest concentrations of glutathione (P = 0.8). Whey is a source of precursors (cysteine-rich proteins) for glutathione synthesis and may be important in providing protection to the host by stimulating glutathione synthesis. A positive correlation was observed between mean fecal fat concentrations for rats in each treatment group and large intestinal tumor burden (r2 = 0.898, P = 0.05). Fecal fat could be involved in aiding initiation and/or promotion of carcinogenesis. Whatever the mechanism(s), dairy proteins, and whey proteins in particular, offer considerable protection to the host against dimethylhydrazine-induced tumors relative to the other protein sources examined.

Maximising olive oil by‐products

Maximising olive oil by‐products

Autophagy-Related Gene WD Repeat Domain 45B Promotes Tumor Proliferation and Migration of Hepatocellular Carcinoma through the Akt/mTOR Signaling Pathway

Hepatocellular carcinoma (HCC) is a highly aggressive malignant tumor. It has been found that autophagy plays a role both as a tumor promoter and inhibitor in HCC carcinogenesis. However, the mechanism behind is still unveiled. This study aims to explore the functions and mechanism of the key autophagy-related proteins, to shed light on novel clinical diagnoses and treatment targets of HCC. Bioinformation analyses were performed by using data from public databases including TCGA, ICGC, and UCSC Xena. The upregulated autophagy-related gene WDR45B was identified and validated in human liver cell line LO2, human HCC cell line HepG2 and Huh-7. Immunohistochemical assay (IHC) was also performed on formalin-fixed paraffin-embedded (FFPE) tissues of 56 HCC patients from our pathology archives. By using qRT-PCR and Western blots we found that high expression of WDR45B influenced the Akt/mTOR signaling pathway. Autophagy marker LC3- II/LC3-I was downregulated, and p62/SQSTM1 was upregulated after knockdown of WDR45B. The effects of WDR45B knockdown on autophagy and Akt/mTOR signaling pathways can be reversed by the autophagy inducer rapamycin. Moreover, proliferation and migration of HCC can be inhibited after the knockdown of WDR45B through the CCK8 assay, wound-healing assay and Transwell cell migration and invasion assay. Therefore, WDR45B may become a novel biomarker for HCC prognosis assessment and potential target for molecular therapy.

Virulence Factors of the Periodontal Pathogens: Tools to Evade the Host Immune Response and Promote Carcinogenesis.

Periodontitis is the most common chronic, inflammatory oral disease that affects more than half of the population in the United States. The disease leads to destruction of the tooth-supporting tissue called periodontium, which ultimately results in tooth loss if uncured. The interaction between the periodontal microbiota and the host immune cells result in the induction of a non-protective host immune response that triggers host tissue destruction. Certain pathogens have been implicated periodontal disease formation that is triggered by a plethora of virulence factors. There is a collective evidence on the impact of periodontal disease progression on systemic health. Of particular interest, the role of the virulence factors of the periodontal pathogens in facilitating the evasion of the host immune cells and promotion of carcinogenesis has been the focus of many researchers. The aim of this review is to examine the influence of the periodontal pathogens Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans), Porphyromonas gingivalis (P. gingivalis), and Fusobacterium nucleatum (F. nucleatum) in the modulation of the intracellular signaling pathways of the host cells in order to evade the host immune response and interfere with normal host cell death and the role of their virulence factors in this regard.

ROLE OF RADIOPROTECTORS IN MINIMIZATION OF STOCHASTIC EFFECTS OF RADIATION INCIDENTS.

Thereal threat of emergency situations in Ukraine dictates theneed to take into account theexperience of previous radiation accidents, during which a significant part of thepopulation was exposed to low-dose radiation. In such a case clinical manifestations of irradiation were mostly absent, while thedanger of stochastic (carcinogenic) effects remained. Therefore, at present, thestrategy of radiation protection of thepopulation should be aimed at revising and choosing effective and low-toxic anti-radiation means. Themain criterion for thedevelopment of stochastic consequences of exposure is radiation-induced genome instability, which is a promoter of carcinogenesis. Theuse of radiomitigators, which are able to weaken theharmful effect of ionizing radiation on critical highly radiosensitive systems of thehuman body, is promising. Our research showed theradiomitigative effect of inosine in cultured human T-lymphocytes on thegenetic level with thesignificant decrease in thefrequency of gamma-induced chromosome aberrations. Theresults experimentally justified an expediency of use of radiomitigators in theconditions of an emergency situation to minimize theoccurrence and development of stochastic effects in population.

The Emerging Role of MicroRNAs and Autophagy Mechanism in Pancreatic Cancer Progression: Future Therapeutic Approaches.

Pancreatic cancer constitutes the fourth most frequent cause of death due to malignancy in the US. Despite the new therapeutic modalities, the management of pancreatic ductal adenocarcinoma (PDAC) is considered a difficult task for clinicians due to the fact that is usually diagnosed in already advanced stages and it is relatively resistant to the current chemotherapeutic agents. The molecular background analysis of pancreatic malignant tumors, which includes various epigenetic and genetic alterations, opens new horizons for the development of novel diagnostic and therapeutic strategies. The interplay between miRNAs, autophagy pathway, and pancreatic carcinogenesis is in the spotlight of the current research. There is strong evidence that miRNAs take part in carcinogenesis either as tumor inhibitors that combat the oncogene expression or as promoters (oncomiRs) by acting as oncogenes by interfering with various cell functions such as proliferation, programmed cell death, and metabolic and signaling pathways. Deregulation of the expression levels of various miRNAs is closely associated with tumor growth, progression, and dissemination, as well as low sensitivity to chemotherapeutic agents. Similarly, autophagy despite constituting a pivotal homeostatic mechanism for cell survival has a binary role in PDAC, either as an inhibitor or promoter of carcinogenesis. The emerging role of miRNAs in autophagy gets a great deal of attention as it opens new opportunities for the development of novel therapeutic strategies for the management of this aggressive and chemoresistant malignancy. In this review, we will shed light on the interplay between miRNAs and the autophagy mechanism for pancreatic cancer development and progression.

Immune-hormonal imbalance in chemical cancerogenesis

The present article deals with experimental and clinical aspects of immuno-hormonal interactions in chemical carcinogenesis i.e., formation of DNA-adducts with chemical carcinogens as a trigger of tumor initiation; synthesis of specific antibodies as markers of human exposure to environmental carcinogens; immunomodulation of chemical carcinogenesis by the specific antibodies in experimental studies; interactions of antibodies against environmental carcinogens with endogenous steroid hormones in human carcinogenesis; immunological interference and inversion of immuno-hormonal interactions by the action of antibodies against environmental carcinogens; immune stimulation of tumor progression in cancer patients. It is shown that antibodies specific to estradiol and progesterone participate in regulation of serum estradiol and progesterone levels in healthy women. Excessive production of antibodies against benzo[a]pyrene is associated with impaired physiological balance between the levels of antibodies to estradiol and progesterone, thus causing disturbed physiological balance between serum estradiol and progesterone. Immuno-hormonal imbalance promotes tumor initiation, its growth and progression. The new approaches to the personalized cancer immunoprediction and immune prevention are discussed. Coordinated synthesis of antibodies against benzo[a]pyrene and estradiol seems to reflect production of DNA-adducts with genotoxic metabolic effects of these compounds manifesting as synergistic carcinogenic effects upon the target cells. Hence, simultaneously increased levels of serum antibodies against benzo[a]pyrene and estradiol in healthy people may be considered an immunological marker of high oncological risk and an reason to use of new immunoprotective tools against polycyclic aromatic hydrocarbons and phytoestrogens. However, ability of these antibodies to raise the blood serum levels of environmental carcinogens and endogenous estradiol, as shown in vitro and in vivo, excludes the opportunity for active cancer immune prevention. Usage of anticarcinogen vaccines aimed for induction of protective secretory antibodies is likely to further increase high levels of procarcinogenic serum antibodies against benzo[a]pyrene and estradiol, followed by additional enhancement of immuno-hormonal imbalance and promotion of carcinogenesis. Development of probiotics transduced with genes encoding human antibodies against environmental carcinogens may present an alternative approach to cancer immune prevention. The antibodies produced by such probiotics would bind appropriate carcinogens and prevent their invasion into the organism, thus inhibiting emergence of DNA-adducts and suppressing synthesis of specific autoantibodies that may promote carcinogenesis. The aim is to substantiate the concept of immuno-hormonal imbalance for the carcinogen-induced hormone-dependent tumors.