Knowledge Of Carcinogenesis Research Articles

The Key Characteristics of Carcinogens: Relationship to the Hallmarks of Cancer, Relevant Biomarkers, and Assays to Measure Them.

The key characteristics (KC) of human carcinogens provide a uniform approach to evaluating mechanistic evidence in cancer hazard identification. Refinements to the approach were requested by organizations and individuals applying the KCs. We assembled an expert committee with knowledge of carcinogenesis and experience in applying the KCs in cancer hazard identification. We leveraged this expertise and examined the literature to more clearly describe each KC, identify current and emerging assays and in vivo biomarkers that can be used to measure them, and make recommendations for future assay development. We found that the KCs are clearly distinct from the Hallmarks of Cancer, that interrelationships among the KCs can be leveraged to strengthen the KC approach (and an understanding of environmental carcinogenesis), and that the KC approach is applicable to the systematic evaluation of a broad range of potential cancer hazards in vivo and in vitro We identified gaps in coverage of the KCs by current assays. Future efforts should expand the breadth, specificity, and sensitivity of validated assays and biomarkers that can measure the 10 KCs. Refinement of the KC approach will enhance and accelerate carcinogen identification, a first step in cancer prevention.See all articles in this CEBP Focus section, "Environmental Carcinogenesis: Pathways to Prevention."

Somatic Genomic Changes in the Formation of Differentiated Thyroid Carcinoma

Abstract Globally, the diffuse goiter affects more than 10% of the population and in some regions is endemic. Thyroid nodules are found in approximately 5% of the population using the oldest method for thyroid examination – palpation. When performing ultrasound screening, this percentage increases significantly and reaches between 20 and 75% of the total population. Thyroid carcinoma is a rare malignancy and accounts for up to 1% of all malignant tumors. It is the most common endocrine cancer and is clinically manifested as a thyroid nodule. Somatic mutations play an important role in its development. Differentiation of benign and malignant thyroid nodules is of great importance due to the different therapeutic approach. Therefore, new diagnostic tools are sought to help distinguish the two. Despite the progress in our knowledge of carcinogenesis in recent years, a number of key issues still remain unanswered. The establishment of new rare somatic mutations can improve pre-surgical diagnosis and optimize post-operative strategies for the treatment of thyroid carcinoma. Next-generation sequencing (NGS) allows for extensive mutation and genome rearrangements tracking. The results obtained with NGS provide the basis for the development of new approach for systematic genetic screening, at prevention, early diagnosis, accurate prognosis, and targeted therapy of this disorder.

Cancer Development and Damped Electromagnetic Activity

Cancer can be initiated in a cell or a fibroblast by short-circuiting of the cellular electromagnetic field by various fibers, parasitic energy consumption, virus infections, and mitochondrial defects, leading to a damped cellular electromagnetic field. Except short-circuiting (e.g., by asbestos fibers), the central process is mitochondrial dysfunction in cancer cells (the Warburg effect) or in fibroblasts associated with a cancer cell (the reverse Warburg effect), critically lowered respiration, reversed polarity of the ordered water layers around mitochondria, and damped electromagnetic activity of the affected cells. Frequency and power changes of the generated electromagnetic field result in broken communication between cells and possibly in reduced control over chemical reactions, with an increased probability of random genome mutations. An interdisciplinary framework of phenomena related to cancer development is presented, with special attention to the causes and consequences of disturbed cellular electromagnetic activity. Our framework extends the current knowledge of carcinogenesis, to clarify yet unexplained phenomena leading to genome mutation and cancer initiation.

Types of Gastric Carcinomas

Gastric cancer has reduced prevalence, but poor prognoses. To improve treatment, better knowledge of carcinogenesis and cells of origin should be sought. Stomach cancers are typically localized to one of the three mucosae; cardial, oxyntic and antral. Moreover, not only the stem cell, but the ECL cell may proliferate and give rise to tumours. According to Laurén, the classification of gastric carcinomas seems to reflect biological important differences and possible different cell of origin since the two subtypes, intestinal and diffuse, do not transform into the other and show different epidemiology. The stem cell probably gives rise to the intestinal type, whereas the ECL cell may be important in the diffuse type. Elevation of gastrin may be the carcinogenic factor for Helicobacter pylori as well as the recently described increased risk of gastric cancer due to proton pump inhibitor treatment. Therefore, it is essential to determine the role of the gastrin target cell, the ECL cell, in gastric carcinogenesis. Clinical trials with gastrin antagonists could improve prognoses in those with gastrin receptor positive tumours. However, further studies on gastric carcinomas applying relative available methods and with the highest sensitivity are warranted to improve our knowledge of gastric carcinogenesis.

Interference with the androgen receptor protein stability in therapy-resistant prostate cancer.

The androgen receptor (AR) plays a central role in the pathogenesis of prostate cancer (PCa). Most PCa cases develop eventually from an androgen-dependent stage to castration-resistant prostate cancer (CRPC) with AR-signaling still being active. Thus, inhibition of AR remains a well-established promising drug target in CRPC. However, despite the improvements of current treatment for CRPC by targeting the AR, the evolution of adaptive AR-signaling leads to therapy-resistant CRPC. Treatment failure is based mostly on the inability to keep AR under long-term restraint due to adaptive responses of AR-signaling. One underlying mechanism appears to be the increased AR protein stability. Therefore, the regulation of AR protein stability and its degradation is another interesting path that could enhance our knowledge of carcinogenesis and tumor evolution possibly leading to novel therapeutic targets. In this review, we discuss various molecular mechanisms and factors that stabilize AR protein levels directly or indirectly. We summarize novel approaches to interfere with AR stability including targeting the glucocorticoid receptor (GR), heat shock proteins, and co-chaperones as well as E3-ligases using small chimeric molecules. These novel approaches in combination with antiandrogen treatment inhibit PCa growth through the regulation of AR protein levels.

Germline gene polymorphisms predisposing domestic mammals to carcinogenesis.

Cancer is a complex disease caused in part by predisposing germline gene polymorphisms. Knowledge of carcinogenesis in companion mammals (dog and cat) and some livestock species (pig and horse) is quite advanced. The prevalence of certain cancers varies by breed in these species, suggesting the presence of predisposing genetic variants in susceptible breeds. This review summarizes the present understanding of germline gene polymorphisms, including BRCA1, BRCA2, MC1R, KIT, NRAS and RAD51, associated with predisposition to melanoma, mammary cancer, osteosarcoma and histiocytic sarcoma in dogs, cats, pigs and horses. The predisposing variants in these species are discussed in the context of human germline gene polymorphisms associated with the same types of cancer.

Characterization of Chromosomal Translocation Breakpoint Sequences in Solid Tumours: “An In Silico Analysis”

Chromosomal translocations that results in formation and activation of fusion oncogenes are observed in numerous solid malignancies since years back. Expression of fusion kinases in these cancers drives the initiation & progression that ultimately leads to tumour development and thus comes out to be clinically imperative in terms of diagnosis and treatment of cancer. Nonetheless, molecular mechanisms beneath these translocations remained unexplored consequently limiting our knowledge of carcinogenesis and hence is the current field where further research is required. The issue of prime focus is the precision with which the chromosomes breaks and reunites within genome. Characterization of Genomic sequences located at Breakpoint region may direct us towards the thorough understanding of mechanism leading to chromosomal rearrangement. A unique computational multi-parametric analysis was performed for characterization of genomic sequence within and around breakpoint region. This study turns out to be novel as it reveals the occurrence of Segmental Duplications flanking the breakpoints of all translocation. Breakpoint Islands were also investigated for the presence of other intricate genomic architecture and various physico-chemical parameters. Our study particularly highlights the probable role of SDs and specific genomic features in precise chromosomal breakage. Additionally, it pinpoints the potential features that may be significant for double-strand breaks leading to chromosomal rearrangements.

The application of cell cultures, body fluids and tissues in oncoproteomics

Mass spectrometry (MS)-based proteomics is a rapidly developing technology for the large scale analysis of proteins, their interactions and subcellular localization. In recent years proteomics has attracted much attention in medicine. Since a single biomarker might not have sufficient sensitivity and specificity in clinical practice, the identification of biomarker panels that comprise several proteins would improve the detection and clinical management of cancer patients. Additionally, the characteristics of protein profiles of most severe human malignancies certainly contribute to the understanding of the biology of cancer and fill the gap in our knowledge of carcinogenesis. This knowledge also is likely to result in the discovery of novel potential cancer markers and targets for molecular therapeutics. It is believed that the novel biomarkers will help in the development of personalized therapy tailored to the individual patient and will thereby reduce the mortality rate from cancer. In this review, the use of different types of human clinical samples (cell cultures, tissues and body fluids) in oncoproteomics is explained and the latest advances in mass spectrometry-based proteomics biomarker discovery are discussed.

Immunophenotyping of male breast cancer

Male breast cancer is a rare disease, and knowledge of carcinogenesis is limited. Conflicting results, based on small series, have been reported for clinically relevant biomarkers. One hundred and thirty-four cases of male breast cancer were immunohistochemically stained on tissue microarrays for oestrogen receptor (ER), progesterone receptor (PR), androgen receptor, human epidermal growth factor receptor 2 (HER2), BRST2, cyclin D1, bcl-2, p53, p16, p21, Ki67, cytokeratin (CK) 5/6, CK14, and epidermal growth factor receptor. Data were correlated with clinicopathological features and patient outcome. High mitotic count and high grade were correlated with high Ki67, HER2 amplification/overexpression, p53 accumulation, high p21 expression, low PR expression, and low bcl-2 expression. PR negativity (P=0.009) and p53 accumulation (P=0.042) were correlated with decreased 5-year survival and were independent markers for patient outcome in Cox regression. In unsupervised hierarchical clustering, four groups were identified that were correlated with distinctive clinicopathological features. The hormone negative/ER-positive/high-grade cluster was significantly associated with decreased survival (P=0.011) and was an independent prognostic factor in Cox regression. Several tissue biomarkers are associated with an aggressive phenotype in male breast cancer. PR and p53 are the most promising individual prognostic markers. On the basis of immunophenotype, four distinctive and prognostically relevant male breast cancer groups were identified, indicating that protein expression profiling may be clinically useful in male breast cancer.

The 2007 Marie Curie prize: the linear no threshold relationship and advances in our understanding of carcinogenesis

Better knowledge of carcinogenesis has improved the assessment of the putative carcinogenic effects of low doses of Ionising Radiation (IR). Cancer induction is a main threat to multicellular organisms and safeguards have been introduced during evolution. Mutations result from endogenous agents, mainly Reactive Oxygen Species (ROS), and exogenous agents. IR and solar ultraviolet (UV) have existed since the onset of life and the existence of some congenital diseases, such as Xeroderma Pigmentosum (XP), demonstrates that without such defence mechanisms, life would have been impossible. Low doses of IR damage DNA but also activate cell defences: anti-oxidative mechanisms, DNA repair, adaptive responses, elimination of aberrant and preneoplastic cells, and immune reactions. The effectiveness of these defences decreases with the dose and is modulated by several time factors. The cell defence strategy varies with the dose, the irradiated volume and the damage inflicted on neighbouring cells. No cancer induction is detected in humans or animals for acute doses below 100 mSv. In patients treated by fractionated radiotherapy or submitted to iterative X-ray examination, the lowest dose that induces cancer appears to be at about 0.5 mSv, but doses as low as 20 mSv have a cumulative effect. Experimental studies, in vitro or on animals, suggest the existence of a threshold. In the low-dose range (< 100 mSv), epidemiological surveys do not bring any convincing data in favour of a Linear No Threshold relationship.

Real-time telomerase activity measurements for detection of cancer

Since the hallmark report of the PCR-based telomeric repeat amplification protocol (TRAP) in 1994, there has been a flurry of investigations of telomerase activity on normal, benign, premalignant and cancerous samples representative of the various stages of tumorigenesis. Basic research and technological advances in human genetics, biochemistry and model systems have brought much progress towards the understanding of human infectious, hereditary and somatically acquired diseases. The knowledge of carcinogenesis has increased very rapidly in the past few years, particularly with the development of automated molecular biologic analysis of tumors and preneoplastic lesions. Despite the wide variety of studies on the potential use of telomerase as a cancer biomarker, the variability of reported telomerase activity and the lack of a transferable detection method have prevented it from becoming a routine clinical application. Real-time PCR is a clinically transferable method and the advancement of real-time measurements of telomerase will facilitate moving telomerase activity and technologies towards clinical validation. It is expected that the next 5 years will see telomerase integrated into the initial detection and follow-up monitoring of cancer patients. The hope is that the use of telomerase will finally translate into a diagnostic to help realize longer survival and a better quality of life.