Species differences in nitrosamine carcinogenesis

Summary The carcinogenic action of approximately 50 N-nitroso compounds, nitrosamines, and nitrosoalkylamides has been compared in rats and in Syrian golden hamsters. The compounds were administered PO, as far as possible at comparable dose rates. The relative potencies of the treatments were assessed mainly by the time to death of the animals with tumors. The esophagus and other parts of the upper gastrointestinal tract were the most common sites for tumor induction in rats, but the esophagus was hardly ever affected in hamsters, although several compounds induced tumors of the forestomach in both rats and hamsters. No conclusion could be drawn about the relative susceptibility of the rat and hamster to these N-nitroso compounds, which varied with different compounds. Few generalizations can be made about these results, although it appeared that the 2-hydroxypropyl group was usually necessary for the induction of pancreas tumors in hamsters.Dedicated to Professor Hermann Druckrey on the occasion of his 80th birthdayResearch sponsored by the National Cancer Institute, DHHS, under contract No. NO1-CO-23909 with Litton Bionetics, Inc. The contents of this publication do not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government     

Use of cultured human tissues and cells in carcinogenesis research

Summary A variety of approaches are used to study carcinogenesis. Recent advances in techniques for culture of human tissues and cells have provided additional experimental systems of study the process of carcinogenesis and the genetics of cancer.The Journal of Cancer Research and Clinical Oncology publishes in loose succession Editorials and Guest Editorials on current and/or controversial problems in experimental and clinical oncology. These contributions represent exclusively the personal opinion of the author.     

Methylation in esophageal carcinogenesis

INTRODUCTION Esophageal cancer is one of the least studied and deadliest cancers, with a remarkable geographical distribution and a low likelihood of cure[1]. Therefore, the current challenges in the management of esophageal cancer are to obtain a better understanding of the underlying molecular biological alterations to provide new treatment options. Cancer of the esophagus exists in two main forms with different etiological and pathological characteristics-esophagealsquamous cell carcino…     

MicroRNA在胃癌中的研究进展

MicroRNA(miRNA)是一类进化过程中高度保守的内源性非编码小RNA.他们具有高度保守性、时序性和组织特异性,通过参与基因表达调控,在肿瘤的发生发展过程中扮演着重要的角色.本文就miRNA在胃癌方面的研究进展作一综述.     

Midkine translocated to nucleoli and involved in carcinogenesis

Midkine （MK） is a heparin-binding growth factor with its gene first identified in embryonal carcinoma cells at early stages of retinoic acid-induced differentiation. MK is frequently and highly expressed in a variety of human carcinomas. Furthermore, the blood MK level is frequently elevated with advance of human carcinomas, decreased after surgical removal of the tumors. Thus, it is expected to become a promising marker for evaluating the progress of carcinomas. There is mounting evidence that MK plays a significant role in carcinogenesis-related activities, such as proliferation, migration, anti-apoptosis, mitogenesis, transforming, and angiogenesis. In addition, siRNA and anti-sense oligonucleotides for MK have yielded great effects in anti-tumor activities. Therefore, MK appears to be a potential candidate molecular target of therapy for human carcinomas. In this paper, we review MK targeting at nucleoli in different tumor cells and its role in carcinogenesis to deepen our understanding of the mechanism of MK involved in carcinogenesis.     

Hormonal regulation of pituitary FSH sialylation in male rats

Sialic acid content in FSH is modulated by GnRH and sexual steroids. Galβ1,3GlcNAcα2,3-sialyltransferase (ST3Gal III) and Galβ1,4GlcNAcα2,6-sialyltransferase (ST6Gal I) incorporate sialic acid residues into FSH oligosaccharides. The aim of the present study was to assess pituitary FSH molecular microheterogeneity and ST3Gal III/ST6Gal I expression during sexual development and after castration in male rats. Preparative isoelectric focusing and lectin chromatography were used to isolate FSH glycosylation variants according to charge and complexity of their oligosaccharides; RT-PCR and immunohistochemistry were employed to analyse sialyltransferase expression. Sexual development was associated with a progressive shift towards more acidic/sialylated FSH glycoforms concomitantly with an increment in ST6Gal I gene and protein expression. After castration, a transient decrease followed by a marked increase in ST6Gal I expression were observed. Less acidic/sialylated FSH glycoforms bearing incomplete oligosaccharides increased after castration, despite high ST6Gal I expression. ST3Gal III expression remained unchanged in all the experimental conditions examined. These results show that the synthesis of FSH isoforms possessing α2,6-linked sialic acid is hormonally regulated in male rats.     

Deuterium isotope effects in carcinogenesis by N-nitroso compounds

Summary A number of N-nitroso compounds and an azoxyalkane have been labeled with deuterium in various positions and have been administered to rats, hamsters, or mice in parallel with the unlabeled compounds. The treatments with the labeled and analogous unlabeled compounds were equimolar and for the same time. Mortality rates from tumors and tumor incidences were compared between deuteriumlabeled and the unlabeled analogs. In many cases more than one dose level was used for the comparisons. An increased rate of mortality from tumors or an increased incidence of induced tumors was considered an index of increased potency of one treatment compared with the other. Using these criteria deuterium in the alpha positions of nitrosodimethylamine, nitrosomorpholine, nitrosoheptamethyleneimine, and nitrosoazetidine reduced carcinogenic potency compared with the unlabeled compounds. This indicated that cleavage of a carbon-hydrogen bond in the alpha position was a rate-limiting step in carcinogenesis by these nitrosamines. In both nitrosomethylethylamine and nitroso-2,6-dimethylmorpholine, the presence of deuterium at different positions increased or decreased carcinogenic potency, suggesting that competition for oxidation between these sites might be the determining factor in activation of the molecule. This also applied to nitrosomethyl-n-butylamine and nitrosomethylphenylethylamine with deuterium at the methyl group or at the alpha carbon of the butyl or phenylethyl groups, and to azoxymethane with deuterium in the 1-methyl or 4-methyl group. In nitrosomethylcyclohexylamine, nitrosomethyl-n-dodecylamine, and dinitroso-2,6-dimethylpiperazine there was no detectable effect of deuterium on carcinogenic potency, suggesting that the conditions did not provide sufficient sensitivity for detection of an isotope effect, or that oxidation at the alpha carbon was not a rate-limiting step in carcinogenesis by these molecules.Research sponsored by the National Cancer Institute, DHHS, under contract No. N01-Co-23909 with Litton Bionetics, Inc. The contents of this publication do not necessarily reflect the views or policies of the Department of Helath and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government     

Dissecting characteristics and dynamics of differentially expressed proteins during multistage carcinogenesis of human colorectal cancer

AIM: To discover novel biomarkers for early diagnosis, prognosis or treatment of human colorectal cancer. METHODS: i TRAQ 2D LC-MS/MS analysis was used to identify differentially expressed proteins(DEPs) in the human colonic epithelial carcinogenic process using laser capture microdissection-purified colonic epithelial cells from normal colon, adenoma, carcinoma in situ and invasive carcinoma tissues. RESULTS: A total of 326 DEPs were identified, and four DEPs(DMBT1, S100A9, Galectin-10, and S100A8) with progressive alteration in the carcinogenic process were further validated by immunohistochemistry. The DEPs were involved in multiple biological processes including cell cycle, cell adhesion, translation, m RNA processing, and protein synthesis. Some of the DEPs involved in cellular process such as "translation" and "m RNA splicing" were progressively up-regulated, while some DEPs involved in other processes such as "metabolism" and "cell response to stress" was progressively downregulated. Other proteins with up- or down-regulation at certain stages of carcinogenesis may play various roles at different stages of the colorectal carcinogenic process. CONCLUSION: These findings give insights into our understanding of the mechanisms of colorectal carcinogenesis and provide clues for further investigation of carcinogenesis and identification of biomarkers.     

Gastric carcinogenesis

Gastric cancer is the second most common cancer worldwide and the second most common cause of cancer-related deaths. Despite complete resection of gastric cancer and lymph node dissection, as well as improvements in chemotherapy and radiotherapy, there are still 700 000 gastric cancer-related deaths per year worldwide and more than 80% of patients with advanced gastric cancer die of the disease or recurrent disease within 1 year after diagnosis. None of the treatment modalities we have been applying today can influence the overall survival rates: at present, the overall 5-year relative survival rate for gastric cancer is about 28%. Cellular metaplasia due to chronic inflammation, injury and repair are the most documented processes for neoplasia. It appears that chronic inflammation stimulates tumor development and plays a critical role in initiating, sustaining and advancing tumor growth. It is also evident that not all inflammation is tumorigenic. Additional mutations can be acquired, and this leads to the cancer cell gaining a further growth advantage and acquiring a more malignant phenotype. Intestinalization of gastric units, which is called “intestinal metaplasia”; phenotypic antralization of fundic units, which is called “spasmolytic polypeptide-expressing metaplasia”; and the development directly from the stem/progenitor cell zone are three pathways that have been described for gastric carcinogenesis. Also, an important factor for the development of gastrointestinal cancers is peritumoral stroma. However, the initiating cellular event in gastric metaplasia is still controversial. Understanding gastric carcinogenesis and its precursor lesions has been under intense investigation, and our paper attempts to highlight recent progress in this field of cancer research.     

Molecular mechanism of cholangiocarcinoma carcinogenesis

Cholangiocarcinoma (CCA) is a highly malignant cancer of the biliary tract with a poor prognosis, which often arises from conditions causing long‐term inflammation, injury, and reparative biliary epithelial cell proliferation. Several conditions are known to be major risk factors for cancer in the biliary tract or gallbladder, including primary sclerosing cholangitis, liver fluke infection, pancreaticobiliary maljunction, and chemical exposure in proof‐printing workers. Abnormalities in various signaling cascades, molecules, and genetic mutations are involved in the pathogenesis of CCA. CCA is characterized by a series of highly recurrent mutations in genes, including KRAS, BRF, TP53, Smad, and p16^INK4a. Cytokines that are affected by inflammatory environmental conditions, such as interleukin‐6 (IL‐6), transforming growth factor‐β (TGF‐β), tumor necrosis factor‐α (TNF‐α), and platelet‐derived growth factor (PDGF), play an important role in cancer pathogenesis. Prominent signaling pathways important in carcinogenesis include TGF‐β/Smad, IL‐6/STAT‐3, PI3K/AKT, Wnt, RAF/MEK/MAPK, and Notch. Additionally, some microRNAs regulate targets in critical pathways of CCA development and progression. This review article provides the understanding of the genetic and epigenetic mechanism(s) of carcinogenesis in CCA, which leads to the development of new therapeutic targets for the prevention and treatment of this devastating cancer.     

Experimental animal models of pancreatic carcinogenesis and metastasis

Pancreatic cancer is a lethal disease characterized by early metastasis, local invasion, and resistance to conventional therapies. To understand its etiology and eventually make prevention of it possible and effective, appropriate carcinogenesis models will certainly help us understand the effects of environmental and genetic elements on pancreatic carcinogenesis. The development of new treatment strategies to control cancer metastasis is of immediate urgency. Fulfillment of this task relies on our knowledge of the cellular and molecular biology of pancreatic cancer metastasis and the availability of biologically and clinically relevant model systems. Many of the existing pancreatic cancer carcinogenesis and metastasis animal models are described in this review. The advantages and disadvantages of each model and their clinical implications are discussed, and special attention is focused on experimental therapeutic strategies targeting pancreatic cancer metastasis.     

Connection between inflammation and carcinogenesis in gastrointestinal tract: Focus on TGF-β signaling

Inflammation is a primary defense process against various extracellular stimuli,such as viruses,pathogens,foods,and environmental pollutants.When cells respond to stimuli for short periods of time,it results in acute or physiological inflammation.However,if the stimulation is sustained for longer time or a pathological state occurs,it is known as chronic or pathological inflammation.Several studies have shown that tumorigenesis in the gastrointestinal (GI) tract is closely associated with chronic inflammati...     

Role of cyclooxygenase-2 gene polymorphisms in pancreatic carcinogenesis

AIM:To evaluate the clinical significance of-765G/C and-1195G/A cyclooxygenase-2 (COX-2) gene polymorphisms in patients with pancreatic cancer (PC).METHODS:The study included 201 patients:85 with PC and 116 healthy controls.-765G/C and-1195G/A COX-2 gene polymorphisms were studied in DNA isolated from blood samples.The associations of the analyzed genotypes and clinical data at diagnosis were evaluated.RESULTS:We found an increased frequency of the homozygous-1195AA COX-2 genotype in patients with PC (53.7%...     

PTEN在胃癌中的研究进展

第10号染色体同源缺失性磷酸酶-张力蛋白基因(phosphatase and tensin homolog deleted on chromosome ten,PTEN)是继p533之后发现的另一重要的抑癌基因,其编码的蛋白质可调控多种细胞信号转导通路或功能分子,构成一个复杂的网络系统,在调控细胞增殖与凋亡、迁移与黏附...     

Hormonal approaches to male contraception: approaching reality

The ‘pre-testicular’ suppression of gonadotrophins is the most likely approach for reversible therapeutic male fertility control to reach imminent clinical application. Maintenance of spermatogenesis depends on adequate gonadotrophin and intratesticular testosterone concentrations. Hormonal contraception for men interrupts this physiological axis by various means of gonadotrophin suppression; this interferes with spermatogonial differentiation and meiosis entry resulting in reversible azoospermia or severe oligozoospermia in virtually all men. Clinical trials have confirmed that high contraceptive efficacy, similar to female hormonal contraceptives, can be reliably attained with few side effects. However, the simultaneous suppression of Leydig cell steroidogenesis mandates the requirement for testosterone replacement in hormonal male contraception. Combination regimens of new synthetic progestins and androgens at various stages of development are being investigated with the lead products poised to go into phase III trials. Heterogeneity in response to spermatogenesis suppression has been observed within and between population; the mechanisms are unclear. This new method of reversible and effective contraception has registered high acceptability in surveys of both men and women. The recent entry of pharmaceutical companies into this area of research and development has considerably enhanced the prospects of translating years of academic efforts into new products which provide added family planning choice for many couples.     

Bile acids promote carcinogenesis in the remnant stomach of rats

Summary We examined the tumor-promoting activity of sodium taurocholate in the remnant stomach of rats. Ninety male Wistar rats, 8 weeks of age, were separated into four groups. In group I, the rats were given N-methyl-N-nitro-N-nitrosoguanidine (MNNG) at a concentration of 83 mg/l in drinking water for 15 weeks, and distal partial gastrectomy was performed by Roux-en-Y procedure to prevent duodenal reflux into the remnant stomach. Thereafter, a diet containing 0.25% sodium taurocholate was given for 43 weeks. The group II rats were given MNNG and gastrectomy and were then given the usual commercial diet. The rats in group III were given gastrectomy and sodium taurocholate and no previous administration of MNNG. Only MNNG was given to the rats in group IV. The incidence of malignant tumors in the remnant stomach was 40.9% (9/22), 27.3% (6/22), and 0% (0/22) in groups I, II, and III, respectively, while the incidence in the area corresponding to the remnant stomach (control) was 8.3% (2/24) in group IV. The difference in tumor incidence was statistically significant (P<0.05) between groups I and IV but not between groups II and IV, and not between groups I and II. Six of nine tumors in group I and all six tumors in group II were located in the anastomotic area. These results suggest that sodium taurocholate promotes tumor production in the remnant stomach, and that the surgical procedure may well be associated with this enhanced tumor occurrence.Abbreviation MNNG N-methyl-N-nitro-N-nitrosoguanidine