Clinical implications of current studies in carcinogenesis

Summary Carcinogenesis probably proceeds through a succession of cellular events. Understanding of these events may provide a rational basis for the development of anticarcinogenic treatments. These will be designed to reverse or delay the evolution of a tumor before the stage at which invasion develops. The design and conduct of trials of such agents will be easiest if they are aimed at relatively late stages in the carcinogenic process.Recent research on viral and cellular oncogenes, growth factors, and the cellular mechanism of action of phorbol ester tumor promoters raises the hope that each will be understood and related to the others by their effects on different components of a set of central controls for cellular growth and differentiation. This may ultimately provide a means for rational design of anticarcinogenic treatment. Understanding is still very far from complete, however, and we are still a long way from potential clinical application. An immediate alternative to the long-term rational approach is an empirical one based, for example, on the use of retinoids. The design and interpretation of empirically based trials of anticarcinogenic agents requires careful thought.The Journal of Cancer Research and Clinical Oncology publishes in loose succession Editorials and Guest Editorials on curent/or controversial problems in experimental and clinical oncology. These contributions represent exclusively the personal opinion of the author.Based on a lecture to the Grand Council of the European Organisation for Research and Treatment of Cancer, November 1983     

Neither dietary ethanol nor beer augments experimental colon carcinogenesis in rats

There is an epidemiologic association between beer consumption and rectal cancer. Beer and ethanol were tested in the rat-dimethylhydrazine (DMH) experimental carcinogenesis model in order to verify this observation. Ethanol was found not to affect the number of colonic tumors induced by DMH (86 vs. 77 controls,P=0.764). In rats fed beer and treated with DMH, there was a decrease in gastrointestinal tumor induction (P=0.043). This instance then becomes one of many in which conclusions drawn from epidemiologic studies have been contradicted when subjected to analysis in an experimental colon carcinogenesis model. Supported by John W. Ruettinger and the University of Illinois Foundation. Read in part at the Joint Meetings of the American Society of Colon and Rectal Surgeons with the Section of Colo-Proctology, Royal Society of Medicine, and the Section of Colonic and Rectal Surgery, Royal Australasian College of Surgeons, New Orleans, Louisiana, May 6 to 11, 1984, and San Diego, California, May 5 to 10, 1985.     

Effect of combined tigason and selenium treatment on colon carcinogenesis

Summary The modifying effect of an aromatic retinoic acid analog, Tigason, alone or in a combined regimen with selenium on the incidence of colon tumors induced by 1,2-dimethylhydrazine was investigated in BD rats. Treatment with the carcinogen alone resulted in induction of colon adenocarcinomas in 29 rats (92%). In comparison to the 1,2-dimethylhydrazinetreated group, administration of Tigason or Tigason plus selenium reduced tumor incidence (71% and 68%, respectively). The effect of combined treatment with Tigason and selenium, however, was not additive. Although some researchers have been unable to demonstrate any protective effect of different synthetic retinoids against 1,2-dimethylhydrazine or N-methyl-N-nitrosourea-induced colon tumors, our findings suggest that the process of tumor initiation in colon mucosa can be significantly influenced by the aromatic retinoid Tigason or by simultaneous administration of Tigason and selenium.     

The effect of antioxidants on MNNG-induced stomach carcinogenesis in rats

Summary The effect of vitamins A, C and E, butylated hydroxytoluene (BHT) and glutathione (GSH) on gastric carcinogenesis induced by N-methyl-N-nitro-N-nitrosoguanidine (MNNG) was investigated. Male and female BD-VI rats 2–3 months old received a single oral application of MNNG dissolved in corn oil. The male rats were divided into four groups: Group-I: MNNG 250 mg/kg by intubation; Group-II: MNNG+ vitamin C daily in the drinking water (400 mg/l); Group-III: MNNG+vitamin C (400 mg/1) +100 g of milk broth (for each of 10 rats) containing vitamin A (40 000 IU), vitamin E (0.5 g) and BHT (0.1 g) three times a week. The treatment with antioxidants started 7 days before the MNNG administration and continued until the end of experiment. Group-IV rats received MNNG+oxyferriscorbone, i.p. as a single dose of 1.0 mg/kg, daily during the week before and the week after MNNG exposure and than 3 times a week till the end of the experiment. Female rats were divided into two groups: Group-I: MNNG 333 mg/kg by intubation; Group-II: MNNG +GSH orally at a dose of 100 mg/rat 1 h before and 5, 24, 48, and 72 h after MNNG intubation.The incidence of gastric tumors after 15 months of treatment was as follows: male rats, 82.4% in Group-I, 40.0% in Group-II, 40.7% in Group-III, and 50.0% in Group-IV; female rats; 72.7% in Group-I, and 36.0% in Group-II.     

Clinical and molecular genetics of acromegaly: MEN1, Carney complex, McCune–Albright syndrome, familial acromegaly and genetic defects in sporadic tumors

Pituitary tumors are among the most common neoplasms in man; they account for approximately 15% of all primary intracranial lesions (Jagannathan et al., Neurosurg Focus, 19:E4, 2005). Although almost never malignant and rarely clinically expressed, pituitary tumors may cause significant morbidity in affected patients. First, given the critical location of the gland, large tumors may lead to mass effects, and, second, proliferation of hormone-secreting pituitary cells leads to endocrine syndromes. Acromegaly results from oversecretion of growth hormone (GH) by the proliferating somatotrophs. Despite the significant efforts made over the last decade, still little is known about the genetic causes of common pituitary tumors and even less is applied from this knowledge therapeutically. In this review, we present an update on the genetic syndromes associated with pituitary adenomas and discuss the related genetic defects. We next review findings on sporadic, non-genetic, pituitary tumors with an emphasis on pathways and animal models of pituitary disease. In conclusion, we attempt to present an overall, integrative approach to the human molecular genetics of both familiar and sporadic pituitary tumors.     

Experimental investigation on the influence upon chemical carcinogenesis: 4th communication

Summary In a total of 446 Sprague-Dawley rats it was tested whether colon carcinogenesis induced by 1,2-dimethylhydrazine (DMH) (7-monthly applications of 30 mg/kg bodyweight) can be influenced by different diets (vegetarian, high fat, and high cholesterol and rich in carbohydrates). The rats treated with a vegetarian diet or a diet that was rich in carbohydrates showed apparently longer induction times (median induction time 347 days and 323 days, respectively) of the malignant tumors (colon, kidney, liver, ear duct) than animals of the other test groups (median induction times between 250 and 282 days); animals treated with the diet that was rich in carbohydrates developed more benign liver tumors (86%) than animals treated with a standard (19%) or vegetarian diet (14%). It is emphasized that quantitative differences in carcinogen treatment might be responsible for some of the differences observed.     

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.     

Molecular pathology of AIDS-related lymphomas

Summary A high frequency of lymphoma in human immunodeficiency virus-infected individuals has been reported since the outbreak of the acquired immunodeficiency syndrome (AIDS) epidemic in 1982. AIDS-associated non-Hodgkin's lymphoma (AIDS-NHL) is almost invariably derived from B cells and is classified as high- or intermediate-grade NHL, according to the working formulation. Two main histologic types are recognized, including small noncleaved cell lymphoma (SNCCL) and diffuse large cell lymphoma (DLCL). Pre-existing host factors putatively involved in lymphoma development include disrupted immunosurveillance, deregulated cytokine production, chronic antigen stimulation, and infection by Epstein-Barr virus (EBV). These alterations are associated with the development of multiple oligoclonal expansions which correspond to the clinical phase known as persistent generalized lymphadenopathy (PGL). The appearance of a true AIDS-NHL is characterized by the presence of a monoclonal B-cell population displaying several genetic lesions, including monoclonal EBV infection, c-MYC and BCL-6 rearrangements, RAS mutations, p53 inactivation, and 6q deletions. These genetic lesions cluster into two distinct molecular pathways, which specifically associate with the different histologic subtypes of AIDS-NHL, i.e., AIDS-SNCCL and AIDS-DLCL. The presence of distinct genetic pathways for AIDS-SNCCL and AIDS-DLCL correlate with a number of clinical features which distinguish these two groups of tumors, including differences in the age of onset, CD4 counts at the time of presentation, time elapsed since HIV infection, and clinical outcome.     

Enhancing effect of cholecystectomy on colon carcinogenesis induced by methylazoxymethanol acetate in hamsters

The effect of cholecystectomy on colon carcinogenesis induced by methylazoxymethanol (MAM) acetate was examined in four groups of Syrian golden hamsters. For the sexes combined, the incidences of total large intestinal neoplasms and adenomas in Group 1, which received cholecystectomy and a single intravenous injection of MAM acetate (20 mg/kg body weight), were significantly higher than those of hamsters in Group 2, which were given MAM acetate alone. The combined multiplicities of total large intestinal neoplasms from male and female hamsters, and the multiplicities of those in females of Group 1 were also significantly higher than those in animals in Group 2, respectively. No intestinal tumors were observed in hamsters in Group 3 (cholecystectomy alone) or Group 4 (untreated control). These results indicate an enhancing effect of cholecystectomy on MAM acetate-induced large intestinal carcinogenesis in hamsters     

Molecular and cellular features of esophageal cancer cells

More than 70 cell lines were established from esophageal cancer, including 15 TE-series cell lines established by the authors. This article reviews molecular and cellular features of esophageal cancer cells from studies using these cell lines as well as primary tumors. The subjects reviewed include primary cultures of normal epithelium of the esophagus and of esophageal tumors, their growth and differentiation properties, chromosomal aberrations, protein kinase C, growth factors and their receptors, oncogenes, and tumor-suppressor genes. Lesions of genetic loci in esophageal cancer include the absence of mutations inras genes in primary tumors, amplification and overexpression of the c-erbB gene, co-amplification ofhst-1 andint-2 genes, mutations, and allelic loss of tumor suppressor genes, p53, Rb, APC, and MCC. Future clinical improvement will be achieved on the basis of the understanding of molecular and cellular features of esophageal cancer cells.Abbreviations PKC protein kinase C - PCR polymerase chain reaction - O⁶-MedG O⁶-methyldeoxyguanosine 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 The EditorsThis work was supported by grants-in-aid from the Ministry of Health and Welfare (1978–1982) and the Ministry of Education (1991)     

Causes and consequences of microsatellite instability in gastric carcinogenesis

Loss of DNA mismatch repair(MMR) function, due to somatic or germline epi/genetic alterations of MMR genes leads to the accumulation of numerous mutations across the genome, creating a molecular phenotype known as microsatellite instability(MSI). In gastric cancer(g C), MSI occurs in about 15% to 30% of the cases. This review summarizes the current knowledge on the molecular mechanisms underlying the acquisition of MSI in g C as well as on the clinic, pathologic and molecular consequences of the MSI phenotype. Additionally, current therapeutic strategies for g C and their applicability in the MSI subset are also discussed.     

Molecular mechanisms of H. pylori associated gastric carcinogenesis

H.Pyloriinfectshalf0ftheworldp0pulationandtheprevalencevarieswidelyindifferentpartsoftheworldwithaverageratesof4O%-50%inwesterncountries,risingtomorethan90%inthedevel0pingworld[1l2.Compellingevidencefromepidemiol0gicalandhistopathologicalstudieshaslinkedH.Pyloriinfectiont0thesubsequentdevelopmentofgastriccarcinogenesisL'].Furthermore,Watanabeandcolleaguesrecentlyinducedgastricadenocarcinomain37%oforallyinfectedM0ngoliangerbils,whichwereprecededwithaseriesofpremalignantchangesingastricmucosao…     

Estrogen and progesterone receptor isoforms expression in the stomach of Mongolian gerbils

AIM： We studied the estrogen receptor （ER） and progesterone receptor （PR） isoforms expression in gastric antrum and corpus of female gerbils and their regulation by estradiol （E2） and progesterone （P4）.
METHODS： Ovariectomized adult female gerbils were subcutaneously treated with E2, and E2 ＋ P4. Uteri and stomachs were removed, the latter were cut along the greater curvature, and antrum and corpus were excised. Proteins were immunoblotted using antibodies that recognize ER-alpha, ER-beta, and PR-A and PR-B receptor isoforms. Tissues from rats treated in the same way were used as controls.
RESULTS： Specific bands were detected for ERalpha （68 KDa）, and PR isoforms （85 and 120 KDa for PR-A and PR-B isoforms, respectively） in uteri, gastric antrum and corpus. We could not detect ER-beta isoform. PR isoforms were not regulated by E2 or P4 in uterus and gastric tissues of gerbils. ER-alpha isoform content was significantly down-regulated by E2 in the corpus, but not affected by hormones in uterus and gastric antrum.
CONCLUSION： The presence of ER-alpha and PR isoforms in gerbils stomach suggests that E2 and P4 actions in this organ are in part mediated by their nuclear receptors.     

尿激酶型纤溶酶原激活剂及其受体与胃癌关系的研究进展

尿激酶型纤溶酶原激活剂(uPA)及其受体(uPAR)是纤溶系统的重要组成部分,主要通过激活纤溶酶降解细胞外基质,促进肿瘤的浸润与转移。此文就它们与胃癌之间的关系及在临床中的应用作一综述,旨在为胃癌的诊断和治疗提供新方法、开辟新途径。     

Promoter hypomethylation of protease-activated receptor 2 associated with carcinogenesis in the stomach

BACKGROUND AND AIM: Trypsin acting at protease-activated receptor 2 (PAR2) contributes to a progression of malignant tumors. An abnormal DNA methylation has been recognized as an important molecular mechanism for the genesis of various types of cancers. We attempted to clarify the relationship between the promoter methylation of PAR2 and gastric cancer. METHOD: We estimated the methylation of the PAR2 promoter in both antral non-cancerous mucosa and cancer lesions in 94 patients with gastric cancer. We employed a methylation-specific PCR method. RESULTS: Regarding the methylation ratio (MR) of antral-non-cancerous mucosa, no significant difference was despite among gender, age and Helicobacter pylori infection status, whereas MR increased rising inflammation scores. The MR of cancer lesions was significantly lower than that of antral non-cancerous mucosa. This finding was not dependent on tumor staging, but also histological classification. In venous invasion, lymph node metastasis, or peritoneal dissemination negative cases, this significant lower MR was also seen. CONCLUSION: The promoter methylation of PAR2 seems to be increased with a progression of chronic inflammation and has an inhibitory effect on carcinogenesis of the stomach.     

Therapeutic implications of colon cancer stem cells

Colorectal cancer is the second most common cause of cancer-related death in many industrialized countries and is characterized by a heterogenic pool of cells with distinct differentiation patterns. Recently, the concept that cancer might arise from a rare population of cells with stem cell-like properties has received support with regard to several solid tumors, including colorectal cancer. According to the cancer stem cell hypothesis, cancer can be considered a disease in which mutations either convert no...     

miRNA与食管癌

动植物中广泛存在着一大类小的非编码蛋白质的RNA,21-25个核苷酸长度,被命名为microRNA(miRNA). miRNA在物种进化中相当保守,其表达有组织特异性和时序特异性. 其功能为负调控基因表达,进而调节细胞的代谢,增殖,分化和凋亡等基本的生理过程. 因此,miRNA的改变必会导致一些严重的病理过程. 研究已证实miRNA在肿瘤的发生和发展起着癌基因或抑癌基因的作用,miRNA的表达谱可用于某些肿瘤的诊断、分期和判断预后,并且在肿瘤分类方面较mRNA有更大地优越性. 本文着重介绍miRNA的产生,作用机制,与肿瘤的关系,检测方法及其在食管癌的诊断、分期和生物治疗方面的潜在作用.