Carcinogenesis

About: Carcinogenesis is a research topic. Over the lifetime, 60368 publications have been published within this topic receiving 3192599 citations. The topic is also known as: oncogenesis & tumorigenesis.

For better or for worse: the role of Pim oncogenes in tumorigenesis.

Abstract: Pim oncogenes are overexpressed in a wide range of tumours from a haematological and epithelial origin. Pim genes encode serine/threonine kinases that have been shown to counteract the increased sensitivity to apoptosis induction that is associated with MYC-driven tumorigenesis. Recently, considerable progress has been made in characterizing the pathways of PIM-mediated survival signalling. Given the unique structure of their active site and the minimal phenotype of mice mutant for all Pim family members, these oncogenes might be promising targets for highly specific and selective drugs with favourable toxicity profiles. In this Review, we discuss the physiological functions and oncogenic activities of Pim kinases.

Oncogenic K-Ras decouples glucose and glutamine metabolism to support cancer cell growth

Abstract: Oncogenes such as K-ras mediate cellular and metabolic transformation during tumorigenesis. To analyze K-Ras-dependent metabolic alterations, we employed 13 C metabolic flux analysis (MFA), non-targeted tracer fate detection (NTFD) of 15 N-labeled glutamine, and transcriptomic profiling in mouse fibroblast and human carcinoma cell lines. Stable isotope-labeled glucose and glutamine tracers and computational determination of intracellular fluxes indicated that cells expressing oncogenic K-Ras exhibited enhanced glycolytic activity, decreased oxidative flux through the tricarboxylic acid (TCA) cycle, and increased utilization of glutamine for anabolic synthesis. Surprisingly, a non-canonical labeling of TCA cycle-associated metabolites was detected in both transformed cell lines. Transcriptional profiling detected elevated expression of several genes associated with glycolysis, glutamine metabolism, and nucleotide biosynthesis upon transformation with oncogenic K-Ras. Chemical perturbation of enzymes along these pathways further supports the decoupling of glycolysis and TCA metabolism, with glutamine supplying increased carbon to drive the TCA cycle. These results provide evidence for a role of oncogenic K-Ras in the metabolic reprogramming of cancer cells.

Lung tumors in mice: application to carcinogenesis bioassay.

Abstract: Publisher Summary This chapter provides information on lung tumors in mice, with emphasis on the use of mouse lung for quantitative investigations in carcinogenesis, especially bioassay of chemicals for carcinogenic activity. The lung-tumor response in strain A mice is easily and clearly positive to all major types of chemical carcinogens. Strain A mice are the most susceptible to a wide variety of carcinogens, in terms of the earlier appearance and greater multiplicity of tumors. The lung-tumor response in strain A mice is easily and clearly positive to all major types of chemical carcinogens. Estrogenic and other steroid hormones, with the targets of endocrine-regulated tissues, are an exception. The lung tumor of the mouse has demonstrated its ability to pick up undetected, unpredicted neoplastic responses such as to urethane and to isoniazid. The carcinogens picked up by the lung tumor system have been shown to be carcinogenic for other tissues and in other species of animals. The mouse lung tumor is a reproducible, stable, and rapid biological model for a wide variety of quantitative investigations in carcinogenesis. It provides a three-dimensional lattice of the lung in which a known, identifiable subpopulation of cells—the type 2 alveolar pneumocytes—can be accelerated into conversion into neoplasms.

Dietary Restriction Reduces Insulin-like Growth Factor I Levels, Which Modulates Apoptosis, Cell Proliferation, and Tumor Progression in p53-deficient Mice

Abstract: Diet contributes to over one-third of cancer deaths in the Western world, yet the factors in the diet that influence cancer are not elucidated. A reduction in caloric intake dramatically slows cancer progression in rodents, and this may be a major contribution to dietary effects on cancer. Insulin-like growth factor I (IGF-I) is lowered during dietary restriction (DR) in both humans and rats. Because IGF-I modulates cell proliferation, apoptosis, and tumorigenesis, the mechanisms behind the protective effects of DR may depend on the reduction of this multifaceted growth factor. To test this hypothesis, IGF-I was restored during DR to ascertain if lowering of IGF-I was central to slowing bladder cancer progression during DR. Heterozygous p53-deficient mice received a bladder carcinogen, p-cresidine, to induce preneoplasia. After confirmation of bladder urothelial preneoplasia, the mice were divided into three groups: (a) ad libitum; (b) 20% DR; and (c) 20% DR plus IGF-I (IGF-I/DR). Serum IGF-I was lowered 24% by DR but was completely restored in the IGF-I/DR-treated mice using recombinant IGF-I administered via osmotic minipumps. Although tumor progression was decreased by DR, restoration of IGF-I serum levels in DR-treated mice increased the stage of the cancers. Furthermore, IGF-I modulated tumor progression independent of changes in body weight. Rates of apoptosis in the preneoplastic lesions were 10 times higher in DR-treated mice compared to those in IGF/DR- and ad libitum-treated mice. Administration of IGF-I to DR-treated mice also stimulated cell proliferation 6-fold in hyperplastic foci. In conclusion, DR lowered IGF-I levels, thereby favoring apoptosis over cell proliferation and ultimately slowing tumor progression. This is the first mechanistic study demonstrating that IGF-I supplementation abrogates the protective effect of DR on neoplastic progression.

Activating c-kit gene mutations in human germ cell tumors.

Abstract: The c-kit gene encodes a tyrosine kinase receptor (KIT) that is required in normal spermatogenesis and is expressed in seminomas and dysgerminomas, a subset of human germ cell tumors (GCTs). To determine whether activating mutations of the c-kit gene occur in GCTs, primary tissue samples of 33 testicular and ovarian tumors were examined for mutations in the juxtamembrane and phosphotransferase domains by polymerase chain reaction amplification and DNA sequencing. A novel missense mutation (D816H) was found in the phosphotransferase domain in tumors of seminoma/dysgerminoma differentiation. The c-kit alleles in nonneoplastic tissues from these patients were wild type, suggesting that the mutant alleles were acquired and selected for during malignant transformation. In cell transfection experiments, the D816H mutant protein was a constitutively activated kinase and was constitutively phosphorylated on tyrosine residues. This is the first description of an activating c-kit mutation in GCTs and is evidence that the KIT signal transduction pathway is important in the pathogenesis of neoplasms with seminoma differentiation.