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.

Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas

Abstract: Persistently activated or tyrosine-phosphorylated STAT3 (pSTAT3) is found in 50% of lung adenocarcinomas. pSTAT3 is found in primary adenocarcinomas and cell lines harboring somatic-activating mutations in the tyrosine kinase domain of EGFR. Treatment of cell lines with either an EGFR inhibitor or an src kinase inhibitor had no effect on pSTAT3 levels, whereas a pan-JAK inhibitor (P6) blocked activation of STAT3 and inhibited tumorigenesis. Cell lines expressing these persistently activated mutant EGFRs also produced high IL-6 levels, and blockade of the IL-6/gp130/JAK pathway led to a decrease in pSTAT3 levels. In addition, reduction of IL-6 levels by RNA interference led to a decrease in tumorigenesis. Introduction of persistently activated EGFR into immortalized breast epithelial cells led to tumorigenesis, IL-6 expression, and STAT3 activation, all of which could be inhibited with P6 or gp130 blockade. Furthermore, inhibition of EGFR activity in multiple cell lines partially blocked transcription of IL-6 and concurrently decreased production and release of IL-6. Finally, immunohistochemical analysis revealed a positive correlation between pSTAT3 and IL-6 positivity in primary lung adenocarcinomas. Therefore, mutant EGFR could activate the gp130/JAK/STAT3 pathway by means of IL-6 upregulation in primary human lung adenocarcinomas, making this pathway a potential target for cancer treatment.

Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice

Abstract: Pancreatic cancer is almost invariably associated with mutations in the KRAS gene, most commonly KRASG12D, that result in a dominant-active form of the KRAS GTPase However, how KRAS mutations promote pancreatic carcinogenesis is not fully understood, and whether oncogenic KRAS is required for the maintenance of pancreatic cancer has not been established To address these questions, we generated two mouse models of pancreatic tumorigenesis: mice transgenic for inducible KrasG12D, which allows for inducible, pancreas-specific, and reversible expression of the oncogenic KrasG12D, with or without inactivation of one allele of the tumor suppressor gene p53 Here, we report that, early in tumorigenesis, induction of oncogenic KrasG12D reversibly altered normal epithelial differentiation following tissue damage, leading to precancerous lesions Inactivation of KrasG12D in established precursor lesions and during progression to cancer led to regression of the lesions, indicating that KrasG12D was required for tumor cell survival Strikingly, during all stages of carcinogenesis, KrasG12D upregulated Hedgehog signaling, inflammatory pathways, and several pathways known to mediate paracrine interactions between epithelial cells and their surrounding microenvironment, thus promoting formation and maintenance of the fibroinflammatory stroma that plays a pivotal role in pancreatic cancer Our data establish that epithelial KrasG12D influences multiple cell types to drive pancreatic tumorigenesis and is essential for tumor maintenance They also strongly support the notion that inhibiting KrasG12D, or its downstream effectors, could provide a new approach for the treatment of pancreatic cancer

In search of the tumour-suppressor functions of BRCA1 and BRCA2

Abstract: Hereditary breast and ovarian cancer syndromes can be caused by loss-of-function germline mutations in one of two tumour-suppressor genes, BRCA1 and BRCA2 (ref 1) Each gene product interacts with recombination/DNA repair proteins in pathways that participate in preserving intact chromosome structure However, it is unclear to what extent such functions specifically suppress breast and ovarian cancer Here we analyse what is known of BRCA gene function and highlight some unanswered questions in the field

Molecular Mechanisms of Estrogen Carcinogenesis

Abstract: In western society, the causes of several cancers--including breast, endometrium, ovary, liver, and prostate--have been linked to inappropriate and/or prolonged exposure to synthetic or endogenous steroidal hormones. In this review, we discuss the mechanisms of estrogen carcinogenesis with a focus on estrogen metabolism to 16 alpha-hydroxy estrone and 2- and 4-hydroxy catechol estrogens and the potential effects of these metabolites in vitro and in vivo on hamster liver and kidney and rat liver carcinogenesis models. The examples demonstrate that the parent compounds and their metabolites cause both nongenotoxic cell proliferative effects as well as direct and indirect genotoxic effects, which illustrates the complex nature of estrogen carcinogenesis. These effects, in combination with the metabolic state of the tissue and the timing of its exposure, may determine the cell type (organ) of tumor development and the severity of disease.