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.

Ras-induced Interleukin-8 expression plays a critical role in tumor growth and angiogenesis

Abstract: 1749 Ras proteins are important regulators of cell proliferation and their constitutive activation is a key event in cancer development. To discover novel effector pathways that might contribute to the oncogenic properties of Ras, we used oligonucleotide-based DNA microarrays to analyze transcriptional changes resulting from constitutive Ras signaling. We performed the expression analyses with HeLa stable cell lines expressing activated RasG12→V transgenes under a tetracycline responsive promoter (Tet-Off™ Expression System). This system not only mediates tight on/off regulation of gene expression; it also permits the titration of protein levels on a single cell basis allowing the study of dose dependent aspects of gene activity. Ras signaling leads to a significant induction of Interleukin-8 (IL-8) mRNA, which is accompanied by a corresponding increase in protein levels. IL-8 is a chemotactic factor for leukocytes and closely associated with the initiation of an acute inflammatory response. Analysis of signal transduction pathways that link Ras to IL-8 up-regulation suggests a direct effect of Ras on the IL-8 promoter, mediated by the synergistic activation of both MAPK-cascades and the PI3K > NFκB pathway. In addition, the Ras-induced accumulation of IL-8 protein is dependent on the activation of p38 MAP-kinase through a post-transcriptional mechanism involving an increase in IL-8 mRNA stability. Investigation of the functional importance of IL-8 in the context of tumorigenesis shows that IL-8 plays a decisive role in RasV12-mediated acceleration of tumor growth in a nude mouse xenograft model. Ablation of IL-8 function is accompanied by a significant reduction in tumor size. This effect is not due to decreased cell proliferation rates, since we observe no change in the mitogenic index of tumors after inhibition of IL-8. However, tumors devoid of functional IL-8 show a marked reduction in vascularization accompanied by vast tissue necrosis. These observations can be correlated with an IL-8-mediated initiation of an early inflammatory reaction in developing neoplasms that triggers tumor vascularization. In addition, IL-8 may act directly to support angiogenesis by promoting endothelial cell proliferation and migration. These results provide a novel mechanism by which tumor cells harboring oncogenic Ras can appropriate inflammatory mediators to recruit immune cells to the tumor site and facilitate neo-angiogenesis, thus setting the stage for subsequent progression to malignancy.

Apaf-1 and caspase-9 in p53-dependent apoptosis and tumor inhibition.

Abstract: The ability of p53 to promote apoptosis in response to mitogenic oncogenes appears to be critical for its tumor suppressor function. Caspase-9 and its cofactor Apaf-1 were found to be essential downstream components of p53 in Myc-induced apoptosis. Like p53 null cells, mouse embryo fibroblast cells deficient in Apaf-1 and caspase-9, and expressing c-Myc, were resistant to apoptotic stimuli that mimic conditions in developing tumors. Inactivation of Apaf-1 or caspase-9 substituted for p53 loss in promoting the oncogenic transformation of Myc-expressing cells. These results imply a role for Apaf-1 and caspase-9 in controlling tumor development.

The PIK3CA gene is mutated with high frequency in human breast cancers

Abstract: The phosphatidylinositol 3-kinases (PI3Ks) are known regulators of cellular growth and proliferation. It has recently been reported that somatic mutations within the PI3K subunit p110alpha (PIK3CA) are present in human colorectal and other cancers. Here we show that thirteen of fifty-three breast cancers (25%) contain somatic mutations in PIK3CA, with the majority of mutations located in the kinase domain. These results demonstrate that PIK3CA is the most mutated oncogene in breast cancer and support a role for PIK3CA in epithelial carcinogenesis.

Inhibition of cyclo-oxygenase 2 expression in colon cells by the chemopreventive agent curcumin involves inhibition of NF-kappaB activation via the NIK/IKK signalling complex.

Abstract: Colorectal cancer is a major cause of cancer deaths in Western countries, but epidemiological data suggest that dietary modification might reduce these by as much as 90%. Cyclo-oxygenase 2 (COX2), an inducible isoform of prostaglandin H synthase, which mediates prostaglandin synthesis during inflammation, and which is selectively overexpressed in colon tumours, is thought to play an important role in colon carcinogenesis. Curcumin, a constituent of turmeric, possesses potent anti-inflammatory activity and prevents colon cancer in animal models. However, its mechanism of action is not fully understood. We found that in human colon epithelial cells, curcumin inhibits COX2 induction by the colon tumour promoters, tumour necrosis factor alpha or fecapentaene-12. Induction of COX2 by inflammatory cytokines or hypoxia-induced oxidative stress can be mediated by nuclear factor kappa B (NF-kappaB). Since curcumin inhibits NF-kappaB activation, we examined whether its chemopreventive activity is related to modulation of the signalling pathway which regulates the stability of the NF-kappaB-sequestering protein, IkappaB. Recently components of this pathway, NF-kappaB-inducing kinase and IkappaB kinases, IKKalpha and beta, which phosphorylate IkappaB to release NF-kappaB, have been characterised. Curcumin prevents phosphorylation of IkappaB by inhibiting the activity of the IKKs. This property, together with a long history of consumption without adverse health effects, makes curcumin an important candidate for consideration in colon cancer prevention.

Diet, microorganisms and their metabolites, and colon cancer

Abstract: Colorectal cancer is one of the so-called westernized diseases and the second leading cause of cancer death worldwide. On the basis of global epidemiological and scientific studies, evidence suggests that the risk of colorectal cancer is increased by processed and unprocessed meat consumption but suppressed by fibre, and that food composition affects colonic health and cancer risk via its effects on colonic microbial metabolism. The gut microbiota can ferment complex dietary residues that are resistant to digestion by enteric enzymes. This process provides energy for the microbiota but culminates in the release of short-chain fatty acids including butyrate, which are utilized for the metabolic needs of the colon and the body. Butyrate has a remarkable array of colonic health-promoting and antineoplastic properties: it is the preferred energy source for colonocytes, it maintains mucosal integrity and it suppresses inflammation and carcinogenesis through effects on immunity, gene expression and epigenetic modulation. Protein residues and fat-stimulated bile acids are also metabolized by the microbiota to inflammatory and/or carcinogenic metabolites, which increase the risk of neoplastic progression. This Review will discuss the mechanisms behind these microbial metabolite effects, which could be modified by diet to achieve the objective of preventing colorectal cancer in Western societies.