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.

REVIEW Role of Transforming Growth Factor- Signaling in Cancer

Abstract: Signaling from transforming growth factor- (TGF-) through its unique transmembrane receptor serine– threonine kinases plays a complex role in carcinogenesis, having both tumor suppressor and oncogenic activities. Tumor cells often escape from the antiproliferative effects of TGF- by mutational inactivation or dysregulated expression of components in its signaling pathway. Decreased receptor function and altered ratios of the TGF- type I and type II receptors found in many tumor cells compromise the tumor suppressor activities of TGF- and enable its oncogenic functions. Recent identification of a family of intracellular mediators, the Smads, has provided new paradigms for understanding mechanisms of subversion of TGF- signaling by tumor cells. In addition, several proteins recently have been identified that can modulate the Smad-signaling pathway and may also be targets for mutation in cancer. Other pathways such as various mitogen-activated protein kinase cascades also contribute substantially to TGF- signaling. Understanding the interplay between these signaling cascades as well as the complex patterns of cross-talk with other signaling pathways is an important area of investigation that will ultimately contribute to understanding of the bifunctional tumor suppressor/oncogene role of TGF- in carcinogenesis. [J Natl Cancer Inst 2000;92:1388–402]

Constitutive activation of STAT3 in breast cancer cells: A review.

Abstract: Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in numerous cancer types, including more than 40% of breast cancers. In contrast to tight regulation of STAT3 as a latent transcription factor in normal cells, its signaling in breast cancer oncogenesis is multifaceted. Signaling through the IL-6/JAK/STAT3 pathway initiated by the binding of IL-6 family of cytokines (i.e., IL-6 and IL-11) to their receptors have been implicated in breast cancer development. Receptors with intrinsic kinase activity such as EGFR and VEGFR directly or indirectly induce STAT3 activation in various breast cancer types. Aberrant STAT3 signaling promotes breast tumor progression through deregulation of the expression of downstream target genes which control proliferation (Bcl-2, Bcl-xL, Survivin, Cyclin D1, c-Myc and Mcl-1), angiogenesis (Hif1α and VEGF) and epithelial-mesenchymal transition (Vimentin, TWIST, MMP-9 and MMP-7). These multiple modes of STAT3 regulation therefore make it a central linking point for a multitude of signaling processes. Extensive efforts to target STAT3 activation in breast cancer had no remarkable success in the past because the highly interconnected nature of STAT3 signaling introduces lack of selectivity in pathway identification for STAT3 targeted molecular therapies or because its role in tumorigenesis may not be as critical as it was thought. This review provides a full spectrum of STAT3's involvement in breast cancer by consolidating the knowledge about its role in breast cancer development at multiple levels: its differential regulation by different receptor signaling pathways, its downstream target genes, and modification of its transcriptional activity by its coregulatory transcription factors.

Nitric oxide-induced p53 accumulation and regulation of inducible nitric oxide synthase expression by wild-type p53.

Abstract: The tumor suppressor gene product p53 plays an important role in the cellular response to DNA damage from exogenous chemical and physical mutagens. Therefore, we hypothesized that p53 performs a similar role in response to putative endogenous mutagens, such as nitric oxide (NO). We report here that exposure of human cells to NO generated from an NO donor or from overexpression of inducible nitric oxide synthase (NOS2) results in p53 protein accumulation. In addition, expression of wild-type (WT) p53 in a variety of human tumor cell lines, as well as murine fibroblasts, results in down-regulation of NOS2 expression through inhibition of the NOS2 promoter. These data are consistent with the hypothesis of a negative feedback loop in which endogenous NO-induced DNA damage results in WT p53 accumulation and provides a novel mechanism by which p53 safeguards against DNA damage through p53-mediated transrepression of NOS2 gene expression, thus reducing the potential for NO-induced DNA damage.

The Approaching Era of the Tumor Suppressor Genes

Abstract: Genes that can inhibit the expression of the tumorigenic phenotype have been detected by the fusion of normal and malignant cells, the phenotypic reversion of in vitro transformants, the induction of terminal differentiation of malignant cell lineages, the loss of "recessive cancer genes," the discovery of regulatory sequences in the immediate vicinity of certain oncogenes, and the inhibition of tumor growth by normal cell products Such tumor suppressor genes will probably turn out to be as, if not more, diversified as the oncogenes Consideration of both kinds of genes may reveal common or interrelated functional properties