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.

Activating mutations for the Met tyrosine kinase receptor in human cancer

Abstract: Recently, mutations in the Met tyrosine kinase receptor have been identified in both hereditary and sporadic forms of papillary renal carcinoma. We have introduced the corresponding mutations into the met cDNA and examined the effect of each mutation in biochemical and biological assays. We find that the Met mutants exhibit increased levels of tyrosine phosphorylation and enhanced kinase activity toward an exogenous substrate when compared with wild-type Met. Moreover, NIH 3T3 cells expressing mutant Met molecules form foci in vitro and are tumorigenic in nude mice. Enzymatic and biological differences were evident among the various mutants examined, and the somatic mutations were generally more active than those of germ-line origin. A strong correlation between the enzymatic and biological activity of the mutants was observed, indicating that tumorigenesis by Met is quantitatively related to its level of activation. These results demonstrate that the Met mutants originally identified in human papillary renal carcinoma are oncogenic and thus are likely to play a determinant role in this disease, and these results raise the possibility that activating Met mutations also may contribute to other human malignancies.

Telomerase modulates expression of growth-controlling genes and enhances cell proliferation

Abstract: Most somatic cells do not express sufficient amounts of telomerase to maintain a constant telomere length during cycles of chromosome replication Consequently, there is a limit to the number of doublings somatic cells can undergo before telomere shortening triggers an irreversible state of cellular senescence Ectopic expression of telomerase overcomes this limitation, and in conjunction with specific oncogenes can transform cells to a tumorigenic phenotype However, recent studies have questioned whether the stabilization of chromosome ends entirely explains the ability of telomerase to promote tumorigenesis and have resulted in the hypothesis that telomerase has a second function that also supports cell division Here we show that ectopic expression of telomerase in human mammary epithelial cells (HMECs) results in a diminished requirement for exogenous mitogens and that this correlates with telomerase-dependent induction of genes that promote cell growth Furthermore, we show that inhibiting expression of one of these genes, the epidermal growth factor receptor (EGFR), reverses the enhanced proliferation caused by telomerase We conclude that telomerase may affect proliferation of epithelial cells not only by stabilizing telomeres, but also by affecting the expression of growth-promoting genes

Microtubule-targeted anticancer agents and apoptosis.

Abstract: Over the past decade, significant progress has been made in our understanding of the biology of microtubule (MT) assembly into the mitotic spindle during mitosis and the molecular signaling and execution of the various pathways to apoptosis. In the same period, the microtubule-targeted tubulin-polymerizing agents (MTPAs), notably paclitaxel and taxotere, have come to occupy a central role in the treatment of a variety of human epithelial cancers. Following their binding to B-tubulin, MTPAs inhibit MT dynamic instability, cell cycle G2/M phase transition and mitotic arrest of cancer cells. MTPA-induced anti-MT and cell cycle effects trigger the molecular signaling for the mitochondrial pathway of apoptosis. This triggering is orchestrated through different molecular links and determined by the threshold for apoptosis that is set and controlled diversely in various cancer types. The complexity and regulatory potential of the links and the apoptosis threshold are integral to the transformed biology of the cancer cell. The emerging understanding of this biology and how it is influenced by treatment with MTPAs has highlighted novel strategies to further enhance the antitumor activity and overcome resistance to MTPA-induced apoptosis in cancer cells.