Cancer genetics: Finding the right mix

Boehm, Jesse S.; Hahn, William C.

doi:10.1038/sj.ejhg.5201477

Cited by 5 publications

(6 citation statements)

References 8 publications

(8 reference statements)

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“…These include the actual identity of the oncoprotein, the cell type in which it is expressed, the species of origin, the extracellular environment, and the pre-existing levels and activities of other endogenous oncoproteins and tumor suppressors [12,13]. What has recently been appreciated is that the cellular responses tend to be graded and belong to more general genotoxic stress response pathways.…”

Section: Cellular Stress Responses To Onco-gene Deregulationmentioning

confidence: 97%

“…Unlike rodent cells, primary human cells require a greater number of genetic lesions for transformation [13,25,78,79]. In addition to Ras over-expression, these requirements include the concurrent inactivation of CDKN2A pathway members (often accomplished by expressing SV40 large T antigen, which targets both p53 and Rb), the activation of telomerase (or c-Myc, which induces telomerase), and the inactivation of protein phosphatase 2A, whose role remains somewhat obscure.…”

Section: Chronic Transformationmentioning

confidence: 99%

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c-Myc: Linking Transformation and Genomic Instability

Prochownik

2008

CMM

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CMYC has long been known to be among the most frequently de-regulated oncogenes in human cancer. Only recently, however has a clear understanding begun to emerge of how it promotes transformation. Through its role as a transcription factor, c-Myc alters the expression of hundreds of target genes, many of which are themselves oncogenes or tumor suppressors. The deregulation of c-Myc is both necessary and sufficient for the "acute" type of rapid in vitro transformation that occurs in certain established rodent cell lines. Transformation of primary rodent cells in vitro is also rapid but requires the contribution of at least one additional cooperating oncogene such as Ras. In contrast, the "chronic" form of in vivo transformation by c-Myc is a rare event that requires the acquisition of multiple mutations in other genes affecting cell cycle, senescence, and apoptosis. By greatly accelerating the intrinsic mutation rate at several levels, c-Myc increases the likelihood that these additional mutational "hits" will occur. Among the types of genomic instability mediated by c-Myc are single nucleotide substitutions and double-stranded breaks arising via the induction of reactive oxygen species, gene amplification and the generation of extrachromosomal elements, and numerical chromosomal defects resulting from aberrant DNA synthesis and defects in the mitotic spindle checkpoint. These non-mutually exclusive activities ensure a constant and varied source of genotoxic insults and suggest that c-Myc over-expression imposes a "mutator phenotype". This may be an early and necessary requirement for the initial steps in chronic transformation as well as for subsequent evolutionary changes that produce important tumor behaviors such as invasiveness, metastasis, and acquisition of chemotherapy resistance.

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Section: Cellular Stress Responses To Onco-gene Deregulationmentioning

confidence: 97%

Section: Chronic Transformationmentioning

confidence: 99%

c-Myc: Linking Transformation and Genomic Instability

Prochownik

2008

CMM

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“…It is notable that, aside from aberrant VEGF signaling, there have been no reports of oncogenic changes that clearly distinguish EC neoplasias from other cancers, such as epithelial cancers. Hence, genetic models of EC neoplasias have largely relied on combinations that have also been shown to transform epithelial cells (Boehm and Hahn, 2005). …”

Section: Perspectives and Conclusionmentioning

confidence: 99%

Modeling human endothelial cell transformation in vascular neoplasias

Wen

MacKenzie

2013

Disease Models &Amp; Mechanisms

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Endothelial cell (EC)-derived neoplasias range from benign hemangioma to aggressive metastatic angiosarcoma, which responds poorly to current treatments and has a very high mortality rate. The development of treatments that are more effective for these disorders will be expedited by insight into the processes that promote abnormal proliferation and malignant transformation of human ECs. The study of primary endothelial malignancy has been limited by the rarity of the disease; however, there is potential for carefully characterized EC lines and animal models to play a central role in the discovery, development and testing of molecular targeted therapies for vascular neoplasias. This review describes molecular alterations that have been identified in EC-derived neoplasias, as well as the processes that underpin the immortalization and tumorigenic conversion of ECs. Human EC lines, established through the introduction of defined genetic elements or by culture of primary tumor tissue, are catalogued and discussed in relation to their relevance as models of vascular neoplasia.

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“…Moreover, experimental transformation of normal human cells to tumor cells requires hTERT-mediated immortalization, as well as inactivation of p53 and pRb genes (9).…”

mentioning

confidence: 99%