Mutation analysis of K‐<i>ras</i>‐2 in liver angiosarcoma and adjacent nonneoplastic liver tissue from patients occupationally exposed to vinyl chloride

Weihrauch, Markus; Bader, Michael; Lehnert, G.; Koch, Bernd; Wittekind, Christian; Wrbitzky, Renate; Tannapfel, Andrea

doi:10.1002/em.10084

Cited by 35 publications

(25 citation statements)

References 18 publications

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“…angiosarcomas, as sporadic or thorotrast (thorium dioxide)-induced human liver angiosarcomas did not display this mutation . The G>A transition at the second base of the K-ras-2 protooncogene results in expression of the mutant Asp 13 (instead of Gly) of the encoded p21 protein Smith et al, 1998;Weihrauch et al, 2002a). Also, mutation spectra characteristic of vinyl chloride were reported for the p53 gene, mostly involving A>T changes (Hollstein et al, 1994;Trivers et al, 1995).…”

Section: E Tumor Mutation Spectra and Oncogene Activationmentioning

confidence: 92%

Vinyl Chloride—A Classical Industrial Toxicant of New Interest

Bolt

2005

Critical Reviews in Toxicology

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The carcinogenicity of vinyl chloride in humans was recognized in 1974 based on observations of hepatic angiosarcomas in highly exposed workers. A multiplicity of endpoints has been demonstrated. The primary target organ, the liver, displays differential susceptibilities of hepatocytes and sinusoidal cells, which are modified by factors of age and dose. There is consistency in organotropism between experimental animals and humans. Vinyl chloride is a pluripotent carcinogen, predominantly directed toward hepatic endothelial (sinusoidal) cells, and second toward the parenchymal cells of the liver. The similarity of results between experimental animals and humans is a solid basis of an amalgamation of experimental and epidemiological risk estimates. Vinyl chloride requires metabolic activation for carcinogenicity and mutagenicity, and toxicokinetics are a key to interpret the dose response. Practically the entire initial metabolism of vinyl chloride is oxidative. At higher exposure concentrations this is nonlinear, and metabolic saturation of metabolism in rats is reached at about 250 ppm. This is consistent with the plateau of hepatic angiosarcoma incidence in rat bioassays. Physiologically based pharmacokinetic/toxicokinetic (PBPK) models have been developed and successfully applied within the frame of human cancer risk assessments. The major DNA adduct induced by vinyl chloride (approximately 98% of total adducts in rats), 7-(2-oxoethyl)guanine, is almost devoid of promutagenic activity. The clearly promutagenic "etheno" adducts N2,3-ethenoguanine and 3,N4-ethenocytosine each represent approximately 1% of the vinyl chloride DNA adducts in rats, and 1,N6-ethenoadenine is found at even lower concentrations. Etheno adducts appear to have a long persistence and are repaired by glycosylases. Vinyl chloride represents a human carcinogen for which a series of mechanistic events connects exposure with the carcinogenic outcome. These include (1) metabolic activation (to form chloroethylene oxide), (2) DNA binding of the reactive metabolite (to exocyclic etheno adducts), (3) promutagenicity of these adducts, and (4) effects of such mutations on protooncogenes/tumor suppressor genes at the gene and gene product levels. In rat hepatocytes, a further event is a biomarker response. Cancer prestages (enzyme-altered foci), as quantitative biomarkers, provide a tool to study dose response even within low dose ranges where a carcinogenic risk cannot be seen in cancer bioassays directly. Such biomarker responses support a linear nonthreshold extrapolation for low-dose assessment of carcinogenic risks due to vinyl chloride. Published risk estimates based on different sets of data (animal experiments, epidemiological studies) appear basically consistent, and on this basis an angiosarcoma risk of approximately 3 x 10(-4) has been deduced by extrapolation, for exposure to 1 ppm vinyl chloride over an entire human working lifetime. An important point that should be considered in regulatory standard settings is the presence of a physiolo...

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Section: E Tumor Mutation Spectra and Oncogene Activationmentioning

confidence: 92%

Vinyl Chloride—A Classical Industrial Toxicant of New Interest

Bolt

2005

Critical Reviews in Toxicology

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“…To date, angiosarcoma has no clearly defined causative mutation, although activating mutations in key signaling molecules have been reported in AS subtypes. For example, K-Ras2 mutations have been detected in 9 of 24 sporadic hepatic angiosarcomas (4) and also in hepatic AS after occupational exposure to vinyl chloride (5, 6). Ten percent of AS tumors showed activating mutations in KDR, the kinase insert domain receptor (also known as VEGFR2) (7).…”

Section: Introductionmentioning

confidence: 99%

Pharmacologic Inhibition of MEK Signaling Prevents Growth of Canine Hemangiosarcoma

Andersen

Nickoloff

Dykema

et al. 2013

Molecular Cancer Therapeutics

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Angiosarcoma (AS) is a rare neoplasm of endothelial origin that has limited treatment options and poor five-year survival. As a model for human AS, we studied primary cells and tumorgrafts derived from canine hemangiosarcoma (HSA), which is also an endothelial malignancy with similar presentation and histology. Primary cells isolated from HSA showed constitutive ERK activation. The MEK inhibitor CI-1040 reduced ERK activation and the viability of primary cells derived from visceral, cutaneous, and cardiac HSA in vitro. HSA-derived primary cells were also sensitive to sorafenib, an inhibitor of B-Raf and multi-receptor tyrosine kinases. In vivo, CI-1040 or PD0325901 decreased the growth of cutaneous cell-derived xenografts and cardiac-derived tumorgrafts. Sorafenib decreased tumor size in both in vivo models, although cardiac tumorgrafts were more sensitive. In human AS, we noted that 50% of tumors stained positively for phosphorylated ERK1/2 and that the expression of several MEK-responsive transcription factors was up-regulated. Our data showed that MEK signaling is essential for the growth of HSA in vitro and in vivo and provided evidence that the same pathways are activated in human AS. This indicates that MEK inhibitors may form part of an effective therapeutic strategy for the treatment of canine HSA or human AS, and it highlights the utility of spontaneous canine cancers as a model of human disease.

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“…Mice haploinsufficient for NF1 show enhanced angiogenesis in a corneal and retinal neovascularization assay (9). The importance of normal Ras regulation in the growth control of endothelial cells is underscored by the finding that devastating tumors of endothelial cell origin, angiosarcomas, both sporadic and following exposure to vinyl chlorides, are associated with Ras mutations (10, 11). Collectively these data suggest that unregulated Ras can compromise normal vascular growth control, morphogenesis, and function.…”

Section: Introductionmentioning

confidence: 99%

Activation of Endothelial Ras Signaling Bypasses Senescence and Causes Abnormal Vascular Morphogenesis

et al. 2010

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Angiogenesis is crucial for embryogenesis, reproduction, and wound healing and is a critical determinant of tumor growth and metastasis. The multifunctional signal transducer Ras is a proto-oncogene and frequently becomes mutated in a variety of human cancers, including angiosarcomas. Regulation of Ras is important for endothelial cell function and angiogenesis. Hyperactivation of Ras is linked with oncogene-induced senescence in many cell types. Given links between vascular malformations and angiosarcoma with activated Ras signaling, we sought to determine the consequence of sustained Ras activation on endothelial cell function. We find that sustained Ras activation in primary endothelial cells leads to prolonged activation of progrowth signaling, accompanied by a senescence bypass, enhanced proliferation, autonomous growth, and increased survival. Moreover, Ras severely compromises the ability of these cells to organize into vascular structures, instead promoting formation of planar endothelial sheets. This abnormal phenotype is regulated by phosphoinositide 3-kinase signaling, highlighting the therapeutic potential of agents targeting this axis in dealing with vascular morphogenic disorders and vascular normalization of tumors. Cancer Res; 70(9); 3803-12. ©2010 AACR.

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Mutation analysis of K‐ras‐2 in liver angiosarcoma and adjacent nonneoplastic liver tissue from patients occupationally exposed to vinyl chloride

Cited by 35 publications

References 18 publications

Vinyl Chloride—A Classical Industrial Toxicant of New Interest

Vinyl Chloride—A Classical Industrial Toxicant of New Interest

Pharmacologic Inhibition of MEK Signaling Prevents Growth of Canine Hemangiosarcoma

Activation of Endothelial Ras Signaling Bypasses Senescence and Causes Abnormal Vascular Morphogenesis

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