mTOR contributes to the acquired apoptotic resistance of human mesothelioma multicellular spheroids.

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mTOR contributes to the acquired apoptotic resistance of human mesothelioma multicellular spheroids.

J Biol Chem. 2008 Mar 13;

Authors: Barbone D, Yang TM, Morgan JR, Gaudino G, Broaddus VC

When grown as 3D structures, tumor cells can acquire an additional multicellular resistance to apoptosis that may mimic the chemoresistance found in solid tumors. We developed a multicellular spheroid model of malignant mesothelioma to investigate molecular mechanisms of acquired apoptotic resistance. We found that mesothelioma cell lines, when grown as multicellular spheroids, acquired resistance to a variety of apoptotic stimuli, including combinations of TRAIL, ribotoxic stressors, histone deacetylase and proteasome inhibitors, that were highly effective against mesothelioma cells when grown as monolayers. Inhibitors of the PI3K/Akt/mTOR pathway, particularly rapamycin, blocked much of the acquired resistance of the spheroids, suggesting a key role for mTOR. Knockdown by siRNA of S6K, a major downstream target of mTOR, reproduced the effect of rapamycin, thereby confirming the role of mTOR and of S6K in the acquired resistance of 3D spheroids. Rapamycin or S6K knockdown increased TRAIL-induced caspase 8 cleavage in spheroids, suggesting initially that mTOR inhibited apoptosis by actions at the death receptor pathway; however, isolation of the apoptotic pathways by means of Bid knockdown ablated this effect showing that mTOR actually controls a step distal to Bid, probably at the level of the mitochondria. In sum, mTOR and S6K contribute to the apoptotic resistance of mesothelioma cells in 3D, not in 2D, cultures. The 3D model may reflect a more clinically relevant in vitro setting in which mTOR exhibits anti-apoptotic properties.

PMID: 18339627 [PubMed - as supplied by publisher]

March 18, 2008 | Filed Under Oncology | Leave a Comment 

Medico-legal aspects of mesothelioma.

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Medico-legal aspects of mesothelioma.

Ann Ital Chir. 2007 Sep-Oct;78(5):401-3

Authors: Partemi S, De Giorgio F

The Authors, reviewing the Literature on asbestos-related Malignant Mesothelioma (MM), found that because of its very peculiar characteristics, the causal link between professional asbestos exposure and the development of this tumour is very difficult to define in respect to: diagnosis, causal link and individuation of possible culpable conducts. The evaluation of causal link in different medico-legal areas is studied by different criteria. In civil law the criterion of weak causality is followed to allow compensation for damages. For institutional purposes in INAIL, the definition of causal link is particularly facilitated by the legal presumption of origin. In fact it is sufficient, that asbestos-related lesions are ascertained in individuals who are or were exposed at any time of their professional life to the risk of inhaling asbestos fibres. In criminal law, the current approach of the Supreme Court is to demand evidence of strong causality, with a high logical probability and rational credibility, and beyond reasonable doubt, because criminal liability is personal as established in article 27 of the Italian Constitution. It is worth pointing out that all the levels of evidence indicated above must pass the test of scientific suitability or possibility.

PMID: 18338548 [PubMed - in process]

March 18, 2008 | Filed Under Oncology | 1 Comment 

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