mTOR Mediates Survival Signals in Malignant Mesothelioma Grown as Tumor Fragment Spheroids

Wilson, Shannon M.; Barbone, Dario; Yang, Tsung‐Ming; Jablons, David M.; Bueno, Raphael; Sugarbaker, David J.; Nishimura, Stephen L.; Gordon, Gavin J.; Broaddus, V. Courtney

doi:10.1165/rcmb.2007-0460oc

Cited by 60 publications

(54 citation statements)

References 40 publications

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“…In 3D spheroids of mesothelioma tumor cells, we previously identified an acquired resistance to combinatorial therapies that was due, at least in part, to the mammalian target of rapamycin (mTOR) pathway, which demonstrated an antiapoptotic effect in spheroids that was not evident in monolayers (21). We then confirmed that the mTOR pathway also exerted a survival function in tumor fragments grown from human mesothelioma (22); clinical trials will confirm whether inhibition of the pathway offers benefit in patients with mesothelioma. By such studies, it is hoped that 3D models will elucidate mechanisms of apoptotic resistance that may provide clues to the therapeutic resistance seen clinically.…”

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confidence: 67%

“…Our previous studies in mesothelioma showed that mTOR contributes to the apoptotic resistance in multicellular spheroids generated from cell lines, and in tumor fragment spheroids generated from actual tumor (21,22). Hence, we evaluated whether mTOR also contributes to the multicellular resistance of A549 spheroids by using rapamycin, a TOR complex 1 inhibitor, and PI-103, an inhibitor of PI3K and TOR complex 1 and -2.…”

Section: Inhibitors Of Pi3k/akt/mtor Do Not Reduce the Apoptotic Resimentioning

confidence: 99%

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Bcl-2 Family Proteins Contribute to Apoptotic Resistance in Lung Cancer Multicellular Spheroids

Yang¹,

Barbone²,

Fennell³

et al. 2009

Am J Respir Cell Mol Biol

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Combinatorial therapies using the proteasome inhibitor, bortezomib, have been found to induce synergistic apoptosis in cancer cells grown as monolayers; however, three-dimensional spheroid culture may be a better model for the multicellular resistance found in solid tumors, such as lung cancer. We tested the combinatorial apoptotic strategy of using bortezomib together with TNF-related apoptosis-inducing ligand (TRAIL), both in monolayers and in spheroids of A549 lung cancer cells. Indeed, bortezomib plus TRAIL induced synergistic apoptosis in A549 cells grown as monolayers, but had little effect on A549 cells grown as three-dimensional multicellular spheroids. The acquired resistance of spheroids was not due to a limitation of diffusion, to survival pathways, such as NF-kB or PI3K/Akt/mTOR, or to the up-regulation of FLIP S (Fasassociated death domain-like IL-1b-converting enzyme inhibitory protein, short). We then investigated a role for the Bcl-2 family of anti-and proapoptotic proteins. When cells formed spheroids, antiapoptotic Bcl-2 increased, whereas antiapoptotic Mcl-1 decreased. ABT-737, a small molecule that inhibits Bcl-2, but not Mcl-1, abolished the multicellular resistance of A549 spheroids to bortezomib plus TRAIL. In another lung cancer cell line, H1299, acquisition of multicellular resistance in spheroids was also accompanied by an increase in Bcl-2 and decrease in Mcl-1. In H1299 spheroids compared with those of A549, however, Mcl-1 remained higher, and Mcl-1 knockdown was more effective than ABT-737 in removing multicellular resistance. Our study suggests that the balance of Bcl-2 family proteins contributes to the acquired multicellular resistance of spheroids, and suggests a possible target for improving the response of lung cancer to bortezomib therapies.

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confidence: 67%

Section: Inhibitors Of Pi3k/akt/mtor Do Not Reduce the Apoptotic Resimentioning

confidence: 99%

Bcl-2 Family Proteins Contribute to Apoptotic Resistance in Lung Cancer Multicellular Spheroids

Yang¹,

Barbone²,

Fennell³

et al. 2009

Am J Respir Cell Mol Biol

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“…Survival pathways, such as PI3K/Akt/mammalian target of rapamycin (mTOR), are involved in cell growth and resistance to apoptosis, and are often activated in mesothelioma. mTOR was shown to mediate survival signals in many mesothelioma tumours and inhibition of mTOR was also proposed as a nontoxic adjunct to therapy directed against mesothelioma [91]. Inflammation has also been incriminated and it was recently shown that inflammation precedes mesothelioma formation.…”

Section: Figurementioning

confidence: 99%

Malignant pleural mesothelioma: history, controversy and future of a manmade epidemic

2015

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Asbestos is the term for a family of naturally occurring minerals that have been used on a small scale since ancient times. Industrialisation demanded increased mining and refining in the 20th century, and in 1960, Wagner, Sleggs and Marchand from South Africa linked asbestos to mesothelioma, paving the way to the current knowledge of the aetiology, epidemiology and biology of malignant pleural mesothelioma. Pleural mesothelioma is one of the most lethal cancers, with increasing incidence worldwide. This review will give some snapshots of the history of pleural mesothelioma discovery, and the body of epidemiological and biological research, including some of the controversies and unresolved questions. Translational research is currently unravelling novel circulating biomarkers for earlier diagnosis and novel treatment targets. Current breakthrough discoveries of clinically promising noninvasive biomarkers, such as the 13-protein signature, microRNAs and the BAP1 mesothelioma/cancer syndrome, are highlighted. The asbestos history is a lesson to not be repeated, but here we also review recent in vivo and in vitro studies showing that manmade carbon nanofibres could pose a similar danger to human health. This should be taken seriously by regulatory bodies to ensure thorough testing of novel materials before release in the society. @ERSpublications Malignant pleural mesothelioma is a cancer with increasing death tolls due to the past and present use of asbestos http://ow.ly/DhA2y

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“…This pathway is dysregulated in mesothelioma, and in vitro cell growth can be inhibited using mTOR or PI3K inhibition [28]. The mTOR inhibitor rapamycin reduced resistance to apoptosis ex vivo in a novel assay using human tumor spheroids [29]. Combining sirolimus with cisplatin may enhance the cytotoxicity of the latter [30].…”

Section: Other Potential Targetsmentioning

confidence: 99%

Novel Targeted Therapies and Vaccination Strategies for Mesothelioma

Bagia

Nowak

2011

Curr. Treat. Options in Oncol.

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Novel targeted therapies have found a niche in the treatment of many cancers, although the most responsive populations, best biomarkers of response, and appropriate treatment settings are still under investigation. With few exceptions, cancer vaccination strategies have not entered into routine management. In malignant mesothelioma, combination first-line chemotherapy with a platinum and pemetrexed remains the standard of care when systemic therapy is considered. Second-line chemotherapy is used but benefits are uncertain in the absence of appropriately controlled randomized trials. Currently, there are no novel targeted therapies or vaccinations that should be used in this disease outside the context of a clinical trial.

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mTOR Mediates Survival Signals in Malignant Mesothelioma Grown as Tumor Fragment Spheroids

Cited by 60 publications

References 40 publications

Bcl-2 Family Proteins Contribute to Apoptotic Resistance in Lung Cancer Multicellular Spheroids

Bcl-2 Family Proteins Contribute to Apoptotic Resistance in Lung Cancer Multicellular Spheroids

Malignant pleural mesothelioma: history, controversy and future of a manmade epidemic

Novel Targeted Therapies and Vaccination Strategies for Mesothelioma

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