Published ahead of print on May 29, 2008, doi:10.1165/rcmb.2007-0460OC Am. J. Respir. Cell Mol. Biol., Volume 39, Number 5, November 2008, 576-583 A more recent version of this article appeared on November 1, 2008
Submitted on December 20, 2007 mTOR Mediates Survival Signals in Malignant Mesothelioma Grown as Tumor Fragment SpheroidsShannon M Wilson1,1 University of California San Francisco, Lung Biology Center, San Francisco, CA, United States, 2 University of California San Francisco, Lung Biology Center, San Francisco, CA, United States; University of California San Francisco, Comprehensive Cancer Center, San Francisco, CA, USA, 3 University of California San Francisco, Comprehensive Cancer Center, San Francisco, CA, USA; Department of Surgery, University of California San Francisco, San Francisco, CA, USA, 4 Brigham and Women's Hospital, Harvard Medical School, The Division of Thoracic Surgery, Boston, MA, USA, 5 Department of Pathology, University of California San Francisco, San Francisco, CA, USA; University of California San Francisco, Comprehensive Cancer Center, San Francisco, CA, USA * To whom correspondence should be addressed. E-mail: cbroaddus{at}medsfgh.ucsf.edu.
Solid tumors such as mesothelioma exhibit a stubborn resistance to apoptosis that may derive from survival pathways, such as PI3K/Akt/mTOR, that are activated in many tumors including mesothelioma. To address the role of PI3K/Akt/mTOR, we used a novel approach to study mesothelioma ex vivo as tumor fragment spheroids. Freshly resected mesothelioma tissue from 15 different patients was grown in vitro as 1-2 mm diameter fragments, exposed to apoptotic agents for 48 h with or without PI3K/Akt/mTOR inhibitors and doubly stained for cytokeratin and cleaved caspase 3 to identify apoptotic mesothelioma cells. Mesothelioma cells within the tumor spheroids exhibited striking resistance to apoptotic agents such as TRAIL plus gemcitabine that were highly effective against monolayers. In a majority of tumors (67%; 10 of 15), apoptotic resistance could be reduced by more than 50% by rapamycin, an mTOR inhibitor, but not by LY294002, a PI3K inhibitor. Responsiveness to rapamycin correlated with staining for the mTOR target, p-S6K, in the original tumor, but not for p-Akt. As confirmation of the role of mTOR, siRNA knockdown of S6K reproduced the effect of rapamycin in 3 rapamycin-responsive tumors. Finally, in 37 mesotheliomas on tissue microarray, p-S6K correlated only weakly with p-Akt suggesting the existence of Akt-independent regulation of mTOR. We propose that mTOR mediates survival signals in many mesothelioma tumors. Inhibition of mTOR may provide a non-toxic adjunct to therapy directed against malignant mesothelioma, especially in those with high baseline expression of p-S6K.
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