Abstract
Three-dimensional (3D) cultures are a valuable platform to study acquired multicellular apoptotic resistance of cancer. We used spheroids of cell lines and actual tumor to study resistance to the proteasome inhibitor bortezomib in mesothelioma, a highly chemoresistant tumor. Spheroids from mesothelioma cell lines acquired resistance to bortezomib by failing to upregulate Noxa, a pro-apoptotic sensitizer BH3-only protein that acts by displacing Bim, a pro-apoptotic Bax/Bak-activator protein. Surprisingly, despite their resistance, spheroids also upregulated Bim and thereby acquired sensitivity to ABT-737, an inhibitor of anti-apoptotic Bcl-2 molecules. Analysis using BH3 profiling confirmed that spheroids acquired a dependence on anti-apoptotic Bcl-2 proteins and were ‘primed for death'. We then studied spheroids grown from actual mesothelioma. ABT-737 was active in spheroids grown from those tumors (5/7, ∼70%) with elevated levels of Bim. Using immunocytochemistry of tissue microarrays of 48 mesotheliomas, we found that most (33, 69%) expressed elevated Bim. In conclusion, mesothelioma cells in 3D alter the expression of Bcl-2 molecules, thereby acquiring both apoptotic resistance and sensitivity to Bcl-2 blockade. Mesothelioma tumors ex vivo also show sensitivity to Bcl-2 blockade that may depend on Bim, which is frequently elevated in mesothelioma. Therefore, mesothelioma, a highly resistant tumor, may have an intrinsic sensitivity to Bcl-2 blockade that can be exploited therapeutically.
Highlights
Understanding multicellular resistance may provide key insights into effective therapies for recalcitrant solid tumors such as human malignant mesothelioma,[6] which usually presents at a late stage as a thick tumor mass.[7]
Because cancer cells in 3D cultures acquire a multicellular resistance that resembles the chemoresistance seen in solid tumors in vivo, 3D models may be a useful platform for investigating novel therapeutic approaches
As in previous studies in our laboratory, we investigated resistance mechanisms using 3D models generated from cell lines that we tested for relevance in tumor grown ex vivo.[8,28]
Summary
Understanding multicellular resistance may provide key insights into effective therapies for recalcitrant solid tumors such as human malignant mesothelioma,[6] which usually presents at a late stage as a thick tumor mass.[7]. Our group[8] and others[9] have found that mesothelioma spheroids acquire multicellular resistance to a variety of treatments.[8,9] We decided to focus on resistance to bortezomib (PS-341, Velcade), an agent that has shown promise in pre-clinical studies of mesothelioma[10,11] and is being evaluated in clinical trials. It is not yet known whether mesothelioma will exhibit resistance to bortezomib, bortezomib resistance, while rare in hematologic cancers,[12] has been a common problem in solid tumors.[13]. This study presents for the first time key insights into the apoptotic repertoire of 3D spheroids and proposes ways to detect the pro-apoptotic potential within mesothelioma and to exploit it therapeutically
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