469 ISSN 2045-0907 10.2217/CNS.13.50 © 2013 Future Medicine Ltd CNS Oncol. (2013) 2(6), 469–472 One may think of tumors as existentially stressed; their rapid, uncontrolled proliferation in the midst of unstable blood supplies results in a hypoxic, nutrient-deprived environment, and the threat of immune system attack is almost constant (if ineffective). Tumors are also subject to our treatment schemes for them, including radiation and chemotherapeutics. To cope with these stresses, tumors upregulate expression of chaperone proteins/heat shock proteins to facilitate protein folding and stability issues, and to reduce the impact of apoptotic drivers. Brain tumors, such as highgrade gliomas/glioblastomas (GBMs), are no exception [1], and these tumors often show high levels of chaperone proteins – some displayed on the surfaces of brain tumor cells – particularly compared with normal brain [2,3]. Whether these stress proteins represent useful immunotherapy moieties [3,4] or drug targets [5] remains to be seen. However, it seems likely that the stresses imposed on tumors, rather than simply inflicting damage, may actually drive processes that allow tumors to survive and even thrive amidst the stresses. Cellular responses to stress take on a variety of forms, and sometimes those responses manifest in different organelles. Subcellularly, the accumulation of unfolded proteins in the endoplasmic reticulum (ER) triggers a multipronged ‘stress management profile’ known as the unfolded protein response (UPR; for excellent reviews see [6,7]). This stress response initiates when sensors within the ER, such as the HSP 70 family member GRP78 (also known as BiP/HSPA5), detect unfolded or malfolded proteins in the ER lumen. Similar events occur in cells with high secretory outputs, where the cells experience large amounts of protein translation into the ER, such as in activated plasma cells that produce large quantities of antibodies. During ‘ordinary’ cellular stasis, one of GRP78’s roles is to bind to the ER lumenal portions of three transmembrane molecules: PERK, IRE1 and ATF6. The interaction of GRP78 with these three ER membrane proteins maintains them in a monomeric state; when GRP78 releases them in order to perform chaperone duties for the unfolded proteins present in the ER, these three proteins now act as transducers of the UPR (it is likely that IRE1 has its own unfolded protein-sensing domain [8] and may not require GRP78’s