Living T9 glioma cells expressing membrane macrophage colony-stimulating factor produce immediate tumor destruction by polymorphonuclear leukocytes and macrophages via a “paraptosis”-induced pathway that promotes systemic immunity against intracranial T9 gliomas

Chen, Yijun; Douglass, Thomas G.; Jeffes, Edward W. B.; Xu, Qingcheng; Williams, Christopher C.; Arpajirakul, Neary; Delgado, Christina; Kleinman, Michael T.; Sánchez, Ramón L.; Dan, Qinghong; Kim, Ronald C.; Wepsic, H. Terry; Jadus, Martin R.

doi:10.1182/blood-2002-01-0174

Cited by 49 publications

(52 citation statements)

References 42 publications

(41 reference statements)

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“…Using the rat T9 tumor model, we have seen that both PMNs and macrophages contributed to the paraptotic killing of the mM-CSF-expressing T9-C2 cells. 31 However in this study, we have only observed a monocytic/macrophagic infiltrate within the implanted MG-2F11 cells. Thus, human tumor cells can be killed via paraptosis by only monocytes/macrophages.…”

Section: Discussionmentioning

confidence: 52%

Human U251MG glioma cells expressing the membrane form of macrophage colony-stimulating factor (mM-CSF) are killed by human monocytes in vitro and are rejected within immunodeficient mice via paraptosis that is associated with increased expression of three different heat shock proteins

et al. 2003

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Human U251MG glioma cells expressing the membrane form of macrophage colony-stimulating factor (mM-CSF) are killed by human monocytes in vitro and are rejected within immunodeficient mice via paraptosis that is associated with increased expression of three different heat shock proteins Martin R Jadus, Human U251MG glioma cells retrovirally transduced with the human gene for the membrane form of macrophage colonystimulating factor (mM-CSF) were investigated. The clones, MG-2F11 and MG-2C4, that expressed the most mM-CSF, but not the viral vector or the parental U251MG cells, were killed by both murine and human monocyte/macrophages in cytotoxicity assays. MG-2F11 cells failed to form subcutaneous tumors in either nude or NIH-bg-nu-xidBR mice, while mice inoculated with the U251MG viral vector (MG-VV) cells developed tumors. Electron microscopy studies showed that 4 hours after subcutaneous injection, the mM-CSF-transduced cells began dying of a process that resembled paraptosis. The dying tumor cells were swollen and had extensive vacuolization of their mitochondria and endoplasm reticulum. This killing process was complete within 24 hours. Macrophage-like cells were immediately adjacent to the killed MG-2F11 cells. Immunohistological staining for the heat shock proteins HSP60, HSP70 and GRP94 (gp96) showed that 18 hours after inoculation into nude mice, the MG-2F11 injection site was two to four times more intensely stained than the MG-VV cells. This study shows that human gliomas transduced with mM-CSF have the potential to be used as a safe live tumor cell vaccine.

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Section: Discussionmentioning

confidence: 52%

Human U251MG glioma cells expressing the membrane form of macrophage colony-stimulating factor (mM-CSF) are killed by human monocytes in vitro and are rejected within immunodeficient mice via paraptosis that is associated with increased expression of three different heat shock proteins

et al. 2003

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“…Although initially disputed, several forms of caspase-independent apoptosis [33][34][35] or forms that are similar to apoptosis ('paraptosis') but also do not involve caspases have been reported. 30,36 Sperandio and colleagues (2000) characterized 'paraptosis' in 293T cells and mouse embryonic fibroblasts as a form of cell death without nuclear fragmentation and apoptotic bodies, but with cytoplasmic vacuolation and late mitochondrial swelling. In addition, death was independent of caspase activity, Bcl-X L , and was executed without DNA fragmentation.…”

Section: Discussionmentioning

confidence: 99%

Intracellular acidification by inhibition of the Na+/H+-exchanger leads to caspase-independent death of cerebellar granule neurons resembling paraptosis

et al. 2004

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Potassium withdrawal is commonly used to induce caspasemediated apoptosis in cerebellar granule neurons in vitro. However, the underlying and cell death-initiating mechanisms are unknown. We firstly investigated potassium efflux through the outward delayed rectifier K þ current (I k ) as a potential mediator. However, tetraethylammoniumchloride, an inhibitor of I k , was ineffective to block apoptosis after potassium withdrawal. Since potassium withdrawal reduced intracellular pH (pH i ) from 7.4 to 7.2, we secondly investigated the effects of intracellular acidosis. To study intracellular acidosis in cerebellar granule neurons, we inhibited the Na þ /H þ exchanger (NHE) with 4-isopropyl-3-methylsulfonylbenzoylguanidine methanesulfonate (HOE 642) and 5-(N-ethyl-Nisopropyl)-amiloride. Both inhibitors concentration-dependently induced cell death and potentiated cell death after potassium withdrawal. Although inhibition of the NHE induced cell death with morphological criteria of apoptosis in light and electron microscopy including chromatin condensation, positive TUNEL staining and cell shrinkage, no internucleosomal DNA cleavage or activation of caspases was detected. In contrast to potassium withdrawal-induced apoptosis, cell death induced by intracellular acidification was not prevented by insulin-like growth factor-1, cyclo-adenosinemonophosphate, caspase inhibitors and transfection with an adenovirus expressing Bcl-X L . However, cycloheximide protected cerebellar granule neurons from death induced by potassium withdrawal as well as from death after treatment with HOE 642. Therefore, the molecular mechanisms leading to cell death after acidification appear to be different from the mechanisms after potassium withdrawal and resemble the biochemical but not the morphological characteristics of paraptosis.

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“…57,58 In vivo there is evidence that inducible nitric oxide synthase and peroxynitrite are present at the subcutaneous mM-CSF tumor cell rejection sites. 16,37 In the current study the exact macrophage-derived mediator responsible for paraptosis induction was not addressed. ROS were detected within 18 min and exogenously added H 2 O 2 and arachidonic acid (data not shown) caused cellular swelling and vacuolization of the U251 glioma cells.…”

Section: Cell Cytotoxicity Occurred After 8-12 H Of Continuous Bk Chamentioning

confidence: 99%

“…The in vivo morphology of the destruction of the rat and human glioma cells was closely examined. 16,37 After subcutaneous injection, membrane M-CSF transduced gliomas began dying within 4 h of the development of the swelling and vacuolization process of paraptosis. In the current study, a putative molecular mechanism was in- (Figure 3).…”

Section: Cell Cytotoxicity Occurred After 8-12 H Of Continuous Bk Chamentioning

confidence: 99%

Human monocytes kill M-CSF-expressing glioma cells by BK channel activation

Hoa

Zhang

Delgado

et al. 2007

Laboratory Investigation

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In this study, human monocytes/macrophages were observed to kill human U251 glioma cells expressing membrane macrophage colony-stimulating factor (mM-CSF) via a swelling and vacuolization process called paraptosis. Human monocytes responded to the mM-CSF-transduced U251 glioma cells, but not to viral vector control U251 glioma cells (U251-VV), by producing a respiratory burst within 20 min. Using patch clamp techniques, functional big potassium (BK) channels were observed on the membrane of the U251 glioma cell. It has been previously reported that oxygen indirectly regulates BK channel function. In this study, it was demonstrated that prolonged BK channel activation in response to the respiratory burst induced by monocytes initiates paraptosis in selected glioma cells. Forced BK channel opening within the glioma cells by BK channel activators (phloretin or pimaric acid) induced U251 glioma cell swelling and vacuolization occurred within 30 min. U251 glioma cell cytotoxicity, induced by using BK channel activators, required between 8 and 12 h. Swelling and vacuolization induced by phloretin and pimaric acid was prevented by iberiotoxin, a specific BK channel inhibitor. Confocal fluorescence microscopy demonstrated BK channels co-localized with the endoplasmic reticulum and mitochondria, the two targeted organelles affected in paraptosis. Iberiotoxin prevented monocytes from producing death in mM-CSF-expressing U251glioma cells in a 24 h assay. This study demonstrates a novel mechanism whereby monocytes can induce paraptosis via the disruption of internal potassium ion homeostasis.

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Living T9 glioma cells expressing membrane macrophage colony-stimulating factor produce immediate tumor destruction by polymorphonuclear leukocytes and macrophages via a “paraptosis”-induced pathway that promotes systemic immunity against intracranial T9 gliomas

Cited by 49 publications

References 42 publications

Human U251MG glioma cells expressing the membrane form of macrophage colony-stimulating factor (mM-CSF) are killed by human monocytes in vitro and are rejected within immunodeficient mice via paraptosis that is associated with increased expression of three different heat shock proteins

Human U251MG glioma cells expressing the membrane form of macrophage colony-stimulating factor (mM-CSF) are killed by human monocytes in vitro and are rejected within immunodeficient mice via paraptosis that is associated with increased expression of three different heat shock proteins

Intracellular acidification by inhibition of the Na+/H+-exchanger leads to caspase-independent death of cerebellar granule neurons resembling paraptosis

Human monocytes kill M-CSF-expressing glioma cells by BK channel activation

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