Increased Ras expression and caspase-independent neuroblastoma cell death: possible mechanism of spontaneous neuroblastoma regression
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Updated: Oct 2, 2026
Defining Gene Functions in Tumorigenesis by Ex vivo Ablation of Floxed Alleles in Malignant Peripheral Nerve Sheath Tumor Cells
Published on: August 25, 2021
Chifumi Kitanaka1, Keisuke Kato, Rieko Ijiri
1Biophysics Division, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan. ckitanak@ncc.go.jp
Background:
Neuroblastoma undergoes spontaneous regression frequently during its natural course. Although programmed cell death (PCD) has been implicated in this process, accumulating evidence suggests that apoptosis, a form of PCD that is regulated by caspases, may not play a major role. We examined the mechanism(s) of spontaneous regression of neuroblastoma, focusing on the role of Ras, a favorable prognostic marker of neuroblastoma.
Methods:
Tumor tissues were analyzed by light microscopy, electron microscopy, and immunohistochemistry to examine cell degeneration and expression of Ras and several indicators of PCD. Cell degeneration was also studied in vitro in neuroblastoma cells transfected with the H-ras gene. All statistical tests were two-sided.
Results:
Immunohistochemical analyses revealed that Ras expression was increased in areas of cellular degeneration lacking apoptotic characteristics. The degenerating cells were fragmented without nuclear condensation and, essentially, lacked caspase-3 activation and apoptotic DNA fragmentation. These cells had ultrastructural features of autophagic degeneration, another form of PCD that is distinct from apoptosis. Focal areas of degeneration associated with Ras expression were seen more frequently in tumors from patients detected in a mass-screening program (53 [60.9%] of 87) than in tumors from clinically detected, advanced-stage patients over 1 year of age (7 [29.2%] of 24) (P =.006; chi-square test), suggesting a positive relationship between Ras-associated degeneration and probability of spontaneous regression/favorable prognosis. The characteristic features of Ras-associated nonapoptotic degeneration observed in tumor samples were recapitulated in vitro by transfection-mediated Ras expression, and Ras-mediated degeneration was augmented by TrkA, another favorable prognostic marker.
Conclusions:
High-level expression of H-Ras in neuroblastoma cells is associated with caspase cascade-independent, nonapoptotic PCD. This Ras-mediated nonapoptotic tumor cell death may play a key role in spontaneous regression of neuroblastoma.
Insights
Ras protein promotes non-apoptotic programmed cell death (PCD) in neuroblastoma, driving spontaneous tumor regression. This Ras-mediated cell death offers a new understanding of neuroblastoma
Area of Science:
- Oncology
- Cell Biology
- Cancer Research
Background:
- Neuroblastoma frequently undergoes spontaneous regression.
- Apoptosis, a caspase-regulated programmed cell death (PCD), is not the primary mechanism.
- Ras, a favorable prognostic marker, is investigated for its role in regression.
Purpose of the Study:
- To elucidate the mechanism of spontaneous neuroblastoma regression.
- To investigate the role of Ras in neuroblastoma cell degeneration.
- To differentiate the type of PCD involved in regression.
Main Methods:
- Analysis of tumor tissues using microscopy and immunohistochemistry.
- Examination of cell degeneration and expression of Ras and PCD indicators.
- In vitro studies of neuroblastoma cells transfected with H-ras gene.
Main Results:
- Increased Ras expression correlated with non-apoptotic cellular degeneration.
- Degenerating cells lacked typical apoptotic markers like caspase-3 activation and DNA fragmentation.
- Ras-associated degeneration was more frequent in tumors with favorable prognosis, suggesting a link to spontaneous regression.
Conclusions:
- High H-Ras expression in neuroblastoma is linked to caspase-independent, nonapoptotic PCD.
- Ras-mediated nonapoptotic cell death is a key factor in neuroblastoma's spontaneous regression.
- This finding provides insights into the mechanisms of favorable neuroblastoma outcomes.
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