Failure to dispose of unneeded cells during development linked to cancer
A new research study reveals that a diverse group of apparently unrelated genes that are associated with pheochromocytoma intersect at a common pathway that drives the necessary culling of cells. Mutations in these genes disrupt the normal disposal of unneeded or damaged cells during development, thereby allowing potentially dangerous premalignant cells that should not have survived to persist. The mechanism described in the work, published in the August issue of Cancer Cell, may play a role in other forms of pediatric and hereditary cancer as well.
Pheochromocytomas are tumors that are derived from neural crest cells, which also give rise to the sympathetic nervous system. Inherited cases of pheochromocytoma are associated with mutations in a group of very dissimilar genes, presenting an intriguing puzzle as to how disruption of such different genes could cause the same disease. Further, noninherited somatic pheochromocytomas rarely exhibit mutations in the same genes that have been linked to the familial cancer. Dr. William G. Kaelin, Jr. from the Dana-Farber Cancer Institute and Brigham and Women's Hospital and colleagues found that all the genetic lesions associated with inherited pheochromocytomas result in a reduction of programmed cell death, called apoptosis, during development.
The researchers show that mutations in each of the disparate genes that cause familial pheochromocytoma, NF1, c-RET, SDH, and VHL, ultimately can interfere with the normal activity of EglN3, an enzyme that is required for apoptosis during development. Reduced apoptosis results in sympathetic neuronal progenitors that can elude developmental apoptosis and have a high risk of becoming cancerous later on. These results explain why NF1, c-RET, SDH, and VHL mutations are rare in somatic pheochromocytomas because mutations in these genes would no longer cause problems after the developmental window during which apoptosis occurs had passed. The authors speculate that escape from developmental apoptosis may play a role in other pediatric tumors that involve neural crest-derived cells, like neuroblastoma and medulloblastoma.
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