Although neuroblastoma is the most common solid tumor in children, the mechanisms that lead to this malignancy are still unclear. The disease accounts for approximately 7 - 10% of childhood cancers. Whereas some infantile neuroblastomas regress spontaneously or mature into benign ganglioneuromas, up to 75% of patients older than one year at diagnosis have aggressive, chemo-resistant, and generally incurable tumors (stage III and IV; event free survival 30 - 40% despite conventional chemotherapy, radiotherapy and high dose chemotherapy). The surviving children of aggressive chemotherapy suffer from considerable side effects, including increased risk of secondary malignancies, a particular dreadful situation in children. Lower stage tumors (stage I and II) differ greatly from the aggressive forms; they are generally sensitive to chemotherapy and highly curable. A proportion of these lower stage tumors as well as disseminated tumors of the stage IVs in patients under the age of one year show spontaneous differentiation and regression.
We are currently working on two major topics: the role of survivin, an inhibitor of programmed cell death located on an amplified gene segment in neuroblastoma tumors and on the function of FoxO-transcription factors that are inactivated in neuroblastoma cells due to deregulated survival signaling.
A) The role of survivin, an apoptosis inhibitor and a proliferation inducing protein in the pathogenesis of neuroblastoma.
The survivin gene codes for the cell cycle regulated member of the inhibitor of apoptosis protein (IAP) family. This proteins favour through inhibition of apoptosis the survival of cells which have a DNA-damage or a deficient cell division cycle and therefore they contribute to tumorigenesis and chemotherapeutica resistance. Survivin not only plays a role in apoptosis inhibition but also in mitosis. In contrast to other members of the IAP family which are widely expressed in human tissues survivin is mostly expressed in various human cancers, but is undetectable in differentiated adult tissue. In tumors the expression of survivin has been reported to correlate with a reduced apoptotic index in vivo, with a shortened overall survival rate and an unfavourable prognosis.
B) The role of FoxO- transcription factors on viability and cell cycle progression in neuroblastoma cells.
The signal proteins phosphoinositol-3-kinase (PI3K) and PKB/Akt are involved in the development and activation of neuronal cells and also in their malignant transformation. PKB/Akt regulates the transcription factors of the FoxO-family and thereby growth, cell cycle progression and cell death. In absence of survival factors these transcription factors are localized to the nucleus where they control the transcription of genes. In neuroblastoma cells the FoxO-transcription factors are not functional because of a deregulated survival signaling thereby their inactivation possibly contributes to malignant transformation (figure 1).
Reactivation of these FoxO-transcription factors may identify new therapeutic possibilities how growth can be specifically inhibited and differentiation and apoptosis can be induced in this malignant tumor.
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