Curable and non-curable malignancies: lessons from paediatric cancer.

The tremendous progress achieved in understanding the molecular basis of cancer, was unfortunately not followed by a mutual improvement in the morbidity and mortality of adult cancer. In contrast, the success rate achieved in paediatric oncology has increased significantly during the past 30 years, and more than two-thirds of the children with cancer can now be cured. p53 has been shown to have a central role on apoptosis in various cells. As apoptosis is a final common pathway for much of our anti cancer therapy, resistance to apoptosis due to a normal activity of p53 is an important mechanism of tumor resistance and treatment failure. Contrary to the findings in most adult tumors, where about 50% of the tumors lack p53 activity, the rate of p53 mutations in childhood cancer is surprisingly low. This may be the key to the much better prognosis of children with cancer. In most adult tumors, multiple genetic events, between five and seven, are usually involved. The oncogenes involved in such tumors usually represent those located upstream of the nuclear transcription factors. In most paediatric tumors, in contrast, the initiating event is the activation of nuclear transcription factors secondary to chromosomal translocations. It can be speculated that multiple events activating various components of the signal transduction machinery are needed for tumorigenesis, and hence the evolution and progression of such tumors is slow. Moreover, if the malignant cell has to accumulate multiple mutations, the chances of crippling the apoptotic mechanism are higher. Genomic instability evidenced by microsatellite variation has been found in colon, pancreas, breast, liver and ovarian adult tumors, and not in paediatric tumors. As multiple somatic mutations are needed for the initiation and progression of the common adult malignancies, inherent genomic instability can dispose to accumulation of multiple mutations. All these molecular interactions are discussed with relevance to the difference between non-curable, mostly adult tumors, and curable, mostly paediatric tumors.