Toren A, Amariglio N, Rechavi G
Pediatric Hemato-Oncology Unit, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
Med Oncol. 1996 Mar;13(1):15-21. doi: 10.1007/BF02988837.
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.
遗憾的是，尽管在理解癌症分子基础方面取得了巨大进展，但成人癌症的发病率和死亡率并未随之得到相应改善。相比之下，儿童肿瘤学在过去30年里取得的成功率显著提高，现在超过三分之二的癌症患儿能够被治愈。p53已被证明在各种细胞的凋亡中起核心作用。由于凋亡是我们许多抗癌治疗的最终共同途径，p53正常活性导致的凋亡抗性是肿瘤抗性和治疗失败的重要机制。与大多数成人肿瘤中约50%的肿瘤缺乏p53活性的发现相反，儿童癌症中p53突变率出奇地低。这可能是癌症患儿预后好得多的关键。在大多数成人肿瘤中，通常涉及五到七个多个基因事件。参与此类肿瘤的癌基因通常代表位于核转录因子上游的那些基因。相比之下，在大多数儿童肿瘤中，起始事件是染色体易位继发的核转录因子激活。可以推测，肿瘤发生需要多个激活信号转导机制各个组分的事件，因此此类肿瘤的演变和进展缓慢。此外，如果恶性细胞必须积累多个突变，破坏凋亡机制的可能性就更高。在结肠、胰腺、乳腺、肝脏和卵巢成人肿瘤中发现了微卫星变异所证明的基因组不稳定性，而在儿童肿瘤中未发现。由于常见成人恶性肿瘤的发生和进展需要多个体细胞突变，固有的基因组不稳定性可能有利于多个突变的积累。所有这些分子相互作用都与不可治愈的（大多为成人肿瘤）和可治愈的（大多为儿童肿瘤）之间的差异相关进行了讨论。
