Molecular Oncology, Internal Medicine/Cancer Research Unit, University Hospital Essen, University of Duisburg-Essen, Hufelandstraße 55, 45147, Essen, Germany.
Genome Informatics, Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Cell Tissue Res. 2018 May;372(2):263-268. doi: 10.1007/s00441-018-2810-5. Epub 2018 Feb 24.
The notion of cancer as a complex evolutionary system has been validated by in-depth molecular analyses of tumor progression over the last years. While a complex interplay of cell-autonomous programs and cell-cell interactions determines proliferation and differentiation during normal development, intrinsic and acquired plasticity of cancer cells allow for evasion of growth factor limitations, apoptotic signals, or attacks from the immune system. Treatment-induced molecular selection processes have been described by a number of studies already, but understanding of those events facilitating metastatic spread, organ-specific homing, and resistance to anoikis is still in its early days. In principle, somatic events giving rise to cancer progression should be easier to follow in childhood tumors bearing fewer mutations and genomic aberrations than their counterparts in adulthood. We have previously reported on the genetic events accompanying relapsing neuroblastoma, a solid tumor of early childhood. Our results indicated significantly higher single nucleotide variants in relapse tumors, gave hints for branched tumor evolution upon treatment and clonal selection as deduced from shifts in allelic frequencies between primary and relapsing neuroblastoma. Here, we will review these findings and give an outlook on dealing with intratumoral heterogeneity and sub-clonal diversity in neuroblastoma for future targeted treatments.
近年来，通过对肿瘤进展的深入分子分析，已经验证了癌症作为一个复杂的进化系统的概念。虽然正常发育过程中细胞自主程序和细胞间相互作用的复杂相互作用决定了增殖和分化，但癌细胞的内在和获得的可塑性允许其逃避生长因子限制、凋亡信号或免疫系统的攻击。已经有许多研究描述了治疗诱导的分子选择过程，但对于促进转移扩散、器官特异性归巢和抗失巢凋亡的那些事件的理解仍处于早期阶段。原则上，与成年肿瘤相比，携带较少突变和基因组异常的儿童肿瘤中引发癌症进展的体细胞事件应该更容易追踪。我们之前曾报道过复发性神经母细胞瘤（一种早期儿童的实体瘤）伴随的遗传事件。我们的结果表明，复发肿瘤中的单核苷酸变异明显更高，提示治疗后肿瘤进化出现分支，并根据原发性和复发性神经母细胞瘤之间等位基因频率的变化推断出克隆选择。在这里，我们将回顾这些发现，并展望未来针对神经母细胞瘤的靶向治疗中如何处理肿瘤内异质性和亚克隆多样性。
