Dempke Wolfram C M, Fenchel Klaus, Uciechowski Peter, Chevassut Timothy
Department of Haematology and Oncology, Klinikum Grosshadern, University of Munich, Munich, Germany.
Oncology. 2017;93(4):213-223. doi: 10.1159/000478703. Epub 2017 Jul 22.
Developmental pathways (e.g., Notch, Hippo, Hedgehog, Wnt, and TGF-β/BMP/FGF) are networks of genes that act co-ordinately to establish the body plan, and disruptions of genes in one pathway can have effects in related pathways and may result in serious dysmorphogenesis or cancer. Interestingly, all developmental pathways are highly conserved cell signalling systems present in almost all multicellular organisms. In addition, they have a crucial role in cell proliferation, apoptosis, differentiation, and finally in organ development. Of note, almost all of these pathways promote oncogenesis through synergistic associations with the Hippo signalling pathway, and several lines of evidence have also indicated that these pathways (e.g., Wnt/β-catenin) may be implicated in checkpoint inhibitor resistance (e.g., CTLA-4, PD-1, and PD-L1). Since Notch inhibition in vivo results in partial loss of its stemness features such as self-renewal, chemoresistance, invasive and migratory potential, and tumorigenesis, these highly conserved developmental pathways are regarded as being critical for regulation of self-renewal in both embryonic and adult stem cells and hence are likely to be implicated in the maintenance of cancer stem cells. Many small molecules are currently in preclinical and early clinical development, and only two compounds are approved for treatment of advanced or metastatic basal cell carcinoma (vismodegib and sonidegib). Furthermore, therapeutic targeting of cancer stem cells using drugs that disrupt activated developmental pathways may also represent an attractive strategy that is potentially relevant to many types of malignancy, notably blood cancers, where the evidence for leukaemia stem cells is well established. Future work will hopefully pave the way for the development of new strategies for targeting these pervasive oncogenic pathways.
发育通路（如Notch、Hippo、Hedgehog、Wnt和TGF-β/BMP/FGF）是协同作用以建立身体结构的基因网络，一条通路中的基因破坏可对相关通路产生影响，并可能导致严重的畸形发生或癌症。有趣的是，所有发育通路都是几乎存在于所有多细胞生物中的高度保守的细胞信号系统。此外，它们在细胞增殖、凋亡、分化以及最终的器官发育中起着关键作用。值得注意的是，几乎所有这些通路都通过与Hippo信号通路的协同关联促进肿瘤发生，并且有几条证据线索也表明这些通路（如Wnt/β-连环蛋白）可能与检查点抑制剂耐药性（如CTLA-4、PD-1和PD-L1）有关。由于体内Notch抑制导致其干性特征如自我更新、化学抗性、侵袭和迁移潜力以及肿瘤发生部分丧失，这些高度保守的发育通路被认为对于胚胎和成体干细胞中自我更新的调节至关重要，因此可能与癌症干细胞的维持有关。目前许多小分子正处于临床前和早期临床开发阶段，只有两种化合物被批准用于治疗晚期或转移性基底细胞癌（维莫德吉和索尼德吉）。此外，使用破坏激活的发育通路的药物对癌症干细胞进行治疗性靶向也可能是一种有吸引力的策略，这可能与许多类型的恶性肿瘤相关，特别是血液癌症，其中白血病干细胞的证据已得到充分证实。未来的工作有望为开发针对这些普遍致癌通路的新策略铺平道路。
