Department of Laboratory Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, 200040, China.
Medical Sciences Division, University of Oxford, Oxford OX3 9DU, UK.
Semin Cancer Biol. 2022 Jun;81:193-205. doi: 10.1016/j.semcancer.2021.04.018. Epub 2021 Apr 30.
The completion-of-tumor hypothesis involved in the dynamic interplay between the initiating oncogenic event and progression is essential to better recognize the foundational framework of tumors. Here we review and extend the gametogenesis-related hypothesis of tumors, because high embryonic/germ cell traits are common in tumors. The century-old gametogenesis-related hypothesis of tumors postulated that tumors arise from displaced/activated trophoblasts, displaced (lost) germ cells, and the reprogramming/reactivation of gametogenic program in somatic cells. Early primordial germ cells (PGCs), embryonic stem (ES) cells, embryonic germ cells (EGCs), and pre-implantation embryos at the stage from two-cell stage to blastocysts originating from fertilization or parthenogenesis have the potential to develop teratomas/teratocarcinomas. In addition, the teratomas/teratocarcinomas/germ cells occur in gonads and extra-gonads. Undoubtedly, the findings provide strong support for the hypothesis. However, it was thought that these tumor types were an exception rather than verification. In fact, there are extensive similarities between somatic tumor types and embryonic/germ cell development, such as antigens, migration, invasion, and immune escape. It was documented that embryonic/germ cell genes play crucial roles in tumor behaviors, e.g. tumor initiation and metastasis. Of note, embryonic/germ cell-like tumor cells at different developmental stages including PGC and oocyte to the early embryo-like stage were identified in diverse tumor types by our group. These embryonic/germ cell-like cancer cells resemble the natural embryonic/germ cells in morphology, gene expression, the capability of teratoma formation, and the ability to undergo the process of oocyte maturation and parthenogenesis. These embryonic/germ cell-like cancer cells are derived from somatic cells and contribute to tumor formation, metastasis, and drug resistance, establishing asexual meiotic embryonic life cycle. p53 inhibits the reactivation of embryonic/germ cell state in somatic cells and oocyte-like cell maturation. Based on earlier and our recent studies, we propose a novel model to complete the gametogenesis-related hypothesis of tumors, which can be applied to certain somatic tumors. That is, tumors tend to establish a somatic asexual meiotic embryonic cycle through the activation of somatic female gametogenesis and parthenogenesis in somatic tumor cells during the tumor progression, thus passing on corresponding embryonic/germ cell traits leading to the malignant behaviors and enhancing the cells' independence. This concept may be instrumental to better understand the nature and evolution of tumors. We rationalize that targeting the key events of somatic pregnancy is likely a better therapeutic strategy for cancer treatment than directly targeting cell mitotic proliferation, especially for those tumors with p53 inactivation.
肿瘤发生的完成肿瘤假说涉及启动致癌事件和进展之间的动态相互作用，对于更好地认识肿瘤的基础框架至关重要。在这里，我们回顾并扩展了肿瘤与配子发生相关的假说，因为高胚胎/生殖细胞特征在肿瘤中很常见。一个世纪以来，肿瘤与配子发生相关的假说认为，肿瘤起源于移位/激活的滋养细胞、移位（丢失）的生殖细胞以及体细胞中配子发生程序的重编程/再激活。早期原始生殖细胞（PGC）、胚胎干细胞（ES 细胞）、胚胎生殖细胞（EGC）和从受精或孤雌生殖开始的两细胞期到囊胚期的着床前胚胎有发展为畸胎瘤/畸胎癌的潜力。此外，畸胎瘤/畸胎癌/生殖细胞出现在性腺和性腺外。毫无疑问，这些发现为该假说提供了强有力的支持。然而，人们认为这些肿瘤类型是例外，而不是验证。事实上，体细胞肿瘤类型与胚胎/生殖细胞发育之间存在广泛的相似性，例如抗原、迁移、侵袭和免疫逃避。有文献记载，胚胎/生殖细胞基因在肿瘤行为中起着关键作用，例如肿瘤的起始和转移。值得注意的是，我们小组在不同的肿瘤类型中发现了处于不同发育阶段的胚胎/生殖细胞样肿瘤细胞，包括 PGC 和卵母细胞到早期胚胎样阶段。这些胚胎/生殖细胞样癌细胞在形态、基因表达、畸胎瘤形成能力以及卵母细胞成熟和孤雌生殖过程方面与天然胚胎/生殖细胞相似。这些胚胎/生殖细胞样癌细胞源自体细胞，有助于肿瘤的形成、转移和耐药性，建立无性减数分裂的胚胎生命周期。p53 抑制体细胞和卵母细胞样细胞成熟过程中胚胎/生殖细胞状态的再激活。基于早期和我们最近的研究，我们提出了一个新的模型来完成肿瘤与配子发生相关的假说，该模型可应用于某些体细胞肿瘤。也就是说，肿瘤在肿瘤进展过程中倾向于通过体细胞雌性配子发生和体细胞孤雌生殖的激活，在体细胞肿瘤细胞中建立体细胞无性减数分裂的胚胎周期，从而传递相应的胚胎/生殖细胞特征，导致恶性行为，并增强细胞的独立性。这一概念可能有助于更好地理解肿瘤的本质和进化。我们认为，针对体细胞妊娠的关键事件可能是一种比直接针对细胞有丝分裂增殖更好的癌症治疗策略，特别是对于那些 p53 失活的肿瘤。
