The foundational framework of tumors: Gametogenesis, p53, and cancer.
The foundational framework of tumors: Gametogenesis, p53, and cancer.
复制标题
DOI：
10.1016/j.semcancer.2021.04.018
复制
发表时间：
2022-06
影响因子：
14.5
通讯作者：
Lin, Hui-Kuan
中科院分区：
文献类型：
--
作者：
Liu, Chunfang;Moten, Asad;Ma, Zhan;Lin, Hui-Kuan
肿瘤完成假说涉及起始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本框架至关重要。在这里，我们回顾和扩展配子发生相关的肿瘤假说，因为高胚胎/生殖细胞性状是常见的肿瘤。肿瘤的配子发生相关假说认为肿瘤是由滋养层细胞移位/激活、生殖细胞移位（丢失）以及体细胞配子发生程序的重编程/再激活引起的。早期原始生殖细胞（PGCs）、胚胎干细胞（ES）、胚胎生殖细胞（EGCs）和来自受精或孤雌生殖的从二细胞期到囊胚期的植入前胚胎具有发展畸胎瘤/畸胎癌的潜力。此外，畸胎瘤/畸胎癌/生殖细胞发生在性腺和性腺外。毫无疑问，这些发现为这一假设提供了有力的支持。然而，人们认为这些肿瘤类型是一个例外，而不是验证。事实上，体细胞肿瘤类型和胚胎/生殖细胞发育之间存在广泛的相似性，例如抗原，迁移，侵袭和免疫逃逸。研究表明，胚胎/生殖细胞基因在肿瘤发生、转移等生物学行为中起着重要作用。值得注意的是，我们的小组在不同的肿瘤类型中鉴定了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经历卵母细胞成熟和孤雌生殖过程的能力方面类似于天然胚胎/生殖细胞。这些胚胎/生殖细胞样癌细胞源自体细胞，有助于肿瘤形成、转移和耐药性，建立无性减数分裂胚胎生命周期。p53抑制体细胞和卵母细胞样细胞成熟中胚胎/生殖细胞状态的再活化。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配子发生相关的肿瘤假说，这可以应用于某些体细胞肿瘤。也就是说，在肿瘤进展过程中，肿瘤倾向于通过激活体细胞肿瘤细胞中的体细胞雌性配子发生和孤雌生殖来建立体细胞无性减数分裂胚胎周期，从而传递相应的胚胎/生殖细胞性状，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性质和演变。我们合理地认为，靶向体细胞妊娠的关键事件可能是一个更好的治疗癌症的治疗策略，而不是直接靶向细胞有丝分裂增殖，特别是对于那些p53失活的肿瘤。
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.
登录
查看更多内容
影响因子：
64.8
作者：
Abad, Maria;Mosteiro, Lluc;Serrano, Manuel
通讯作者：
Serrano, Manuel
影响因子：
4.7
作者：
Coward J;Harding A
通讯作者：
Harding A
影响因子：
3.9
作者：
Bignold, Leon P.;Coghlan, Brian L. D.;Jersmann, Hubertus Pa.
通讯作者：
Jersmann, Hubertus Pa.
影响因子：
64.8
作者：
Boumahdi, Soufiane;Driessens, Gregory;Blanpain, Cedric
通讯作者：
Blanpain, Cedric
影响因子：
64.8
作者：
DONEHOWER, LA;HARVEY, M;BRADLEY, A
通讯作者：
BRADLEY, A