Manzo Giovanni
General Pathology, "La Sapienza" University of Rome, Retired, Botrugno, Italy.
Front Cell Dev Biol. 2019 Mar 7;7:20. doi: 10.3389/fcell.2019.00020. eCollection 2019.
Here, I propose that cancer stem cells (CSCs) would be equivalent to para-embryonic stem cells (p-ESCs), derived from adult cells de-re-programmed to a ground state. p-ESCs would differ from ESCs by the absence of genomic homeostasis. A p-ESC would constitute the cancer cell of origin (i-CSC or CSC0), capable of generating an initial tumor, corresponding to a pre-implantation blastocyst. In a niche with proper signals, it would engraft as a primary tumor, corresponding to a post-implantation blastocyst. i-CSC progeny would form primary pluripotent and slow self-renewing CSCs (CSC1s), blocked in an undifferentiated state, corresponding to epiblast cells; CSC1s would be tumor-initiating cells (TICs). CSC1s would generate secondary CSCs (CSC2s), corresponding to hypoblast cells; CSC2s would be tumor growth cells (TGCs). CSC1s/CSC2s would generate tertiary CSCs (CSC3s), with a mesenchymal phenotype; CSC3s would be tumor migrating cells (TMCs), corresponding to mesodermal precursors at primitive streak. CSC3s with more favorable conditions (normoxia), by asymmetrical division, would differentiate into cancer progenitor cells (CPCs), and these into cancer differentiated cells (CDCs), thus generating a defined cell hierarchy and tumor progression, mimicking somito-histo-organogenesis. CSC3s with less favorable conditions (hypoxia) would delaminate and migrate as quiescent circulating micro-metastases, mimicking mesenchymal cells in gastrula morphogenetic movements. In metastatic niches, these CSC3s would install and remain dormant in the presence of epithelial/mesenchymal transition (EMT) signals and hypoxia. But, in the presence of mesenchymal/epithelial transition (MET) signals and normoxia, they would revert to self-renewing CSC1s, reproducing the same cell hierarchy of the primary tumor as macro-metastases. Further similarities between ontogenesis and oncogenesis involving crucial factors, such as ID, HSP70, HLA-G, CD44, LIF, and STAT3, are strongly evident at molecular, physiological and immunological levels. Much experimental data about these factors led to considering the cancer process as ectopic rudimentary ontogenesis, where CSCs have privileged immunological conditions. These would consent to CSC development in an adverse environment, just like an embryo, which is tolerated, accepted and favored by the maternal organism in spite of its paternal semi-allogeneicity. From all these considerations, novel research directions, potential innovative tumor therapy and prophylaxis strategies might, theoretically, result.
在此，我提出癌症干细胞（CSCs）等同于胚胎旁干细胞（p - ESCs），后者源自重编程至基础状态的成体细胞。p - ESCs与胚胎干细胞（ESCs）的不同之处在于缺乏基因组稳态。一个p - ESC将构成肿瘤起源细胞（i - CSC或CSC0），能够产生初始肿瘤，相当于植入前的囊胚。在具有适当信号的微环境中，它会作为原发性肿瘤着床，相当于植入后的囊胚。i - CSC后代将形成原发性多能且自我更新缓慢的CSCs（CSC1s），停滞在未分化状态，相当于上胚层细胞；CSC1s将是肿瘤起始细胞（TICs）。CSC1s将产生继发性CSCs（CSC2s），相当于下胚层细胞；CSC2s将是肿瘤生长细胞（TGCs）。CSC1s/CSC2s将产生具有间充质表型的三级CSCs（CSC3s）；CSC3s将是肿瘤迁移细胞（TMCs），相当于原条处的中胚层前体。在更有利条件（常氧）下，CSC3s通过不对称分裂将分化为癌症祖细胞（CPCs），进而分化为癌症分化细胞（CDCs），从而产生明确的细胞层级和肿瘤进展，模拟体节 - 组织 - 器官发生。在不太有利条件（低氧）下，CSC3s将脱层并作为静止的循环微转移灶迁移，模拟原肠胚形态发生运动中的间充质细胞。在转移微环境中，这些CSC3s在存在上皮/间充质转化（EMT）信号和低氧的情况下会着床并保持休眠。但是，在存在间充质/上皮转化（MET）信号和常氧的情况下，它们将恢复为自我更新的CSC1s，作为宏观转移灶重现原发性肿瘤的相同细胞层级。在个体发生和肿瘤发生之间，涉及关键因子如ID、HSP70、HLA - G、CD44、LIF和STAT3的进一步相似性在分子、生理和免疫水平上非常明显。关于这些因子的许多实验数据导致将癌症过程视为异位的原始个体发生，其中CSCs具有特殊的免疫条件。这将允许CSCs在不利环境中发育，就像胚胎一样，尽管其具有父本半异源性，但仍被母体生物体耐受、接受和支持。基于所有这些考虑，理论上可能会产生新的研究方向、潜在的创新肿瘤治疗和预防策略。
