Tabu Kouichi, Taga Tetsuya
Department of Stem Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, 113-8510, Japan.
Inflamm Regen. 2022 Nov 30;42(1):54. doi: 10.1186/s41232-022-00240-8.
For all living organisms, the adaptation to outside environments is an essential determinant to survive natural and artificial selections and to sustain the whole ecosystem intact with functional biodiversity. Likewise, cancer cells have similar characteristics that evade not only stresses from the host-internal innate and adaptive immune systems but also those from host-externally administered therapeutic interventions. Such selfish characteristics of cancer cells lead to the formation of cancerous ecosystem with a wide variety of phenotypic heterogeneity, which should be called cancer "egosystem" from the host point of view. Recently increasing evidence demonstrates that cancer stem cells (CSCs) are responsible for this cancer egosystem by effectively exploiting host inflammatory and hematopoietic cells and thereby reconstructing their own advantageous niches, which may well be a driving force in cancer recurrence. CSCs are further likely to render multiple niches mutually interconnected and cooperating as a network to support back CSCs themselves. Here, we summarize a recently identified iron-replenishing niche network self-organized by glioma CSCs (GSCs) through remote regulation of host myeloid and erythroid lineage cells. GSCs recruit bone marrow (BM)-derived inflammatory monocytes into tumor parenchyma, facilitate their differentiation into macrophages (Mφs) and skew their polarization into pro-tumoral phenotype, i.e., tumor-associated Mφs (TAMs). Meanwhile, GSCs distantly enhance erythropoiesis in host hematopoietic organs like BM and spleen potentially by secreting some soluble mediators that maintain continuous supply of erythrocytes within tumors. In addition, as normal red pulp Mφs (RPMs) under steady state conditions in spleen recycle iron by phagocytosing the aged or damaged erythrocytes (a/dECs) and release it in time of need, TAMs at least in gliomas phagocytose the hemorrhaged erythrocytes within tumors and potentially serve as a source of iron, an important nutrient indispensable to GSC survival and glioma progression. Taken together, these studies provide the substantial evidence that CSCs have a unique strategy to orchestrate multiple niches as an ecosystem that threatens the host living, which in this sense must be an egosystem. Targeting such an adaptive subpopulation of CSCs could achieve drastic disturbance of the CSC niches and subsequent extinction of malignant neoplasms.
对于所有生物而言,适应外部环境是在自然选择和人工选择中生存以及维持整个生态系统功能多样性完整的关键决定因素。同样,癌细胞也具有类似的特性,它们不仅能逃避宿主内部先天免疫系统和适应性免疫系统的压力,还能躲避宿主外部给予的治疗干预。癌细胞的这种自私特性导致了具有广泛表型异质性的癌生态系统的形成,从宿主的角度来看,这应该被称为癌症“自我系统”。最近越来越多的证据表明,癌症干细胞(CSCs)通过有效利用宿主的炎症细胞和造血细胞,从而重建自身有利的微环境,对这种癌症自我系统负责,而这很可能是癌症复发的驱动力。癌症干细胞进一步可能使多个微环境相互连接并作为一个网络协同工作,以支持其自身。在此,我们总结了最近发现的由胶质瘤癌症干细胞(GSCs)通过远程调控宿主髓系和红系谱系细胞而自组织形成的铁补充微环境网络。胶质瘤癌症干细胞将骨髓(BM)来源的炎性单核细胞招募到肿瘤实质中,促进它们分化为巨噬细胞(Mφs),并使它们的极化偏向促肿瘤表型,即肿瘤相关巨噬细胞(TAMs)。与此同时,胶质瘤癌症干细胞可能通过分泌一些可溶性介质,在远处增强宿主造血器官(如骨髓和脾脏)中的红细胞生成,从而维持肿瘤内红细胞的持续供应。此外,由于脾脏中稳态条件下的正常红髓巨噬细胞(RPMs)通过吞噬衰老或受损的红细胞(a/dECs)来回收铁,并在需要时释放铁,至少在胶质瘤中,肿瘤相关巨噬细胞吞噬肿瘤内出血的红细胞,并可能作为铁的来源,铁是胶质瘤癌症干细胞存活和胶质瘤进展所必需的重要营养物质。综上所述,这些研究提供了充分的证据,表明癌症干细胞有一种独特的策略,将多个微环境编排成一个威胁宿主生命的生态系统,从这个意义上说,这必定是一个自我系统。靶向这种适应性的癌症干细胞亚群可以实现对癌症干细胞微环境的剧烈干扰,进而使恶性肿瘤消亡。
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