Department of Experimental and Clinical Biomedical Sciences, Università degli Studi di Firenze, Florence, Italy.
Cancer Research Institute, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Adv Exp Med Biol. 2019;1143:129-145. doi: 10.1007/978-981-13-7342-8_6.
The relationship of the homing of normal hematopoietic stem cells (HSC) in the bone marrow to specific environmental conditions, referred to as the stem cell niche (SCN), has been intensively studied over the last three decades. These conditions include the action of a number of molecular and cellular players, as well as critical levels of nutrients, oxygen and glucose in particular, involved in energy production. These factors are likely to act also in leukemias, due to the strict analogy between the hierarchical structure of normal hematopoietic cell populations and that of leukemia cell populations. This led to propose that leukemic growth is fostered by cells endowed with stem cell properties, the leukemia stem cells (LSC), a concept readily extended to comprise the cancer stem cells (CSC) of solid tumors. Two alternative routes have been proposed for CSC generation, that is, the oncogenic staminalization (acquisition of self-renewal) of a normal progenitor cell (the "CSC in normal progenitor cell" model) and the oncogenic transformation of a normal (self-renewing) stem cell (the "CSC in normal stem cell" model). The latter mechanism, in the hematological context, makes LSC derive from HSC, suggesting that LSC share SCN homing with HSC. This chapter is focused on the availability of oxygen and glucose in the regulation of LSC maintenance within the SCN. In this respect, the most critical aspect in view of the outcome of therapy is the long-term maintenance of the LSC subset capable to sustain minimal residual disease and the related risk of relapse of disease.
在过去的三十年中，人们对正常造血干细胞（HSC）在骨髓中的归巢与特定环境条件（称为干细胞龛（SCN））的关系进行了深入研究。这些条件包括许多分子和细胞因子的作用，以及特定营养物质、氧气和葡萄糖水平的作用，这些物质都参与了能量产生。由于正常造血细胞群体和白血病细胞群体的层次结构之间存在严格的相似性，这些因素可能也会在白血病中起作用。这导致人们提出白血病的生长是由具有干细胞特性的细胞（白血病干细胞（LSC））促进的，这一概念很容易扩展到包括实体瘤的癌症干细胞（CSC）。已经提出了两种用于 CSC 生成的替代途径，即正常祖细胞（“正常祖细胞中的 CSC”模型）的致癌干细胞化（获得自我更新）和正常（自我更新）干细胞（“正常干细胞中的 CSC”模型）的致癌转化。在后一种机制中，在血液学背景下，LSC 源自 HSC，这表明 LSC 与 HSC 共享 SCN 归巢。本章重点介绍 SCN 中调节 LSC 维持的氧气和葡萄糖的可用性。在这方面，就治疗效果而言，最关键的方面是能够维持最小残留疾病和相关疾病复发风险的 LSC 亚群的长期维持。
