How to say NO to vascular disruption and stem cell mobilization.
How to say NO to vascular disruption and stem cell mobilization.
复制标题
如何对血管破坏和干细胞动员说“不”。
DOI：
10.1080/14728222.2018.1486821
复制
发表时间：
2018
影响因子：
5.8
通讯作者：
Passaro D
中科院分区：
文献类型：
--
作者：
Passaro D
急性髓系白血病 (AML) 是一种侵袭性癌症，主要影响成人和老年患者。几十年来，常见的临床实践一直保持不变，包括标准化疗的连续疗程。由于这种非特异性治疗，治疗后经常出现耐药和复发。移植来自供体的健康干细胞是另一种主要的干预措施，旨在用正常造血细胞补充骨髓（BM）。然而，最近的临床前研究结果证明，AML异种移植物的骨髓中发生了严重的血管病理，导致血管渗漏和健康干细胞动员到外周，将它们驱逐出其保护性生态环境，从而使它们暴露于药物毒性。这种血管功能障碍可能是干细胞移植方法成功的严重障碍，限制了患者残留干细胞和供体来源的干细胞对白血病克隆的竞争效应（移植物与白血病）。因此，找到一种在骨髓中保持健康干细胞的策略可以显着改善治疗结果。因此，最近研究干细胞锚定于生态位的分子机制的文献强调一氧化氮（NO）是一个潜在的有价值的靶点。选择最佳治疗策略需要进一步表征 BM 微环境中 NO 产生的调节机制。然而，最具挑战性的一步是将这些研究从实验室转移到临床，以对其与标准化疗相结合的疗效进行临床评估。
Acute myeloid leukemia (AML) is an aggressive cancer affecting mostly adult and elderly patients. The common clinical practice remains unchanged since decades, consisting of sequential courses of standard chemotherapy. As a result of this non-specific treatment, resistance and relapse frequently occur after treatment. Transplantation of donor-derived healthy stem cells represents another major line of intervention, aimed to replenish the bone marrow (BM) with normal hematopoietic cells. However, recent preclinical findings have evidenced a severe vascular pathology occurring in the BM of AML xenografts, causing vascular leakiness and mobilization of healthy stem cells to the periphery, chasing them away from their protective niche environment and therefore exposing them to drug toxicity. This vascular dysfunction could represent a severe obstacle to the success of the stem cell transplantation approach, limiting the out-competition effect of both patient residual and donor-derived stem cell on the leukemic clones (graft versus leukemia). Thus, finding a strategy to keep healthy stem cells in the BM could significantly improve treatment outcome. Hence, recent literature addressing the molecular mechanisms of stem cell anchorage to the niche highlighted nitric oxide (NO) as a potential valuable target. The choice of the best therapeutic strategy would require further characterization of the mechanisms regulating NO production in the BM microenvironment. Yet, the most challenging step would be to move these studies from the bench to the bedside for a clinical assessment of their efficacy in combination with standard chemotherapy.