Sanquin Research and Landsteiner Laboratory, Department of Hematopoiesis, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
Princess Maxima Center for Pediatric Oncology, Utrecht, the Netherlands.
Stem Cells Dev. 2021 Jan 15;30(2):59-78. doi: 10.1089/scd.2020.0142.
Neuroblastoma (NB) is the second most common solid cancer in childhood, accounting for 15% of cancer-related deaths in children. In high-risk NB patients, the majority suffers from metastasis. Despite intensive multimodal treatment, long-term survival remains <40%. The bone marrow (BM) is among the most common sites of distant metastasis in patients with high-risk NB. In this environment, small populations of tumor cells can persist after treatment (minimal residual disease) and induce relapse. Therapy resistance of these residual tumor cells in BM remains a major obstacle for the cure of NB. A detailed understanding of the microenvironment and its role in tumor progression is of utmost importance for improving the treatment efficiency of NB. In BM, mesenchymal stromal cells (MSCs) constitute an important part of the microenvironment, where they support hematopoiesis and modulate immune responses. Their role in tumor progression is not completely understood, especially for NB. Although MSCs have been found to promote epithelial-mesenchymal transition, tumor growth, and metastasis and to induce chemoresistance, some reports point toward a tumor-suppressive effect of MSCs. In this review, we aim to compile current knowledge about the role of MSCs in NB development and progression. We evaluate arguments that depict tumor-supportive versus -suppressive properties of MSCs in the context of NB and give an overview of factors involved in MSC-NB crosstalk. A focus lies on the BM as a metastatic niche, since that is the predominant site for NB metastasis and relapse. Finally, we will present opportunities and challenges for therapeutic targeting of MSCs in the BM microenvironment.
神经母细胞瘤（NB）是儿童期第二大常见实体瘤，占儿童癌症相关死亡人数的 15%。在高危 NB 患者中，大多数患者发生转移。尽管采用了强化的多模式治疗，但长期生存仍然<40%。骨髓（BM）是高危 NB 患者中最常见的远处转移部位之一。在这种环境中，治疗后（微小残留病）仍会有少量肿瘤细胞持续存在，并诱导复发。这些 BM 中残留肿瘤细胞的治疗耐药性仍然是 NB 治愈的主要障碍。详细了解微环境及其在肿瘤进展中的作用对于提高 NB 的治疗效率至关重要。在 BM 中，间充质基质细胞（MSCs）构成微环境的重要组成部分，它们支持造血并调节免疫反应。其在肿瘤进展中的作用尚不完全清楚，尤其是对于 NB。尽管已经发现 MSCs 可促进上皮-间充质转化、肿瘤生长和转移，并诱导化疗耐药性，但一些报道指出 MSCs 具有肿瘤抑制作用。在这篇综述中，我们旨在汇编目前关于 MSCs 在 NB 发生和进展中的作用的知识。我们评估了在 NB 背景下描绘 MSCs 的肿瘤支持与抑制特性的论点，并概述了参与 MSC-NB 串扰的因素。重点放在 BM 作为转移部位，因为这是 NB 转移和复发的主要部位。最后，我们将介绍在 BM 微环境中靶向 MSC 的治疗机会和挑战。
