Mesenchymal Stromal Cells in Neuroblastoma: Exploring Crosstalk and Therapeutic Implications

Abstract

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.

Keywords: bone marrow; chemoresistance; mesenchymal stromal cells; metastasis; neuroblastoma; targeted therapy.

FIG. 1.

Crosstalk between MSCs and NB cells at the primary tumor site and migration to/from the BM. (A) MSCs are attracted from the BM to the primary site (among others through CXCR1/IL-8 and CCR1/CCL5 signaling) [52]. (B) Unknown MSC-derived mediators can exert a tumor-suppressive effect [68]. (C) The CXCR4/CXCL12 axis plays a role in proliferation and survival of tumor cells and decreased apoptosis rates [74]. MMP-9 [99,100] might play a role in promoting EMT and metastasis: unknown signaling events from MSCs induce MMP-9 expression in NB cells [100], whereas MSCs potentially also secrete MMP-9 themselves (dashed line). (D) NB cells are attracted to the BM metastatic niche through the CXCR4/CXCL12 axis [100,109] and can dock to the BM endothelial cells (ECs) through IGF-1R, subsequently migrating toward IGF-1 in the BM stroma [115]. BM, bone marrow; CCR1/CCL5, CC chemokine receptor 1/CC chemokine ligand 5; CXCR1, C-X-C motif chemokine receptor-1; ECM, extracellular matrix; EMT, epithelial-to-mesenchymal transition; IGF-1, insulin-like growth factor 1; IL-8, interleukin-8; MMP-9, matrix metalloproteinase-9; MSC, mesenchymal stromal cell; NB, neuroblastoma. Color images are available online.

FIG. 2.

Interactions between MSCs and NB cells in the BM metastatic niche. (A) Several mediators, such as EVs [129], Gal-3BP [133,134], and potentially CAs [169,170] can influence MSCs to secrete tumor-supportive factors that increase NB cell proliferation and survival [109,135,151], promote angiogenesis [130,131] and recruit TAMs to the TME [132]. (B) MSCs, stimulated by Gal-3BP and other unknown NB-derived mediators, secrete IL-6, thereby increasing osteoclast differentiation and driving osteolysis [151]. NB cells secrete RANKL with a similar effect [150]. (C) Increased osteoclastic activity leads to additional bone resorption, releasing bone-derived growth factors (TGF-β, BMP-4, and IGF-1) into the marrow [152–154]. (D) BMP-4, IGF-1, and TGF-β increase osteoblastic differentiation of MSCs [152,153,155]. In addition, IGF-1 could potentially support NB cell survival and proliferation through interaction with IGF-1R (dashed line) [157]. (E) Unknown NB-derived factors drive differentiation of MSCs into osteoblasts through intrinsic VEGF-A signaling [153]. (F) It is hypothesized that CAs create a tumor-supportive environment [167]. NB cells might use this mechanism in both para- and autocrine ways to promote tumor progression. CAs, catecholamines; EVs, extracellular vesicles; Gal-3BP, Galectin-3 binding protein; RANKL, receptor activator of nuclear factor kappa-B ligand; TAMs, tumor-associated macrophages; TGF-β, transforming growth factor-β; TME, tumor microenvironment; VEGF, vascular endothelial growth factor. Color images are available online.

FIG. 3.

Open questions regarding NB–MSC interactions. (A) Metastasis is dependent on the cell's capacity to migrate to distant sites. Whether MSCs are a source of TGF-β and MMP-9 or activate Notch signaling in NB cells, all of which are known to be involved in EMT and invasion in NB [93,100,102], remains to be elucidated in NB. Furthermore, the PI3K/AKT pathway and STAT3 signaling have been implicated to contribute to EMT [94,95]. (B) Additional signaling between NB cells and MSCs through cytokines, chemokines, and growth factors (purple) might contribute to tumor proliferation and -survival. CCL5 [69], MMPs [98], and Notch signaling [213] have been described to contribute to cancer cell motility, invasion, and differentiation into CAFs. MSC-derived IFNα, in contrast, was suggested to inhibit proliferation of cancer cells [212]. Furthermore, the cargo of exosomes derived from metastatic NB cells (red) and the signaling it induces in MSCs is an interesting field of research [123]. (C) To prevent EMDR and induction of dormancy through MSCs, the signaling components from MSCs contributing to these processes need to be studied in detail. It has been described that MSCs induce expression of S1PR1 in NB cells, which protected NB cells from drug-induced apoptosis through the JAK-STAT3 signaling pathway [179]. In breast cancer, miRNA-loaded exosomes promoted quiescence in tumor cells [175,176]. CAF, cancer-associated fibroblast; EMDR, environment-mediated drug resistance; IFNα, interferon α; RTK, receptor tyrosine kinases. Color images are available online.