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 cancerrelated 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.

Bone Marrow Environment in Metastatic Neuroblastoma

“…BM-infiltrating NB cells do not seem to affect the lymphoid lineage in general [ 66 , 67 ], nor specific lymphocyte subsets, such as the immunosuppressive regulatory T cell, Treg and Tr1 [ 68 ]. No information on the features of BM NK cells is presently available, whereas an interesting lymphoid subset, the invariant NKT (iNKT) cells, has been extensively studied in NB tumors.…”

“…Only recently, the mesenchymal cells present in the BM environment have become the subject of specific studies. Hochheuser et al found that the presence of BM-infiltrating NB cells is associated with an increased number of MSCs in the BM [ 66 ]. However, the fraction of MSCs expressing CD271, a marker of clonogenicity, was reduced and the MSC ability to differentiate was skewed towards osteoblasts [ 66 ].…”

“…Hochheuser et al found that the presence of BM-infiltrating NB cells is associated with an increased number of MSCs in the BM [ 66 ]. However, the fraction of MSCs expressing CD271, a marker of clonogenicity, was reduced and the MSC ability to differentiate was skewed towards osteoblasts [ 66 ]. Similar results were reported by Colletti et al showing a higher osteogenic potential of MSC from BM infiltrated with NB cells, as compared to healthy BM MSC [ 83 ].…”

“…Hochheuser et al also found a particular subset of BM MSC, negative for the clonogenic CD271 marker and positive for the osteogenic CD146 marker, associated with the presence of BM-infiltrating NB cells [ 66 ]. Interestingly, this subset was present at diagnosis and at relapse and disappeared during treatment.…”

“…Interestingly, this subset was present at diagnosis and at relapse and disappeared during treatment. Most importantly, their presence after induction therapy is associated with an increased risk of relapse, suggesting a potential role in inducing chemoresistance [ 66 ]. Further studies are needed to clarify whether MSC favors BM infiltration by NB cells or NB cells alter the MSC differentiation process.…”