Abstract
Simple SummaryNeuroblastoma is the second most common solid tumor in children. Our understanding of the contribution of genetic factors (seed) that contribute to neuroblastoma progression has substantially improved in the last 2 decades but the contribution of the tumor microenvironment (TME, soil) is the subject of more recent attention. Here we highlight recent studies pointing to novel mechanisms by which the TME affects neuroblastoma progression. Cancer-associated fibroblasts are present in neuroblastoma tumors and contribute to escape from chemotherapy and immunotherapy. Extracellular vesicles and regulatory micro-RNAs they contain, serve as shuttle mechanisms between neuroblastoma cells and stromal cells. The TME landscape of neuroblastoma differs between MYCN amplified and MYCN-non amplified tumors with the former being “cold” and the latter “hot” and rich in inflammatory cells. These recent observations will have a significant impact on our ability to design precise clinical trials that integrate information on the neuroblastoma cells and on their TME.The contribution of the tumor microenvironment (TME) to cancer progression has been well recognized in recent decades. As cancer therapeutic strategies are increasingly precise and include immunotherapies, knowledge of the nature and function of the TME in a tumor becomes essential. Our understanding of the TME in neuroblastoma (NB), the second most common solid tumor in children, has significantly progressed from an initial focus on its Schwannian component to a better awareness of its complex nature, which includes not only immune but also non-immune cells such as cancer-associated fibroblasts (CAFs), the contribution of which to inflammation and interaction with tumor-associated macrophages (TAMs) is now recognized. Recent studies on the TME landscape of NB tumors also suggest significant differences between MYCN-amplified (MYCN-A) and non-amplified (MYCN-NA) tumors, in their content in stromal and inflammatory cells and their immunosuppressive activity. Extracellular vesicles (EVs) released by cells in the TME and microRNAs (miRs) present in their cargo could play important roles in the communication between NB cells and the TME. This review article discusses these new aspects of the TME in NB and the impact that information on the TME landscape in NB will have in the design of precise, biomarker-integrated clinical trials.
Highlights
Non-malignant cells in the tumor microenvironment (TME) are not innocent bystanders and can positively or negatively affect the growth, survival and metastatic potential of tumor cells [1].Innate and adaptative immune cells such as tumor-associated macrophages (TAMs), dendritic cells (DC), natural killer (NK) cells and NKT cells and T and B lymphocytes have been the focus of much attention recently, with new developments in immunotherapy
We have gained a significantly better understanding of the mechanisms by which non-immune stromal cells in the TME affect the behavior of tumor cells, and of the multiple ways tumor cells and TME cells communicate
A transcriptomic analysis of four datasets including the TARGET database suggests that MYCN-A tumors contain more stromal cells such as osteoblasts (CD44+ CDH1+), which originate from bone marrow derived mesenchymal stromal cells (MSCs) under the influence of vascular endothelial cell growth factor (VEGF) [59], and smooth muscle cells (α-SMA) but not fibroblasts (FSP1) and endothelial cells (ECs) when compared with MYCN-NA
Summary
Non-malignant cells in the tumor microenvironment (TME) are not innocent bystanders and can positively or negatively affect the growth, survival and metastatic potential of tumor cells [1]. These stromal cells express several markers of activated CAFs such as FAP-α and FSP-1, as well as markers of MSCs such as CD105 (aka endoglin), CD90 (aka Thy-1) and CD73 (aka 50 -nucleotidase) and, like MSCs, maintain an ability to differentiate into osteoblasts, adipocytes or chondrocytes [6] These cells, designated CAFs-MSCs, promote NB cell growth and survival, and enhance resistance to chemotherapy by being a source of multiple inflammatory cytokines and chemokines such as IL-6, IL-8, VEGF-A, chemokine C-C motif ligand (CCL)-2 [aka monocyte chemoattractant protein (MCP) 1] and C-X-C motif Ligand (CXCL)-12 [aka stromal-derived factor (SDF)-1] that target NB cells and stromal cells in the TME. As the majority of these studies have been completed in vitro or in animal experiments, our understanding of their contribution to the progression and response to therapies in patients with NB tumors remains limited and will require a better knowledge of the TME landscape in NB tumors at the time of diagnosis and at the time of recurrence
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