Dynamics of Minimal Residual Disease in Neuroblastoma Patients

Abstract

Neuroblastoma is a common extracranial solid tumor of neural crest (NC) origin that accounts for up to 15% of all pediatric cancer deaths. The disease arises from a transient population of NC cells that undergo an epithelial-mesenchymal transition (EMT) and generate diverse cell-types and tissues. Patients with neuroblastoma are characterized by their extreme heterogeneity ranging from spontaneous regression to malignant progression. More than half of newly diagnosed patients present highly metastatic tumors and are stratified into a high-risk group with dismal outcome. As many as 20% of high-risk patients have residual disease that is refractory or progressive during induction chemotherapy. Although a majority of high-risk patients achieve remission, larger part of those patients has minimal residual disease (MRD) that causes relapse even after additional consolidation therapy. MRD is composed of drug-resistant tumor cells and dynamically presented as cancer stem cells (CSCs) in residual tumors, circulating tumor cells (CTCs) in peripheral blood (PB), and disseminated tumor cells (DTCs) in bone marrow (BM) and other metastatic sites. EMT appears to be a key mechanism for cancer cells to acquire MRD phenotypes and malignant aggressiveness. Due to the restricted availability of residual tumors, PB and BM have been used to isolate and analyze CTCs and DTCs to evaluate MRD in cancer patients. In addition, recent technical advances make it possible to use circulating tumor DNA (ctDNA) shed from tumor cells into PB for MRD evaluation. Because MRD can be detected by tumor-specific antigens, genetic or epigenetic changes, and mRNAs, numerous assays using different methods and samples have been reported to detect MRD in cancer patients. In contrast to the tumor-specific gene-rearrangement-positive acute lymphoblastic leukemia (ALL) and the oncogenic fusion-gene-positive chronic myelogenous leukemia (CML) and several solid tumors, the clinical significance of MRD remains to be established in neuroblastoma. Given the extreme heterogeneity of neuroblastoma, dynamics of MRD in neuroblastoma patients will hold a key to the clinical validation. In this review, we summarize the biology and detection methods of cancer MRD in general and evaluate the available assays and clinical significance of neuroblastoma MRD to clarify its dynamics in neuroblastoma patients.

Keywords: cancer stem cell (CSC); circulating tumor DNA (ctDNA); circulating tumor cell (CTC); disseminating tumor cell (DTC); epithelial-mesenchymal transition (EMT); minimal residual disease (MRD); neuroblastoma.

Figure 1

MRD in neuroblastoma. MRD, minimal residual disease; CSC, cancer stem cell; EMT, epithelial-mesenchymal transition.

Figure 2

Dynamics of MRD. MRD, minimal residual disease; CSC, cancer stem cell; CTC, circulating tumor cell; DTC, disseminating tumor cell; ctDNA, circulating tumor DNA; EMT, epithelial-mesenchymal transition.

Figure 3

EMT program in tumor progression. EMT, epithelial-mesenchymal transition; MET, mesenchymal-epithelial transition; CSC, cancer stem cell.

Figure 4

MRD detection methods. MRD, minimal residual disease; CSC, cancer stem cell; CTC, circulating tumor cell; DTC, disseminating tumor cell; ctDNA, circulating tumor DNA; PB, peripheral blood; PBSC, peripheral blood stem cell; BM, bone marrow; IC, immunocytology; FCM, flow cytometry; PCR, polymerase chain reaction; aCGH, array comparative genomic hybridization; MPS, massively paralleled sequencing; RT-PCR, reverse transcriptase-PCR.

Figure 5

Sampling from neuroblastoma patients. MRD, minimal residual disease; PB, peripheral blood; PBSC, peripheral blood stem cell; BM, bone marrow; IC, immunocytology.