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Defining Gene Functions in Tumorigenesis by Ex vivo Ablation of Floxed Alleles in Malignant Peripheral Nerve Sheath Tumor Cells
Published on: August 25, 2021
Trk receptor expression and inhibition in neuroblastomas
Garrett M Brodeur1, Jane E Minturn, Ruth Ho
1Division of Oncology, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4318, USA. brodeur@chop.edu
Abstract:
Neuroblastoma, the most common and deadly solid tumor in children, exhibits heterogeneous clinical behavior, from spontaneous regression to relentless progression. Current evidence suggests that the TRK family of neurotrophin receptors plays a critical role in these diverse behaviors. Neuroblastomas expressing TrkA are biologically favorable and prone to spontaneous regression or differentiation, depending on the absence or presence of its ligand (NGF) in the microenvironment. In contrast, TrkB-expressing tumors frequently have MYCN amplification and are very aggressive and often fatal tumors. These tumors also express the TrkB ligand (BDNF), resulting in an autocrine or paracrine survival pathway. Exposure to BDNF promotes survival, drug resistance, and angiogenesis of TrkB-expressing tumors. Here we review the role of Trks in normal development, the different functions of Trk isoforms, and the major Trk signaling pathways. We also review the roles these receptors play in the heterogeneous biological and clinical behavior of neuroblastomas, and the activation of Trk receptors in other cancers. Finally we address the progress that has been made in developing targeted therapy with Trk-selective inhibitors to treat neuroblastomas and other tumors with activated Trk expression.
Insights
Neurotrophin TRK receptors influence neuroblastoma behavior. TrkA indicates favorable outcomes, while TrkB correlates with aggressive tumors and suggests targeted therapy potential.
Area of Science:
- Oncology
- Molecular Biology
- Developmental Biology
Background:
- Neuroblastoma is a deadly childhood cancer with varied clinical outcomes.
- The TRK family of neurotrophin receptors (TrkA, TrkB, TrkC) is implicated in neuroblastoma's diverse behaviors.
- TrkA expression is linked to favorable prognosis and differentiation, while TrkB is associated with aggressive disease and MYCN amplification.
Purpose of the Study:
- To review the role of TRK receptors in normal development and neuroblastoma.
- To elucidate the distinct functions of Trk isoforms and their signaling pathways.
- To discuss the activation of TRK receptors in other cancers and the development of targeted therapies.
Main Methods:
- Literature review of studies on TRK receptors in neuroblastoma and other cancers.
- Analysis of TRK signaling pathways and their impact on tumor biology.
- Examination of targeted therapies for TRK-activated tumors.
Main Results:
- TrkA signaling, modulated by NGF, promotes differentiation or regression.
- TrkB signaling, activated by BDNF, drives survival, drug resistance, and angiogenesis in aggressive neuroblastomas.
- TRK receptor activation is observed in various cancers beyond neuroblastoma.
Conclusions:
- TRK receptors are critical regulators of neuroblastoma's heterogeneous clinical behavior.
- Targeted therapies inhibiting TRK signaling show promise for treating neuroblastomas and other TRK-driven cancers.
- Understanding TRK pathways is essential for developing effective precision medicines.
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