Full-Length TrkB Variant in NSCLC Is Associated with Brain Metastasis.

Mariangela Lombardi,Vittorio Cardaci,Enrico Rathina Raj,Marco Giordano,Alberto Ricci,Davide Scozzi,Stefania Scarpino,Michela D'Ascanio,Leopoldo Costarelli,Giuseppe Cardillo,Marta Innammorato,Rita Mancini,Andrea Vecchione

doi:10.1155/2020/4193541

Abstract

Despite remarkable therapeutic advances have been made in the last few decades, non-small cell lung cancer (NSCLC) is still one of the leading causes of death worldwide. Brain metastases are a common complication of a wide range of human malignancies and in particular NSCLC. Brain-derived neurotrophic factor (BDNF), binding its high-affinity tyrosine kinase B receptor, has been shown to promote cancer progression and metastasis. We hereby investigated the expression of the BDNF and its TrkB receptor in its full-length and truncated isoform T1, in samples from primary adenocarcinomas (ADKs) of the lung and in their metastasis to evaluate if their expression was related to preferential tumor entry into the central nervous system (CNS). By immunohistochemistry, 80% of the ADKs that metastasize to central nervous system expressed TrkB receptor compared to 33% expressing of ADKs without CNS metastasis. Moreover, ADKs with CNS metastasis showed an elevated expression of the full-length TrkB receptor. The TrkB receptor FL/T1 ratio was statistically higher in primary ADKs with brain metastasis compared to ADKs without brain metastasis. Our data indicate that TrkB full-length isoform expression in primary ADK cells may be associated with higher risk to develop brain metastasis. Therefore, TrkB receptor may possess prognostic and therapeutic implications in lung ADK.

Highlights

non-small cell lung cancer (NSCLC) is an aggressive malignancy with rapid progression and low survival rate [1]
The majority of the advances have been made for the treatment of lung adenocarcinomas (ADKs) which represent the majority of the NSCLC, and that is characterized by considerable molecular heterogeneity [2]
Based on the well-known neurotrophic function displayed by the Brain-derived neurotrophic factor (BDNF)/TRKB axis within the nervous system, we hypothesize that the expression of the TRKB receptors and/or the release of neurotrophic growth factors may allow ADK cells to survive and proliferate in a so specific microenvironment [9]

Summary

Introduction

NSCLC is an aggressive malignancy with rapid progression and low survival rate [1]. the advent of targeted therapies has significantly extended life expectancy, yet only a small percentage of patients are currently eligible. Patients inevitably acquire resistance to this form of treatment over the time [4] These observations highlight the importance of improving the knowledge of NSCLC molecular biology with the aim of developing novel molecular targets able to extend patient survival. Based on the well-known neurotrophic function displayed by the BDNF/TRKB axis within the nervous system, we hypothesize that the expression of the TRKB receptors and/or the release of neurotrophic growth factors may allow ADK cells to survive and proliferate in a so specific microenvironment [9]. The aim of the present study has been to demonstrate if TrkB isoforms and BDNF expression in primary ADKs of the lung may be associated with increasing risk to develop metastasis to the brain

Materials and Methods

Results

Discussion

TrkB-FL

Conclusion

Conflicts of Interest