Role of Exosomes and Endoglin in Neurofibromatosis Progression
Abstract
This project is dedicated to understanding more about the topic area of neurofibromatosis (NF) progression. Findings of the project are expected to clarify molecular mechanisms by which primary NF tumor result in development of malignant peripheral nerve-sheath tumors (MPNST). In addition, outcome of our project may also help in identification of predictive and prognostic biomarkers of NF progression. In childhood, plexiform neurofibromas (pNF) tumors associated with larger nerves are found in 30% of patients with Neurofibromatosis-1 (NF1). pNF can undergo malignant transformation to MPNST. MPNST are highly aggressive soft tissue sarcomas with poor prognosis. MPNSTs behave aggressively, with a high rate of recurrence and a predilection to metastasize. Because of difficulties in predicting the progression and resistance to conventional therapies, NF remains a challenge to clinicians. Although in recent years significant progress has been made in unraveling the mechanisms of NF1 progression resulting modulation of signaling pathways, and genetic events, the critical question remains, how tumors are progressing along time. We hypothesize that exosomes, tiny vesicles (30-100 nm) secreted from the tumor as it develops carry specific proteins such as endoglin relevant for NF1 progression. Exosomes are known to communicate with adjacent as well as distant cells. We rationalize that, although the driving force of NF1 progression is NF genetic deficiency, the main mechanism of progression is due to the secretion of specific proteins in exosomes. We also hypothesize that exosomes from primary tumors can help in local spreading and progression of the disease. These basic studies on exosomes will be extended in humans, in which the exosomes from blood plasma of normal, NF individuals developing pNF or MPNSTs patients will be analyzed for endoglin expression. These translational studies in humans may help in identifying lead candidates of biomarkers for NF1 progression and potential candidates for future targeting. The outcome of this study will help in advancing the field of NF. In the short term, it will be a step forward in understanding the mechanism of NF tumor development and progression and identification of novel biomarkers. In the long term, with further research, we may develop diagnostic test and design therapies to target them. This research is a combination of basic and translational science, eventually leading to therapy biomarkers progression. Preliminary data generated from this proposal will be used for a grant application to different mechanisms to generate more clinically relevant outcome in next 5 years or so. The outcome of this study will help in advancing the field of NF1 by providing potential targets for therapy. As NF1 is a devastating disease for military Service members, the outcome of our project will have a huge impact on them in terms of early diagnosis and/or therapy.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610131
Entities
People
- Hector Peinado Selgas
Organizations
- National Center for Oncological Research
- United States Army