Regulation of Lung Cancer Dormancy and Recurrence by Stress-Activated Neutrophils
Abstract
Lung cancer is the second most common cancer in veterans. It represents critical medical challenge for veterans in their families. This proposal seeks to address the major problem lung cancer recurrence after successful initial treatment and its therapeutic correction. We, for the first time, will establish the role of stress and PMN in reactivation of tumor dormant cells and lung cancer recurrence and identify the mechanism of this process. We will determine the link between the presence of norepinephrine and S100A9 and lung cancer recurrence in cancer patients. We will test, for the first time, the possibility of reducing lung cancer recurrence by blocking S100A9/A proteins and Beta2 adrenergic receptor. The main objective of this study is to identify the mechanism of recurrence of lung cancer and to determine therapeutic targeting strategy to control this process. We propose that reactivation of dormant tumor cells in lung cancer could be caused by prolonged stress with release of neuroendocrine adrenergic hormones. These hormones induce activation of PMN resulting in their sequestration in lungs with release of S100A9/A8 proteins. We propose that binding of S100A9/A8 to receptors on PMN promotes lipid peroxidation via induction of reactive oxygen species and activation of myeloperoxidase (MPO). Local release of oxidized lipids directly drives re-activation of dormant tumor cells. Targeting of S100A9/A8 with Tasquinimod and use of Beta2-adrenergic receptor blockade can substantially reduce tumor recurrence. We expect to offer novel mechanism of therapeutic regulation of lung cancer recurrence. If successful, it may have major impact for patients survival.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2020
- Accession Number
- AD1117427
Entities
People
- Dmitry I. Gabrilovich
Organizations
- Wistar Institute