Protein Interaction in Tissue Microenvironment Initiates the Onset of Cancer in Response to Occupational and Environmental Radiation Exposure
Abstract
In this project, we propose to address two important concerns of the Peer Reviewed Cancer Research Program s special focus on "Cancers related to radiation exposure": (i) elevated cancer risk assessment among active military duty personnel, and (ii) cancer health needs of their family members, retirees, and Veterans. Understanding the cellular mechanisms involved in causing cancer upon radiation exposure (in environmental or intentional situation) and at the same time delineating the molecular processes that are involved in tumor recurrence and metastasis in cancer victims undergoing radiation treatment will have high impact on both active duty Service members and also their families. We propose that two related molecular pathways (called K-Ras and ER-a pathways) triggered by the same signaling mediators (called eNOS/NO signaling) are initiated at the specific cellular component (called endothelial cells) of the blood vessel, the tissue that is spread all over the body and most likely to get exposed whether it is a total body irradiation or during cancer treatment by radiation. Due to cross-talk between the blood vessel and the cells at the adjacent tissue, the signaling mediators (eNOS/NO) will modify those proteins (K-Ras and ER-a) of the projected molecular pathways. These alterations are fixed for a sustained period depending on the dose and duration of the radiation exposure. The modified (nitrosylated) K-Ras protein on one side will potentially transform the normal adjacent tissue into cancerous tissue with time. We propose this pathway may be responsible for elevated cancer risk among the active duty military personnel. Similarly, the other modified protein, ER-alpha, will reprogram the cells to growth response and/or to invasiveness and spread of the tumor into other sites of the body (metastasis). We predict that this pathway is responsible for relapse of tumor in cancer patients after treatment and limit the disease-free survival time and also minimize the quality of life of cancer survivors. This is a novel and potentially high-reward concept. The unique experimental model in which the cells from the inner lining of the blood vessels will be maintained in a local environment called hemodynamic shear stress, a stress the inner lining of the blood vessel undergo due to continuous blood flow. This is very important to determine the true nature of the response of blood vessels to radiation. This has not been largely considered in earlier studies. This model is closer to the whole body situation. Though this model is not identical to whole animal or human, this is the more reliable way one can study the mechanism very precisely and understand the contribution of individual cell type in activating or deactivating specific signaling/molecular pathway. This is an innovative approach. The outcome from this study through understanding elevated cancer risk estimation will help in developing countermeasures by targeting those molecular mediators and protect war personnel from cancer risk. In addition, it will be beneficial for the general public who are exposed unintentionally to accidental or dirty bomb exposures due to terrorist activities. Second, emerging evidence raises the possibilities that radiation while alleviating cancer burden, may itself be responsible for the redevelopment of the disease at the treatment site, which increases the risk of metastasis at distant sites. Understanding this process will advance our knowledge and will significantly improve radiation treatment of various cancers. It will benefit not only the Veterans and their family members, but also the American public who are cancer victims.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510325
Entities
People
- Mohan Natarajan
Organizations
- United States Army
- University of Texas Health Science Center at San Antonio