Chronic Stress and Its Effect on Cancer Therapy: Mechanism and Intervention
Abstract
This application addresses the Fiscal Year 2017 (FY17) Peer Reviewed Cancer Research Program (PRCRP) Military Relevance Focus Area of militarily relevant risk factors associated with cancer. Military personnel and their family members are very likely to experience chronic stress due to many factors associated with their lifestyle, including loneliness, low social support, and combat stress. This application investigates the effect of chronic stress on therapeutic response in colorectal cancer (CRC). CRC, which is the third most commonly diagnosed cancer in the US, is a FY17 PRCRP Topic Area. Epidemiological studies show that chronic stress has a significant negative influence on therapeutic response to human cancer, including CRC. Chemotherapy is an important therapeutic strategy for CRC in addition to surgery. Development of resistance to chemotherapy is a major hurdle for effective chemotherapy and contributes to recurrence and mortality of CRC. The diagnosis of cancer and cancer therapy are very stressful events. Many cancer patients without stress management intervention experience chronic stress. Currently, the role of chronic stress in chemoresponse remains elusive due to the lack of direct evidence from animal models, and furthermore, its mechanisms are unclear. Employing chronic restraint in mice, a well-established model that mimics chronic stress in humans, we established the mouse model systems that directly study the impact of chronic stress upon resistance to chemotherapy. Our preliminary studies showed that chronic stress promotes chemoresistance in colorectal xenograft tumors and tumors in the small intestine and colon of Apcmin/+ mice, a genetic mouse model for human CRC study. Tumor suppressor p53 plays a critical role in therapeutic response of CRC. Loss or decrease of p53 function promotes resistance to chemotherapy in CRC. Our recent studies found that chronic restraint greatly decreases p53 function. Our preliminary studies strongly suggest that chronic stress promotes resistance to chemotherapy in CRC through the downregulation of p53 function mediated by two major neurohormones, glucocorticoids (GLUs) and angiotensin II (AngII), elevated under chronic stress. Our preliminary studies further suggest that SGK1 and LIF are important downstream mediators for GLUs and AngII, respectively, to downregulate p53 function. These results prompt us to hypothesize that chronic stress promotes resistance to chemotherapy in CRC by impairing the function of tumor suppressor p53 and that reactivating p53 via pharmacological blockade of the GLUs/SGK1 and AngII/LIF signaling can increase response to chemotherapy in CRC. To test this hypothesis, we plan to (1) test whether chronic stress promotes resistance to chemotherapy in CRC using several complementary mouse colorectal tumor models. Orthotopic colorectal xenograft tumor models, CRC patient-derived xenografts (PDXs), and Apcmin/+ mice will be employed. Chemotherapeutic agents commonly used for CRC, including 5-FU, cisplatin and camptothecin, will be employed. (2) We will study whether GLUs and AngII elevated under chronic stress downregulate p53 function via SGK1 and LIF, respectively, as an important mechanism whereby chronic restraint promotes chemoresistance in CRC. In this aim, (i) we will examine whether chronic restraint downregulates p53 functions in response to chemotherapy to promote chemoresistance in mouse colorectal tumor models. (ii) We will study the effect of GLUs and AngII on p53 function and chemoresponse in CRC using mouse models. We will further study whether blocking SGK1 abolishes the effect of GLUs on p53 function and chemoresponse, and blocking LIF abolishes the effect of AngII on p53 function and chemoresponse. (3) We will test whether targeting GLUs/SGK1 and AngII/LIF signaling can be a therapeutic strategy to enhance chemosensitivity of CRC under chronic stress. GR antagonists, SGK1 inhibitors, AngII receptor blo
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810238
Entities
People
- Wenwei Hu
Organizations
- Rutgers University
- United States Army