Background: Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the US. Chemotherapy is an important therapeutic strategy for CRC in addition to surgery. Development of chemoresistance is a major hurdle for effective chemotherapy and contributes to recurrence and mortality of CRC. Epidemiological studies strongly suggest that chronic stress has significant negative influences on the cancer therapy 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 mouse model systems that directly study the impact of chronic stress upon chemoresponse in vivo. Our preliminary studies showed that chronic restraint promoted chemoresistance to 5-FU, the most widely used chemotherapeutic agent for CRC, in subcutaneous xenograft tumors and tumors in the small intestine and colon of Apcmin/+ mice, a genetic mouse model for human CRC study. Our results strongly suggest that chronic stress promotes chemoresistance in CRC.Tumor suppressor p53 plays a critical role in therapeutic response of CRC. Loss or decrease of p53 function promotes chemoresistance in CRC. Our recent studies found that chronic restraint decreases p53 function. Our preliminary studies showed that chronic restraint promotes chemoresistance in CRC in a largely p53-dependent manner in mice. These results suggest that the attenuation of p53 function is an important mechanism whereby chronic stress promotes chemoresistance in CRC. Our recent report and preliminary studies showed that glucocorticoids (GLUs) and angiotensin II (AngII), two major stress hormones elevated under chronic stress, decrease p53 function via GLUs/SGK1 and AngII/LIF signaling. These results suggest that GLUs/SGK1 and AngII/LIF mediate the inhibitory effect of chronic stress on p53.Objective/Hypothesis: We hypothesize that chronic stress promotes chemoresistance in CRC by impairing the function of p53; reactivating p53 via pharmacological blockade of the GLUs/SGK1 and AngII/LIF signaling can increase the chemosensitivity in CRC.Specific Aims: To test this hypothesis, we propose following three linked specific aims:(1) Test the hypothesis that chronic restraint stress promotes chemoresistance in CRC using mouse models.(2) Test the hypothesis that GLUs and AngII elevated under chronic stress impair p53 function via SGK1 and LIF, respectively, as an important mechanism whereby chronic restraint promotes chemoresistance in CRC.(3) Test whether targeting GLUs/SGK1 and AngII/LIF signaling can be a therapeutic strategy to enhance chemosensitivity of CRC under chronic stress in mouse models.Study Design:(1) The chronic restraint and CRC mouse tumor models, including orthotopic colorectal xenograft tumor models, CRC patient-derived xenografts and Apcmin/+ mice, will be employed to examine the effect of chronic restraint on chemoresponse. Chemotherapeutic agents commonly used for CRC, including 5-FU, cisplatin, and camptothecin, will be used.(2) CRC mouse tumor models will be employed to investigate: (i) whether chronic restraint impairs p53 function to promote chemoresistance; (ii) whether GLUs and AngII reduce p53 function in response to chemotherapy and promote chemoresistance; and (iii) whether blocking SGK1 and LIF abolishes the effects of GLUs and AngII on p53 function and chemoresistance, respectively.(3) We will investigate whether blocking GLUs/SGK1 and AngII/LIF signaling reduces chronic stress-promoted chemoresistance in CRC in mice. GR antagonists and SGK1 inhibitors will be used to inhibit GLUs/SGK1 signaling, and AngII receptor blockers and LIF neutralization antibody will be used to inhibit AngII/LIF signaling in mice.Military Relevance: This application investigates the effect of chronic stress, the militarily relevant risk factor, on therapeutic response in colorectal cancer, a Fiscal Year 2017 Peer Reviewed Cancer Research Program Topic Area. Military personnel and their family members are very likely to experience chronic stress due to many factors associated with their lifestyle. If this study is completed successfully, results from this study will advance the knowledge and understanding of the therapeutic response of CRC and provide effective CRC treatment options for the benefit of military personnel and other military beneficiaries.
|Effective start/end date||7/15/18 → 7/14/20|
- Congressionally Directed Medical Research Programs (CDMRP)