The role of psychological stress in cervical and prostate carcinogenesis

Sammanfattning: Psychological stress is common in everyday life, and has been well recognized as one of the major contributors to many mental and physical illnesses, such as mental disorders and cardiovascular diseases. The association between psychological stress and carcinogenesis remains largely inconclusive to date, although possible biological mechanisms, i.e., through dysregulation of immune functions and the neuroendocrine axis, have been proposed. The overall aim of this thesis is to investigate the impact of psychological stress on cancer initiation and progression, using cervical cancer as an example, as well as to investigate the mechanistic contributions of immune and neuroendocrine systems to this link in cervical and prostate cancers, respectively. In Paper I, we assessed whether loss of a family member due to death, as an extremely stressful life event, increased the risk of cervical cancer. Based on the Swedish National Cervical Screening Register during 1969 to 2011, we conducted two nested case-control studies and found that loss was consistently associated with increased risks of abnormal cytology, in situ and invasive cervical cancer. Loss was also positively associated with HPV16 infection, particularly high viral load and recurrent infections, as well as high-risk HPV infections, among 1,696 women who had no cervical cancer. In Paper II, we estimated the impact of psychological stress, using stress-related mental disorders and stressful life events as proxies, on cervical cancer progression (i.e. cancerspecific survival) in a national cohort of cervical cancer patients diagnosed during 2002-2011 in Sweden. Patients exposed to a stress-related mental disorder or stressful life event had a 31% increased risk of cancer-specific mortality. The association remained statistically significant (25% risk elevation) after adjustment for multiple clinical characteristics. In Paper III, we examined the signaling of stress-related pathways in tumor tissues of US men with lethal prostate cancer, compared with that of men with nonlethal cancer. Using extreme case-control design, we identified 113 lethal cases and sampled 291 nonlethal cases from the Physicians’ Health Study and the Health Professionals Follow-up Study. We found that differential expression of genes within the adrenergic, glucocorticoid, and serotoninergic pathways was significantly associated with the risk of lethal prostate cancer. In Paper IV, we further evaluated the differential signaling of stress-related pathways between lethal and nonlethal prostate cancers sampled from the Swedish Watchful Waiting Cohort (all with localized disease). The signaling of serotoninergic pathway was significantly associated with the risk of lethal prostate cancer; similar but weaker associations were noted for adrenergic and glucocorticoid pathways. We also explored whether germline genetic variants could explain such differential signaling. We found the variants of rs2296972 (HTR2A) and rs33388 (NR3CI) tended to be associated with lethal prostate cancer, as well as the expression of specific genes of the serotoninergic and glucocorticoid pathways in tumor tissue. In conclusion, psychological stress is associated with increased risks of cervical cancer initiation, possibly through enhanced oncogenic infection, as well as cervical cancer progression. Differential signaling of stress-related neuroendocrine pathways, including the adrenergic, glucocorticoid, and serotoninergic pathways, in tumor tissue may contribute to prostate cancer progression in both early and relatively advanced prostate cancers; such differential signaling in early cancers may, in part, be explained by genetic predisposition.