Psychological Stress and Cellular Aging in Cancer: A Meta-Analysis

2.1. Search Strategy

Peer-reviewed research articles were identified by applying search strategies using databases: PubMed, Scopus, ScienceDirect, SpringerLink, Wiley Online, Taylor & Francis, ArticleFirst, ProQuest, PsycINFO, and EBSCOhost. A combination of search terms and key words included Psychological stress (self-reporting stress, psychosocial stress, major life events, domestic violence, depression, mental disorders) and cancer or tumor or carcinoma and outcomes (risk, incidence, mortality) and their combination. The databases were chosen due to their extensive coverage of cross-disciplinary and biomedical research scope and objectives. In addition, we hand-searched and cross-tabulated the reference lists of relevant articles, reviews, and meta-analysis papers. A comprehensive database search was finalized in September 2019. We limited the search to literature published in English.

2.2. Inclusion and Exclusion Criteria

This review included only the most recent articles reporting observational epidemiologic studies, systematic reviews, meta-analyses, cohort studies, and case-control studies that provide new information on the association between PS among different types of cancer survivors. Other article types such as conference abstracts, short communications, commentaries, editorials, brief reports, position papers, and hypothesis-generating statements were excluded based on lack of scientific merit. Only studies published in peer-reviewed journals were included. Inclusion criteria for this paper were physician-diagnosed cancer, given PS measurement tools, provided information on cancer type and association between PS and cancer type or overall cancers. We included case-control studies when odds ratio (OR) with 95% confidence interval (CI) or P value for statistical significance and numbers of cases and controls for each specific cancer site and type of psychosocial factors measured and matched or adjusted for age. Cohort studies were included if they reported relative risk (RR) or hazard ratio (HR) estimates and incident cases and subject (person-year) or they reported the number of cases and controls, and risk estimates were adjusted for confounding.

2.3. Study Selection

We selected original human studies: case-control studies, hospital-based case-control studies, prospective cohort studies, and prospective cross-sectional studies, which reported estimates of the relationship between self-reported psychosocial stressors, depression, and cancer risk. Outcomes included cancer risk for the following specific cancer sites: breast, brain, pancreas, colon, rectum, stomach, prostate, lung, cervical, bladder, the central nervous system, and white blood system (leukemia).

When considering multiple articles on the same population, the article based on longer follow-up intervals and contained more data was selected for consideration. Finally, 35 studies (26 observational studies and 9 review articles) were included in this review.

2.4. Data Extraction

Two research staff members (J.B. and M.G.) independently screened the titles and abstracts and evaluated the full-text articles. In the case of any disagreements regarding article inclusion, the problem was resolved through discussion with a third member of research staff (J.K.). Details on the type of study, study design, authors, publication journal and year, country where the study was carried out, study design, participant characteristics, specific outcomes, components of PS assessment and measurement tool, subtype of cancer, number of cases, number of controls, follow-up period, effect size, estimates of relationships and their measure with 95% CI or P value, variables of adjustment, statistical methods, and discussion of the study limitation were extracted. Only those articles reporting or assessing risk for cancer disease associated with PS and depression and reporting effect size and 95% CI based on sufficiently large samples were included in this review. Both case-control and cohort studies included in this paper showed key elements of study design, provided eligibility criteria, clearly defined outcomes (type or subtype of cancer and components of PS), had the representative numbers of cases and controls, and reported effect size adjusted for potential confounders.

3.1. Reviews and Meta-analysis Finding

Epidemiological research on this topic was a subject of a number of reviews, including those recently published by Chida et al. [18], Schraub et al. [19], Moreno-Smith et al. [20], Antonova et al. [1], Heikkilä et al. [21], Denaro et al. [2], Jia et al. [16], Chirac et al. [22], and Yang et al. [17] which reviewed studies published between 1940 and 2017.

The previous meta-analysis study by Chida et al. [18] investigated the association between stress-related psychosocial factors and cancer risk. The authors found PS was significantly associated with increased lung cancer incidence among initially healthy individuals; shortened survival time in patients with breast, lung, head and neck, hepatobiliary, and lymphoid cancers; and higher cancer mortality; however, the magnitudes of HRs appeared to be very small. Although the authors' findings were based on a large number of the observational studies (165) and calculated HRs were statistically significant, the meta-analysis study combined data from studies with different variables (e.g., clinical outcome, treatment, population, measurement methods, control for confounding for lifestyle factors for a particular subtype of cancer, and what can influence effect estimates). Thus, the study provided evidence of a low positive association between stress-related psychosocial factors and cancer.

Schraub et al. [19] reviewed 32 studies on the relationship between life-event stress, depression, and the risk of several types of cancers mainly BC, published between 1940 and 2004. The included eighteen studies showed no association between PS factors and cancer risk, and six studies found a significant association in one or several subgroups. The authors estimated PS may increase BC risk, although four of nine studies presented no significant increase, and one study showed a decrease in risk. Majority of the 11 studies noted no significant association between stressful life events and overall cancer risk. For specific cancers (leukemia, lymphoma, melanoma, colon, and cervix), more than a 20% increase in cancer risk was reported. In addition, a 65% increase in the risk for tobacco-related cancers and significantly decreased risk of endometrium cancer (33%) in users of hormone replacement therapy (HRT) and among normal weight women (37%) were noted. Also, a 40% decreased risk of colorectal cancer occurred within the female subgroup for moderate intensity of PS. Findings were controversial for relationships between depression or personality and risk for cancer. The authors found a 38% increase in cancer incidence and 20-96% increase in mortality among individuals suffering from depression (in two of seven studies) and a 20% decrease in the risk (in one study). Only one of the six studies presented a significant increase in cancer risk when personality was a factor. It is noteworthy that Schraub et al. [19] analyzed only cohort studies and case-control in population cohort, but not the classical case-control studies to minimalize the influence of selection bias and recall bias. The authors suggested no conclusions regarding life events or depression and cancer development or progression can be drawn.

Antonova et al. [1] reviewed 16 studies published between 2000 and 2010 focusing on associations between different types of stress-related events (work-related stressors, daily stress, and war- and conflict-related exposures) and BC incidence. The authors noticed inconsistencies in the findings, e.g., a strong causal link between high job demand, job strain, or severe life events (divorce, separation, or death of husband, child, or a close relative) and BC risk (HR ranged between 1.12 (1.0-1.25) and 2.65 (1.06-6.60)) reported in several studies and lower risk associated with high intensity stress HR: 0.60 (0.37-0.97) shown in other studies. The authors concluded the stress hormone cortisol may increase the rate of BC growth and the PS-cancer risk association was strongly dependent on the type of stress and on stress timing, particularly, for the stress induced by major life events, e.g., maternal death in childhood.

A meta-analysis performed by Heikkilä et al. [21] of data from 12 prospective European cohort studies (116,056 individuals aged 17-70 free from cancer at baseline with a follow-up period 1985-2008; 5,765 all cancer cases: 522 colorectal, 374 lung, 1,010 BC, and 865 prostate cancer (PCa) identified) on work stress and high job strain reported multivariable adjusted HR: 0.97 (0.90-1.04) for overall risk of cancer and also nonsignificant risks for the specific cancers.

Denaro et al. [2] reviewed seven observational studies published between 1995 and 2009, including one meta-analysis study. The findings of the meta-analysis did not confirm an overall relationship between PS-related life events and BC risk, although the data reported a modest correlation for death of spouse. Four reviewed studies observed a positive correlation between life events and BC, HR, or OR ranged from 1.12 (1.0-1.25) to 3.70 (2.61-5.26), but two studies were not controlled for confounding factors. The authors concluded epidemiologic evidence provides a strong support for a positive correlation between PS and BC risk, but variables determining the stress-cancer link were numerous and difficult to verify.

Further, the recently published systemic review by Chirac et al. [22] including all studies from 1966 to 2016 (52 eligible studies) on the effect of PS on BC found positive associations between experience of stressful events, personal traits, and BC in 26 observational studies, negative correlations in 18 studies, and data in eight studies could not be classified. Their qualitative analysis suggested a possible association between stressful life events and cancer; however, they highlight the methodological heterogeneity within the studies.

In turn, Moreno-Smith et al. [20] reviewed the association between psychosocial factors, mainly chronic stress, and cancer progression, focusing on biological processes affected by chronic PS. The authors found strong evidence for the effect of chronic stress, depression, and social isolation on cancer progression and limited evidence for the role of behavioral factors in cancer initiation.

The recent systematic review and meta-analysis conducted on January 1, 2017 of 25 studies published during 1988-2015 by Jia et al. [16] on the association between depression and incident of risk for breast, colorectal, colon, liver, lung, and prostate cancers found depression significantly increased RR of overall cancers by 15%, liver cancer by 20%, and lung cancer by 33%. The authors noticed no significant association for BC, PCa, or colorectal/colon cancer and increased risk of overall cancer among North America individuals.

Another meta-analysis of observational studies of Yang et al. [17] on the association of work stress and cancer risk included nine studies (281,290 participants, 9,090 incident cases) published during 2004-2017. The authors found statistically significant effects of work stress on an increase of the risk of several types of cancer: colorectal, RR = 1.36 (1.16-1.59); lung, RR = 1.24 (1.02-1.49); esophagus, RR = 2.12 (1.30-3.47), but not on prostate, breast, or ovarian cancers. However, the authors found the effect of work stress on colorectal cancer risk was significant only among participants from North America and increased risk was high (50%), but the association was not significant among participants from Europe. On the contrary, the effect of work stress on esophagus cancer risk was found to be significant in Europe, but not in North America.

3.2. Observational Studies

A summary of the evidence relating PS to BC risk from observational studies published during 2011-2018 is shown in Table 1.

A hospital-based case-control study by Kruk [23] included a large sample size of women with histopathological confirmation of the cancer (n = 1,943). Participants were characterized by detailed information on potential confounders using a self-administrated structured questionnaire, and the risks of BC were estimated in multivariate analysis and tests for linear dose response was conducted. Several major life events, like death of a close family member, personal injury, illness, troubles with the law, or retirement, were statistically significant in their association with BC risk; the increased risk ranged from 1.58 to 2.94. Additional analysis showed significantly increased risks for two periods of PS events—lifetime and beginning at birth—and ending 5 years before the cancer diagnosis, for life score levels > 70, being the highest for scores > 210. Life events' scores were estimated based on the Holmes and Rahe social readjustment rating scale [33]. The highest mean weight on this scale is 100 scores (death of husband); divorce was scored at 73 points, separation at 65 points, and death of a close family member at 63 points.

Wang et al.'s [24] case-control study identified the association of PS alone and combined lifestyle determinants are considered potential risk factors (low physical activity, alcohol intake, cigarette smoking, diet rich in animal meat, and high intake of fried food) with BC risk. After adjusting for known risk factors, the authors noted a 65% increase in risk for high perceived PS; ORs ranged from 1.89 to 3.36 when perceived stress was combined with these risky lifestyle behaviors.

Li et al. [25] used a comparative case-control study of 582 women with benign BC and 540 controls, aged ≤40 years showing that frequent depression, negative emotion (e.g., fear, worries, nervousness, sorrow, and helplessness), and disharmonious marital status were associated with the development of early onset BC.

Sawada et al. [26] analyzed data from 29,098 women from 23 study areas throughout Japan to find the relationship between BC incidence and psychological traits. PS was evaluated using subjects' response to questions: having “ikigai”, i.e., “something that makes one's life worth living”, decisiveness, ease of anger, and perceived stress of daily life with 3- or 4-point Likert-type response (disagree, neither, agree, and agree strongly). They found that none of the psychological traits were significantly associated with BC risk. However, this study has important limitations noted by the authors, i.e., 1-item measures of stress which could attenuate the true relationship between BC incidence and each item.

In turn, a prospective cohort study by Schoemaker et al. [27] comprising a large sample of women aged ≥16 and focusing on BC etiology used a postal questionnaire of which a follow up was repeated every 2.5-3 years to update risk factor information and obtain data on BC diagnosis. Researchers identified 1,510 cases with invasive cancer and 273 with in situ cancer during an average follow-up period of 6.1 years. The study tested a wide range of PS variables and carried out analyses by estrogen-receptor status, including BC risk factors (physical activity, obesity, alcohol intake, and smoking). This study observed no association between adverse life events, evaluated as the highest score in the Holmes and Rahe scale, and cancer, except a 31% increased BC risk among a subgroup of women under 20 years who experienced maternal death. However, the risk was not elevated when their mother had BC or ovarian cancer.

Yeh and Lee [28] analyzed data from a medical center's outpatient department in Taiwan whose patients were scheduled to receive mammography screening. The authors grouped participants into cases and controls based on pathological biopsy results. The Perceived Stress Scale measured general, life, and work-related stress perception. The Hospital Anxiety and Depression Screens for symptoms of anxiety and depression combined were applied. Participants completed demographic, lifestyle, and medical history basic characteristic questionnaires. The results showed participants with borderline anxiety were approximately 3 times more likely to have BC compared to subjects with no anxiety; subjects with depression had 4.5 times higher BC risk than subjects with no depression. The authors estimated that every point added to the average total stress score increased BC risk by 1.124 times concluding that stress, anxiety, and depression may be predictors of BC risk.

The Özkan et al.'s [29] case-control study analyzed the association between PS and social support with BC risk using the Stress Assessment Form and the Coping Strategy Indicator. The first form included data on childhood trauma (e.g., death of mother, death of father, and divorced parents) and major life events (e.g., death of husband, divorce, and a chronic serious disease). The second form contained 33 items for an evaluation of brief coping inventory. The results showed the increase in BC risk may be related to general life stress, such as existence of a stressor experience, perception of inadequate social support, or use of avoidance social support coping strategies.

The recent prospective cohort study by Butow et al. [30] was comprised of Australasian women aged 18-75 on the relationship between life-event stressors, social support, personality, and risk of developing BC among women with history of increased familial of BC. The authors applied semistructured phone interview, the Life Events and Difficulties Schedule interview protocol, and other questionnaires to estimate social support, optimism, and antiemotionality to obtain data on acute or chronic severity, e.g., death of a spouse/child, handicapped child requiring full-time care, and moderate stress such as buying/selling a home. The authors also identified eight psychosocial variables as predictors or moderators of the effect of stress on BC development, e.g., social support, personality, acute chronic stressors, and optimism. The authors did not report significant associations between any life-event stressors independently on its intensity in unadjusted and adjusted models.

Fisher et al.'s [31] case-control study of women aged 24-75 years identified evidence for life events perceived as stressful (abortion, illness, and relocation) and nonstressful (death of sibling, illness, and illness in family) considered as potential risk factors for BC. After adjustment for known risk factors for BC development, the authors found a cumulation of adverse life events perceived as stressful was significantly linked with increased risk for BC in a dose-response manner (OR = 1.63 (1.00-2.66), P trend = 0.045) and those life events perceived as nonstressful did not show statistical significance in the PS-cancer relationship. Further, regardless of personal illness perception (stressful or nonstressful), previous illness increased BC risk (OR = 2.84 (1.96-4.11), OR = 3.47 (1.34-8.94), respectively). Also, regardless menopausal status, nulliparous women or who had their first child at ≥30 years of age had increased BC risk.

Yildirim et al. [32] used a hospital-based case-control study of 250 cases treated for BC (surgery, chemotherapy, and radiotherapy), aged 27-64 years, to estimate PS influence on BC risk, applying semistructured interview, the Stress Evaluation Form, and the Healthy Lifestyle Behavior Scale. Lifelong stressful events such as childhood trauma (e.g., loss of mother or father, divorce of parents, or serious health problems), major life events (death of a loved one, serious disease, and divorce), chronic stressor (e.g., interpersonal relationship problems), and experience of stress within the last five years before disease were collected. The authors found that loss of father during childhood increased BC risk 2.68 times, inadequate social support 1.83 times, and serious stressor within the last five years 4.72 times. Also, psychiatric history was a factor increasing BC risk (1.95-fold). The authors underlined the particularly important influence of stressful events within the last five years on BC development.

A summary of the evidence linking PS to cancer other than BC is given in Table 2.

A hospital-based case-control study by Cabaniols et al. [34] included patients aged 18 and older with previously untreated glioma grades II-IV. The authors found a 90% significant increase in the risk of malignant primitive brain cancer caused by major PS life events and insignificant decreased risks related to daily stress OR: 0.90 (0.49-1.71) and to stress at work OR: 0.69 (0.27-1.74), measured over five years before cancer diagnosis. The authors suggest genetic factors are involved in glioma cancer and unexpected acute PS may participate in malignant primitive brain tumor development.

The Huang et al. [35] study was a large nested case-control study that included the Swedish population and health registers, which examined whether the death of a child was linked with pancreatic cancer in men and women aged 55 years and older. The authors noted a 9% increase in the risk associated with the death of child (overall). The risk increment to 27% was observed within the first five years after a child's death and also for loss of a child due to suicide (23%). The PS-pancreatic cancer association was only statistically significant in women (a 37% increase in the risk compared to controls) and in men with psychiatric illness, OR = 2.1 (1.52-2.91). In addition, the authors found participants with a history of psychiatric disease experienced increased pancreatic cancer risk to the greatest extent after child loss.

The Vasunilashorn et al. [36] study included a cohort of Taiwanese adults aged above 53 years and characterized the association between perceived stress based on six items dealing with the respondents' and their family health, financial situation and occupation, and mortality risk during the 11-year follow-up period. The authors found perceived stress caused a 19% statistically significant increase in mortality risk only among individuals with poor health outcomes. The authors concluded the observed relationship between perceived stress and mortality may be dependent on a participant's current health.

The large follow-up study conducted by Momen et al. [37] used data from Danish and Swedish national registers studying the association between bereavement by the death of a close relative before 15 years of age as an indicator of severe PS and childhood leukemia cancer. The authors found an approximate 10% increase in the risk of all childhood cancers and a 14% increase for central nervous system tumors due to bereavement. They concluded that experience of PS in early life is linked with a small elevated risk of childhood cancer risk.

The Azizi and Esmaeili [38] case-control study conducted in four Iranian hospitals identified the relationship between stressful life events assessed using the Holmes and Rahe Life Events Questionnaire and colorectal cancer. After adjusting for known risk factors, the authors found 2.49 times higher risk of colorectal cancer linked with the death of loved ones compared with controls. Authors found stressful life events with lower weight on the Holmes and Rahe scale such as family disputes and job problems, and serious financial problems also increased risk, but without statistical significance. The authors suggest stressful life events may be a factor increasing risk of colorectal cancer.

Kikuchi et al. [39] analyzed data from 61,563 participants from the Japan Collaborative Cohort Study to measure the relationship between perceived stress estimated on a 4-point Likert scale and colorectal cancer incidence. The authors found a significant relationship between daily perceived stress of moderate or high/severe intensity and rectal cancer incidence, e.g., 2.16-fold and 1.75-fold increases in the risk among men, respectively, but not for colon cancer incidence. The higher HR for cancer incidence was observed in women at the moderate stress level than at the high/severe stress level, indicating a reverse U-shaped relationship. Due to wide 95% CI of the HRs rectal cancer and a lack of statistical significance for colon cancer, the authors recommend further research with a greater sample size.

The Blanc-Lapierre et al. [40] population-based case-control study analyzed the association between perceived workplace PS over the entire work career and cancer among men. The authors observed that employment in at least one stressful job (e.g., high demand, time pressure, financial issues, and job insecurity) was significantly linked with increased ORs of cancer at 5 of 11 sites, i.e., the lung, colon, bladder, rectal, and stomach with a duration trend. Nonsignificant increases in risk of cancer of the non-Hodgkin lymphoma, kidney, melanoma, pancreas, and esophagus were also noted. Short-term (<15 years) work-related stress was not linked with any cancer. Contrary, significant associations were noted for longer cumulative periods of exposure to perceived job stress (15-30 years or above 30 years) and the lung, colon, bladder, rectum, stomach, and non-Hodgkin lymphoma cancers, and borderline significant risk for prostate cancer. The authors recommend further studies with detailed assessment of all job stressors during employment carried out on larger case and control groups.

Kim et al. [41] examined the prevalence and prognostic significance of psychological distress (PD) in gastric cancer patients. The authors used three methods to measure the severity of anxiety, insomnia, and depression, and the degree of functional impairment. The data showed 33.6% of participants were identified as patients with PD. The patients with PD had worse disease-free survival rates compared with patients without PD. In stage IV of cancer, patients exhibited almost 2.5-times poorer overall survival rates than patients without PD, HR = 2.47 (1.07-5.68). The authors demonstrated that patients with gastric cancer, independent of cancer stage, experienced PD due to worse survival outcomes and recommend further studies on the role of psychotherapeutic intervention on improved patient survival outcomes.

A large cohort study by Chang et al. [42] on the role of depression in overall cancer and hormone-related cancer development in the general population (aged 30-60 years) observed differences in direction and magnitude among relationships in men and women for cervical cancer. Authors identified at baseline major depression in 7.4% men and 10.2% women. Major depression caused a 5% increase of total cancer in men and a 10% decrease in women. In turn, minor depression identified at baseline in 19.3% men and 21.4% women resulted in a 3% increase of the total cancer risk in men and was without effect among women. The authors suggested a lack of the association between depression and cervical cancer and BC development; however, a 13% increase of PCa risk in men affected by minor depression was observed. According to the authors suggestion, the depression-cancer association would benefit from future studies that consider specific cancer subtypes and mechanism interaction.

In turn, a large international study based on data from 19 countries by O'Neill et al. [43] reported the association between a number of retrospectively assessed lifetime prevalence of 16 DSM-IV mental disorders (anxiety disorders, mood disorders, substance use disorders, and impulse control), major depressive dysthymia, and risk of overall cancer. These authors found the positive association between a number of mental disorders (OR ranging from 1.3 to 2.3) and overall cancer risk; the magnitude of the relationship was higher in women, and the possible carcinogenic impact of mental disorders was different in various periods of respondent's life. Significant effects of depression were observed with cancer diagnosis in a subgroup of women up to age 44 and were strongly linked with cancers diagnosed early in respondents' life as well as in women. O'Neill et al. [43] maintain that early diagnosis and treatment of mental disorders is important to avoid the increased risk of cancer occurrence caused by inferior lifestyle characteristics.

The Archer et al. [44] prospective cohort study (Whitehall II, all London-based office staff) of 17.4 years follow-up time analyzed the relationship between chronic depressive symptoms and smoking-related (109 cases), hormone-related (311 cases), and other cancers (356 cases) using the General Health Questionnaire depression subscale among participants aged 35-55 years at baseline. The authors stated chronic depression was not associated with overall cancer incidence when estimated for significant years of follow-up time. However, the authors found significantly increased risk (89%) among patients who experienced a new episode of mental disorder in the first 9 years of follow-up time. In the authors' opinion, subclinical cancer diagnosis can directly affect the brain and elicit sickness behaviors and depressive symptoms.

Li et al. [45] carried out a case-control study nested in Shanghai city with 250 PCa cases and 500 controls, which examined whether psychosocial factors including occupation, marital separation, and suffering predisposed men to PCa risk. After adjustment for confounding hormone-related factors (lifestyle, eating habits), men who presented a high level of stress caused by negative psychosocial factors had significantly increased risk; RRs ranged from 1.61 for occupational factors to 2.37 for sensitivity to personal comments. Marital separation also exhibited a high magnitude of PCa risk increase (1.94-fold). In addition, the authors found decreased PCa risk with regular intake of green vegetables and green tea, increased risk with alcohol, red meat, and processed food consumption.

Song et al. [46] explored the association between perceived stress levels (baseline and updated after a 5-year follow-up period) and overall cancer risk (gastric, esophageal, colon, lung, prostate, breast, liver, rectal, and pancreatic). The authors used self-reported data from the Japan Public Center-based Prospective Study which enrolled 140,420 participants aged 40-69 years. Among them, 101,708 individuals declared perceived stress. Increased risk for overall cancers by 11% was observed among all participants that experienced consistent high intensity PS (P − trend = 0.0002), by a 19% in men (P − trend = 0.0001) and by a 7% nonsignificant risk in women (P − trend = 0.1227) compared to those reporting constantly low stress levels. In separate analyses, cancer risk was significantly increased in men and was especially high among smokers, alcohol drinkers, obese, and those without family history of cancer. Using analysis by type of cancer, the authors reported the highest sensitivity to PS stress was observed for liver cancer (33%), PCa (28%), and pancreatic cancers (26%).

Using a large case-control study, Blanc-Lapierre et al. [47] analyzed the association between perceived lifetime workplace stress and newly diagnosed PCa risk. Individuals answered questions to determine whether their job made them feel tense, anxious, or stressful most of the time. There was a dose-response increased PCa risk across stress duration categories. 58% of respondents recognized that at least one job was stressful during their professional career. The risk was increased among men aged ≤65 who reported more than 30 years of workplace stress by 12% per 10-year increment for both low-grade and high-grade PCa. The researchers concluded that PS was reported more often in white-collar jobs and was significantly linked to PCa diagnosed at a younger age.

Based on a large cohort sample (n = 6571) of cancer-free women from the Danish Nurse Cohort aged 45-70 years at inclusion, Vesterlund et al. [48] analyzed the association between prolonged job strain, measured using single items dealing work speed or load, the number of duties entrusted, and level of participants' ordinary effect on organization of duties during working time across six years and cancer risk (overall cancer, virus immune-related, hormone related, digestive, and the lung) based on self-reported questionnaires on job strain. The authors noted a high percentage of cancer cases with perceived PS, but no evidence of an increased risk of any cancer subtype among the examined group due to prolonged job strain. We suggest that too small numbers of respondents declaring high job-strain level (n = 692 compared with those declaring low job-strain level, n = 4,155) might also affect the results. Although, as the authors emphasize, the effect of job strain may differ between men and women and being dependent on several factors including lifestyle.

The Jafri et al. [49] study estimated the effect of major stressful life events on developing lung cancer using the Holmes and Rahe Life Event Questionnaire. The study was a case-control study matched for age, sex, and smoking status (but not for the duration of smoking exposure) with patients' median age of 64.1 years. The percentage of diabetes among controls was significantly higher than cases as well as diabetes and β-blockers users. The examined groups did not differ in a number of experienced stressors during lifetime, but there was significant difference in a number of major stressful events experienced in the preceding 5 years (higher among cases). The authors found an approximate 2.2-fold increase in the risk of lung cancer, due to stressful events experience within the preceding 5 years. Additionally, the authors observed that use of β-blockers may prevent against lung cancer development.

4.1. Limitations

There are several limitations in this review. First, our conclusions are based to a large extent of reviewed studies on case-control, 11 of 26 observational studies, where selection bias, recall bias, and detection bias are common. Individuals with cancer could have a higher level of PS perception as a factor for cancer than healthy individuals, thus, leading to the over-reporting of stress exposure. Second, selection of information from retrieved articles might be subjective and also lead to bias. In order to minimize potential selection bias, two research staff members independently selected articles for inclusion. Third, we analyzed only studies that met our inclusion criteria and excluded other studies. Finally, we included only articles in English in this overview.

5.1. Future Perspectives

Determining the causal relationship between PS and cancer risk requires large-scale research efforts involving participation from multidisciplinary health specialists. This is due to the multivariate complexities associated with sources of PS, the relationship between stress and cancer disease, and the complicated nature of modifiable behaviors. Future epidemiological observational studies require larger study populations, international collaboration, unselected patient groups, and questionnaires providing detailed behavioral information to assess possible risk factors for particular cancer types considered as potential confounders. In addition, future studies should provide a significant measure of PS regarding the type and duration using valid and reliable scales to ensure a clear dose-response relationship. This approach could clarify existing biological mechanisms and identify additional risk pathways including ROS-induced associated with the relationship between PS and particular cancer types' outcome as well as the role of ROS/RNS in aging.