Role of stress in the pathogenesis of cancer (Review).

Stress is a state of disrupted homeostasis, triggered by intrinsic or extrinsic factors, the stressors, which are counteracted by various physiological and behavioural adaptive responses. Stress has been linked to cancer development and incidence for decades; however, epidemiological studies and clinical trials have yielded contradictory results. The present review discusses the effects of stress on cancer development and the various underlying mechanisms. Animal studies have revealed a clear link between stress and cancer progression, revealing molecular, cellular and endocrine processes that are implicated in these effects. Thus, stress hormones, their receptor systems and their intracellular molecular pathways mediate the effects of stress on cancer initiation, progression and the development of metastases. The mechanisms linking stress and cancer progression can either be indirect, mediated by changes in the cancer microenvironment or immune system dysregulation, or direct, through the binding of neuroendocrine stress­related signalling molecules to cancer cell receptors. Stress affects numerous anti­ and pro­cancer immune system components, including host resistance to metastasis, tumour retention and/or immune suppression. Chronic psychological stress through the elevation of catecholamine levels may increase cancer cell death resistance. On the whole, stress is linked to cancer development and incidence, with psychological stressors playing a crucial role. Animal studies have revealed a better link than human ones, with stress­related hormones influencing tumour development, migration, invasion and cell proliferation. Randomized controlled trials are required to further evaluate the long­term cancer outcomes of stress and its management.

High prevalence of autonomous cortisol and aldosterone secretion from adrenal adenomas.

OBJECTIVES: Previous studies based on standard endocrine testing have shown a variable incidence of autonomous cortisol secretion (ACS) or autonomous aldosterone secretion (AAS) in patients with single adrenal adenomas (SAA). We tested whether the use of appropriate controls and modification of standard testing, aiming at eliminating interference from endogenous ACTH, reveals previously undetected subtle ACS and AAS by SAA. DESIGN: Case control study. Patients We investigated 151 patients with SAA and 72 matched controls with normal adrenal computerized tomography. MEASUREMENTS: All participants had arterial blood pressure recorded, and serum cortisol and aldosterone measured before and after intravenous administration of 250 mug of ACTH, and following dexamethasone administration. Eighty-three patients and all the controls had serum aldosterone and renin measured before and after saline infusion, and after a second saline infusion following dexamethasone administration. RESULTS: Using the mean + 2 SD values obtained from controls after dexamethasone administration and saline infusion following dexamethasone administration, normal cut-off values for cortisol (30.11 nM), aldosterone (67.59 pM), and aldosterone/renin ratio (9.74 pM/mU/l) were developed. Using these cut-off values, the estimated incidence of ACS and AAS in patients with SAA was 56.63% and 24.10%, respectively, whereas 12.05% had autonomous secretion of both cortisol and aldosterone. Systolic and diastolic arterial blood pressure correlated significantly with the aldosterone/renin ratio following AlphaCTH stimulation (P < 0.0002 and P < 0.001, respectively), and after saline infusion following dexamethasone administration (P < 0.003 and P < 0.002, respectively). CONCLUSIONS: By applying new cut-offs, ACS and AAS in patients with a SAA is very common, and aldosterone secretion correlates with arterial blood pressure.

Childhood experiences of parenting and age at menarche, age at menopause and duration of reproductive lifespan: Evidence from the English Longitudinal Study of Ageing.

OBJECTIVES: The parent-child relationship is critical for human development, yet little is known about its association with offsprings' reproductive health outside the context of abuse and neglect. We investigated whether childhood experiences of poor-quality parenting (characterized as decreased parental care and increased parental overprotection) are associated with women's reproductive timing and lifespan. STUDY DESIGN: Observational study of 2383 women aged 55-89 years in 2007 from the English Longitudinal Study of Ageing (ELSA). Multinomial logistic regression models were estimated. MAIN OUTCOME MEASURES: Self-reported ages at menarche and menopause and duration of reproductive lifespan. RESULTS: Increasing maternal and paternal overprotection were associated with later menarche (≥16 years) after adjustment for age and childhood socioeconomic position (relative risk ratio (RRR) 1.11, 95% CI 1.02-1.21 and 1.11, 95% CI 1.01-1.21, respectively, per unit increase in the predictor). Increasing parental overprotection and decreasing paternal care were associated with earlier menarche (≤10 years). However, these associations were marginally non-significant. Maternal and paternal overprotection were also inversely associated with age at natural menopause after adjustment for age, childhood socioeconomic position and age at menarche (p value for linear trend = 0.041 and 0.004, respectively). Further, increasing paternal overprotection was associated with a shorter reproductive lifespan (≤33 years) (RRR 1.09 (1.01-1.18), per unit increase in the predictor) after adjustment for age and childhood socioeconomic position. Adjustment for additional childhood and adult factors did not explain these associations. CONCLUSIONS: Women who experienced poor-quality parenting in childhood, especially increased levels of parental overprotection, might be at increased risk of an unfavourable reproductive health profile that is characterized by late or early menarche, premature menopause and a shorter reproductive lifespan.

Childhood experiences of parenting and cancer risk at older ages: findings from the English Longitudinal Study of Ageing (ELSA).

OBJECTIVES: Despite the importance of childhood experiences for adult health and psychosocial factors for cancer development, parenting, a key childhood psychosocial exposure, has yet to be studied in relation to cancer risk at older ages. We examined whether childhood experiences of poor-quality parenting are associated with an increased risk of cancer at older ages. METHODS: We used a sample of 4471 community dwellers aged ≥ 55 years in 2007. Poor-quality parenting was defined as low levels of parental care and high levels of parental overprotection. RESULTS: Overall poorer experiences of parenting, decreasing parental care and increasing parental overprotection were associated with increased risk of incident all-site and skin cancer in men, but not in women. Increasing paternal overprotection was also associated with increased risk of incident colorectal cancer in men. Overall poorer experiences of parenting and increasing paternal overprotection were associated with increased risk of prevalent all-site and colorectal cancer in women. Adjustment for covariates explained a small part of these associations. CONCLUSIONS: Older adults who reported childhood experiences of poorer quality parenting appear to have an increased risk of cancer. These findings improve our understanding of the role of psychosocial factors in cancer over the life course.

Protein expression in the brain of rat offspring in relation to prenatal caloric restriction.

OBJECTIVE: Intrauterine growth restriction (IUGR) has been associated with decreased supply of crucial substrates to the fetus and affects its growth and development by temporarily or permanently modifying gene expression and function. However, not all neonates born by calorie restricted mothers are IUGR and there are no reports regarding their brain protein expression vis-à-vis that of their IUGR siblings. Here, we investigated the expression of key proteins that regulate growth and development of the brain in non-IUGR newborn pups versus IUGR siblings and control pups. METHODS: Rat brain proteins were isolated from each group upon delivery and separated by two-dimensional gel electrophoresis (2-DE). RESULTS: 14-3-3 Protein, calreticulin, elongation factor, alpha-enolase, fascin, heat-shock protein HSP90 and pyruvate kinase isozymes were significantly increased (p < 0.05) in samples obtained from IUGR newborn pups compared to non-IUGR. Conversely, collapsin response mediator proteins, heat-shock70 and peroxiredoxin2 were decreased in IUGR group compared to non-IUGR. CONCLUSIONS: In our experimental study, IUGR pups showed an altered proteomic profile compared to their non-IUGR siblings and non-IUGR controls. Thus, not all offspring of calorie-restricted mothers become IUGR with the accompanying alterations in the expression of proteins. The differentially expressed proteins could modulate alterations in the energy balance, plasticity and maturation of the brain.

Determinants and consequences of major insulin-like growth factor components among full-term healthy neonates.

The purpose of this research was to investigate determinants of the insulin-like growth factor (IGF) system among healthy full-term newborns and explore their relation with anthropometric variables at birth. Components of the IGF system have been implicated in the pathogenesis of several forms of cancer, and perinatal events have been linked to chronic diseases in later life. Measurements of weight and length, as well as blood samples, were obtained from 331 healthy full-term newborns delivered during 1999 in Athens, Greece. Because the liver is important for IGF production, newborns were chosen to have bilirubin levels either < or = 8 mg/dl or > or = 12 mg/dl to operationally distinguish them according to the liver function. IGF-I, IGF-II, and IGF binding protein-3 were inversely associated with the presence of neonatal jaundice and blood creatinine, after controlling for blood protein levels. IGF-I increased rapidly and significantly over a period of a few days and was strongly positively associated with both birth weight and ponderal index. Newborn levels of IGF-I declined with maternal age. In comparison with first-born newborns, later-born ones had significantly higher blood IGF-I levels. We conclude that IGF-I plays a dominant role in growth during the perinatal period and that all three studied components of the IGF system are sensitive to liver and kidney function. These findings provide an insight into the processes involved in perinatal growth.

Clinical Applications of Procalcitonin in Pediatrics: An Advanced Biomarker for Inflammation and Infection-Can It Also Be Used in Trauma?

Background. Procalcitonin is a small molecular peptide that has gained increased support as an adjunct diagnostic marker of infection in the adult population; the concordant body of evidence for the use of procalcitonin in pediatric populations is far less complete. Objectives. Our objective is to review the current evidence supporting the utilization of procalcitonin in children in a variety of clinical scenarios including SIRS, sepsis, burns, and trauma and to identify existing knowledge gaps. Methods. A thorough review of the literature was performed utilizing PubMed. We focused on using meta-analysis from adult populations to review current practices in interpretation and methodology and find concordant pediatric studies to determine if the same applications are validated in pediatric populations. Results. Current evidence supports the usage of procalcitonin as both a sensitive and a specific marker for the differentiation of systemic inflammatory response syndrome from sepsis in pediatrics with increased diagnostic accuracy compared to commonly used biomarkers including complete blood counts and C-reactive protein. Conclusions. Although the body of evidence is limited, initial observations suggest that procalcitonin can be used in pediatric trauma and burn patients as both a prognostic and a diagnostic marker, aiding in the identification of infection in patients with extensive underlying inflammation.