A longitudinal evaluation of the relationship between first morning urinary and salivary cortisol.

UNLABELLED: Cortisol is one of the most frequently used stress biomarkers in humans. Urine and saliva are the matrices of choice to longitudinally monitor cortisol levels. Salivary and urinary cortisol are often discussed as though they provide similar information. However, the relationship between "free" cortisol levels in urine (nonconjugated) and saliva (non-protein-bound) has yet to be properly evaluated using naturalistic designs. OBJECTIVES: To investigate the longitudinal relationship between salivary cortisol (SC) and first morning urinary cortisol (FMUC), and to compare the advantages and disadvantages of these matrices in assessing longitudinal changes in cortisol secretion using naturalistic designs. METHODS: Cortisol levels from 31 healthy, Kakchiquel Mayan women in Guatemala were compared in one first morning urine (FMU) and four saliva specimens collected daily across three alternate days. Linear mixed-effect regression models including fixed and random effects were used to analyze the repeated-measures data. RESULTS: FMUC levels (16.04-242.18 ng/ml) were higher than SC levels (0.21-5.16 ng/ml). A small but statistically significant relationship was found between FMUC and SC (each 1 ng/ml increase in FMUC predicted a 0.1% increase in SC; P < 0.05). CONCLUSIONS: Nonconjugated FMUC levels are related to non-protein-bound SC levels collected throughout the day. FMU presents several advantages over saliva for the longitudinal assessment of cortisol in naturalistic studies. Cortisol levels are about 53-fold higher in FMU than in saliva, which makes between- and within-individual variation easier to detect, and FMUC levels are less likely to be affected by confounders than diurnal SC levels.

Insulin Enhances Migration and Invasion in Prostate Cancer Cells by Up-Regulation of FOXC2.

Androgen deprivation therapy (ADT) is the standard treatment for advanced prostate cancer (PCa), yet many patients relapse with lethal metastatic disease. With this loss of androgens, increased cell plasticity has been observed as an adaptive response to ADT. This includes gain of invasive and migratory capabilities, which may contribute to PCa metastasis. Hyperinsulinemia, which develops as a side-effect of ADT, has been associated with increased tumor aggressiveness and faster treatment failure. We investigated the direct effects of insulin in PCa cells that may contribute to this progression. We measured cell migration and invasion induced by insulin using wound healing and transwell assays in a range of PCa cell lines of variable androgen dependency (LNCaP, 22RV1, DuCaP, and DU145 cell lines). To determine the molecular events driving insulin-induced invasion we used transcriptomics, quantitative real time-PCR, and immunoblotting in three PCa cell lines. Insulin increased invasiveness of PCa cells, upregulating Forkhead Box Protein C2 (FOXC2), and activating key PCa cell plasticity mechanisms including gene changes consistent with epithelial-to-mesenchymal transition (EMT) and a neuroendocrine phenotype. Additionally, analysis of publicly available clinical PCa tumor data showed metastatic prostate tumors demonstrate a positive correlation between insulin receptor expression and the EMT transcription factor FOXC2. The insulin receptor is not suitable to target clinically however, our data shows that actions of insulin in PCa cells may be suppressed by inhibiting downstream signaling molecules, PI3K and ERK1/2. This study identifies for the first time, a mechanism for insulin-driven cancer cell motility and supports the concept that targeting insulin signaling at the level of the PCa tumor may extend the therapeutic efficacy of ADT.

New players for advanced prostate cancer and the rationalisation of insulin-sensitising medication.

Obesity and type 2 diabetes are recognised risk factors for the development of some cancers and, increasingly, predict more aggressive disease, treatment failure, and cancer-specific mortality. Many factors may contribute to this clinical observation. Hyperinsulinaemia, dyslipidaemia, hypoxia, ER stress, and inflammation associated with expanded adipose tissue are thought to be among the main culprits driving malignant growth and cancer advancement. This observation has led to the proposal of the potential utility of "old players" for the treatment of type 2 diabetes and metabolic syndrome as new cancer adjuvant therapeutics. Androgen-regulated pathways drive proliferation, differentiation, and survival of benign and malignant prostate tissue. Androgen deprivation therapy (ADT) exploits this dependence to systemically treat advanced prostate cancer resulting in anticancer response and improvement of cancer symptoms. However, the initial therapeutic response from ADT eventually progresses to castrate resistant prostate cancer (CRPC) which is currently incurable. ADT rapidly induces hyperinsulinaemia which is associated with more rapid treatment failure. We discuss current observations of cancer in the context of obesity, diabetes, and insulin-lowering medication. We provide an update on current treatments for advanced prostate cancer and discuss whether metabolic dysfunction, developed during ADT, provides a unique therapeutic window for rapid translation of insulin-sensitising medication as combination therapy with antiandrogen targeting agents for the management of advanced prostate cancer.