Ageing is a process characterized by a progressive decline in cellular function, organismal fitness and increased risk of age-related diseases and death. Several hundred theories have attempted to explain this phenomenon. One of the most popular is the 'oxidative stress theory', originally termed the 'free radical theory'. The endocrine system seems to have a role in the modulation of oxidative stress; however, much less is known about the role that oxidative stress might have in the ageing of the endocrine system and the induction of age-related endocrine diseases. This Review outlines the interactions between hormones and oxidative metabolism and the potential effects of oxidative stress on ageing of endocrine organs. Many different mechanisms that link oxidative stress and ageing are discussed, all of which converge on the induction or regulation of inflammation. All these mechanisms, including cell senescence, mitochondrial dysfunction and microRNA dysregulation, as well as inflammation itself, could be targets of future studies aimed at clarifying the effects of oxidative stress on ageing of endocrine glands.

Oxidative stress and the ageing endocrine system

Reactive oxygen species (ROS) are common by-products of normal aerobic cellular metabolism and play important physiological roles in intracellular cell signaling and homeostasis. The human body is equipped with antioxidant systems to regulate the levels of these free radicals and maintain proper physiological function. However, a condition known as oxidative stress (OS) occurs, when ROS overwhelm the body's ability to readily detoxify them. Excessive amounts of free radicals generated under OS conditions cause oxidative damage to proteins, lipids, and nucleic acids, severely compromising cell health and contributing to disease development, including cancer. Biomarkers of OS can therefore be exploited as important tools in the assessment of disease status in humans. In the present review, we discuss different approaches used for the evaluation of OS in clinical samples. The described methods are limited in their ability to reflect on OS only partially, revealing the need of more integrative approaches examining both pro- and antioxidant reactions with higher sensitivity to physiological/pathological alternations. We also provide an overview of recent findings of OS in patients with different types of cancer. Identification of OS biomarkers in clinical samples of cancer patients and defining their roles in carcinogenesis hold great promise in promoting the development of targeted therapeutic approaches and diagnostic strategies assessing disease status. However, considerable data variability across laboratories makes it difficult to draw general conclusions on the significance of these OS biomarkers. To our knowledge, no adequate comparison has yet been performed between different biomarkers and the methodologies used to measure them, making it difficult to conduct a meta-analysis of findings from different groups. A critical evaluation and adaptation of proposed methodologies available in the literature should therefore be undertaken, to enable the investigators to choose the most suitable procedure for each chosen biomarker.

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Approaches and Methods to Measure Oxidative Stress in Clinical Samples: Research Applications in the Cancer Field

Chemoresistance is a major factor driving tumour relapse and the high rates of cancer-related deaths. Understanding how cancer cells overcome chemotherapy-induced cell death is critical in promoting patient survival. One emerging mechanism of chemoresistance is the tumour cell secretome (TCS), an array of protumorigenic factors released by tumour cells. Chemotherapy exposure can also alter the composition of the TCS, known as therapy-induced TCS, and can promote tumour relapse and the formation of an immunosuppressive tumour microenvironment (TME). Here, we outline how the TCS can protect cancer cells from chemotherapy-induced cell death. We also highlight recent evidence describing how therapy-induced TCS can impact cancer stem cell (CSC) expansion and tumour-associated immune cells to enable tumour regrowth and antitumour immunity.

Tumour Cell Secretome in Chemoresistance and Tumour Recurrence

Bone morphogenetic protein 4—a fascinating regulator of cancer cell behavior

Imbalanced regulation of reactive oxygen species (ROS) and antioxidant factors in cells is known as “oxidative stress (OS)”. OS regulates key cellular physiological responses through signal transduction, transcription factors and noncoding RNAs (ncRNAs). Increasing evidence indicates that continued OS can cause chronic inflammation, which in turn contributes to cardiovascular and neurological diseases and cancer development. MicroRNAs (miRNAs) are small ncRNAs that produce functional 18-25-nucleotide RNA molecules that play critical roles in the regulation of target gene expression by binding to complementary regions of the mRNA and regulating mRNA degradation or inhibiting translation. Furthermore, miRNAs function as either tumor suppressors or oncogenes in cancer. Dysregulated miRNAs reportedly modulate cancer hallmarks such as metastasis, angiogenesis, apoptosis and tumor growth. Notably, miRNAs are involved in ROS production or ROS-mediated function. Accordingly, investigating the interaction between ROS and miRNAs has become an important endeavor that is expected to aid in the development of effective treatment/prevention strategies for cancer. This review provides a summary of the essential properties and functional roles of known miRNAs associated with OS in cancers.

MicroRNA Networks Modulate Oxidative Stress in Cancer.

Background: 8-Hydroxydeoxyguanosine (8- OHdG) is a marker of oxidative stress in DNA. This study was undertaken to reveal whether serum 8-OHdG could be a prognostic factor in epithelial ovarian carcinoma (EOC). Patients and Methods: Preoperative serum 8-OHdG levels were examined by enzyme-linked immunosorbent assay in 84 stage I-IV EOC patients. Immunohistochemical (IHC) 8- OHdG expression was determined in 78 of these patients. Results: Strong 8-OHdG immunostaining predicted poor survival. High serum 8-OHdG (>140 pg/ml) was associated with poor ovarian cancer-specific survival (p<0.05) in patients with grade 1-2 EOC (p<0.05), but was not observed among the grade 3 patients. High 8-OHdG levels both in the serum and in the tumour tissue was associated with traditional factors of poor prognosis and serous histology. Conclusion: Both serum and IHC 8-OHdG assessment may serve as prognostic tools in EOC and the role of oxidative stress as a carcinogenic factor in ovarian cancer pathogenesis is also suggested. Ovarian cancer is one of the main causes of cancer-related death in women. Seventy percent of ovarian carcinomas are diagnosed at an advanced stage, most patients relapse within two years and five-year survival at its best is only 40 %. Evidence suggests that ovulation increases the levels of inflammatory agents, which can further lead to mutations in

Elevated Serum 8-OHdG Is Associated with Poor Prognosis in Epithelial Ovarian Cancer

Several angiogenesis-promoting factors have prognostic significance in ovarian cancer. The objective of this study was to evaluate whether traditional chemotherapy affects angiogenesis-related factors in ovarian carcinoma and to assess the clinical significance of these effects. To screen for angiogenesis-related factors of possible relevance, OVCAR-3 and A2780 ovarian cancer cells were treated with IC50 doses of cisplatin (CDDP) or docetaxel, or with bevacizumab, and mRNA expression of several angiogenesis-related factors was analyzed. Thrombospondin-1 (TSP-1), bone morphogenetic protein-4 (BMP-4), endothelin-1, and placental growth factor-2 were statistically significantly induced by CDDP. At protein level, CDDP also induced hypoxia-inducible factor-1α but not vascular endothelial growth factor. In carcinoma samples taken before and after platinum-based neoadjuvant chemotherapy from 28 patients with advanced, high-grade serous ovarian carcinoma, CD105 and factors most induced by CDDP (TSP-1 and BMP-4) were analyzed by immunohistochemistry. Strong expression of BMP-4 before chemotherapy was an independent prognostic factor of longer progression-free time (p = 0.002) and overall survival (p = 0.02), but it was not associated with neovascularization (as evaluated by CD105). However, changes in BMP-4 expression in samples analyzed before and after chemotherapy (observed in 22/28 patients) were not associated with prognosis. TSP-1 expression was not associated with clinical parameters. Our results indicate that in serous ovarian carcinoma, BMP-4 has prognostic significance, which is not angiogenesis-related. We also show that CDDP induces several angiogenesis-related growth factors in vitro and future studies are warranted to clarify the clinical significance of this phenomenon.

Liisa Laatio

Papers

Elevated Serum 8-OHdG Is Associated with Poor Prognosis in Epithelial Ovarian Cancer

BMP-4 expression has prognostic significance in advanced serous ovarian carcinoma and is affected by cisplatin in OVCAR-3 cells