Browse

Adipose tissue is the primary source of many pro-inflammatory cytokines in obesity. Macrophage numbers and pro-inflammatory gene expression are positively associated with adipocyte size. Free fatty acid and tumor necrosis factor-α involve in a vicious cycle between adipocytes and macrophages aggravating inflammatory changes. Thereby, M1 macrophages form a characteristic ‘crown-like structure (CLS)’ around necrotic adipocytes in obese adipose tissue. In obese women, CLSs of breast adipose tissue are responsible for both increase in local aromatase activity and aggressive behavior of breast cancer cells. Interlinked molecular mechanisms between adipocyte–macrophage–breast cancer cells in obesity involve seven consecutive processes: Excessive release of adipocyte- and macrophage-derived inflammatory cytokines, TSC1–TSC2 complex–mTOR crosstalk, insulin resistance, endoplasmic reticulum (ER) stress and excessive oxidative stress generation, uncoupled respiration and hypoxia, SIRT1 controversy, the increased levels of aromatase activity and estrogen production. Considering elevated risks of estrogen receptor (E2R)-positive postmenopausal breast cancer growth in obesity, adipocyte–macrophage crosstalk is important in the aforementioned issues. Increased mTORC1 signaling in obesity ensures the strong activation of oncogenic signaling in E2Rα-positive breast cancer cells. Since insulin and insulin-like growth factors have been identified as tumor promoters, hyperinsulinemia is an independent risk factor for poor prognosis in breast cancer despite peripheral insulin resistance. The unpredictable effects of adipocyte-derived leptin–estrogen–macrophage axis, and sirtuin 1 (SIRT1)–adipose-resident macrophage axis in obese postmenopausal patients with breast cancer are unresolved mechanistic gaps in the molecular links between the tumor growth and adipocytokines.

Breast cancer is a heterogeneous disease, and the complexity of breast carcinogenesis is associated with epigenetic modification. There are several major classes of epigenetic enzymes that regulate chromatin activity. This review will focus on the nine mammalian protein arginine methyltransferases (PRMTs) and the dysregulation of PRMT expression and function in breast cancer. This class of enzymes catalyse the mono- and (symmetric and asymmetric) di-methylation of arginine residues on histone and non-histone target proteins. PRMT signalling (and R methylation) drives cellular proliferation, cell invasion and metastasis, targeting (i) nuclear hormone receptor signalling, (ii) tumour suppressors, (iii) TGF-β and EMT signalling and (iv) alternative splicing and DNA/chromatin stability, influencing the clinical and survival outcomes in breast cancer. Emerging reports suggest that PRMTs are also implicated in the development of drug/endocrine resistance providing another prospective avenue for the treatment of hormone resistance and associated metastasis. The complexity of PRMT signalling is further underscored by the degree of alternative splicing and the scope of variant isoforms (with distinct properties) within each PRMT family member. The evolution of PRMT inhibitors, and the ongoing clinical trials of PRMT inhibitors against a subgroup of solid cancers, coupled to the track record of lysine methyltransferases inhibitors in phase I/II clinical trials against cancer underscores the potential therapeutic utility of targeting PRMT epigenetic enzymes to improve survival outcomes in aggressive and metastatic breast cancer.

Sex differences exist in the regulation of energy homeostasis. Better understanding of the underlying mechanisms for sexual dimorphism in energy balance may facilitate development of gender-specific therapies for human diseases, e.g. obesity. Multiple organs, including the brain, liver, fat and muscle, play important roles in the regulations of feeding behavior, energy expenditure and physical activity, which therefore contribute to the maintenance of energy balance. It has been increasingly appreciated that this multi-organ system is under different regulations in male vs female animals. Much of effort has been focused on roles of sex hormones (including androgens, estrogens and progesterone) and sex chromosomes in this sex-specific regulation of energy balance. Emerging evidence also indicates that other factors (not sex hormones/receptors and not encoded by the sex chromosomes) exist to regulate energy homeostasis differentially in males vs females. In this review, we summarize factors and signals that have been shown to regulate energy homeostasis in a sexually dimorphic fashion and propose a framework where these factors and signals may be integrated to mediate sex differences in energy homeostasis.

The discovery that two rare autosomal recessive high bone mass conditions were caused by the loss of sclerostin expression prompted studies into its role in bone homeostasis. In this article, we aim to bring together the wealth of information relating to sclerostin in bone though discussion of rare human disorders in which sclerostin is reduced or absent, sclerostin manipulation via genetic approaches and treatment with antibodies that neutralise sclerostin in animal models and in human. Together, these findings demonstrate the importance of sclerostin as a regulator of bone homeostasis and provide valuable insights into its biological mechanism of action. We summarise the current state of knowledge in the field, including the current understanding of the direct effects of sclerostin on the canonical WNT signalling pathway and the actions of sclerostin as an inhibitor of bone formation. We review the effects of sclerostin, and its inhibition, on bone at the cellular and tissue level and discuss new findings that suggest that sclerostin may also regulate adipose tissue. Finally, we highlight areas in which future research is expected to yield additional insights into the biology of sclerostin.

Over the last decade, there has been a shift in the focus of cancer therapy from conventional cytotoxic drugs to therapies more specifically directed to cancer cells. These novel therapies include immunotherapy, targeted therapy and precision medicine, each developed in great part with a goal of limiting collateral destruction of normal tissues, while enhancing tumor destruction. Although this approach is sound in theory, even new, specific therapies have some undesirable, ‘off target effects’, in great part due to molecular pathways shared by neoplastic and normal cells. One such undesirable effect is hyperglycemia, which results from either the loss of immune tolerance and autoimmune destruction of pancreatic β-cells or dysregulation of the insulin signaling pathway resulting in insulin resistance. These distinct pathogenic mechanisms lead to clinical presentations similar to type 1 (T1DM) and type 2 (T2DM) diabetes mellitus. Both types of diabetes have been reported in patients across clinical trials, and data on the mechanism(s) for developing hyperglycemia, prevalence, prognosis and effect on cancer mortality is still emerging. With the rapidly expanding list of clinical indications for new cancer therapies, it is essential to understand the impact of their adverse effects. In this review, we focus on hyperglycemia and diabetes related to cancer therapies, describe what is known about mechanism(s) leading to dysregulated glucose metabolism and provide a guide to management of complex oncology patients with a new diagnosis of diabetes.

Bone-forming approaches to treat patients with severe osteoporosis are effective, but treatment options are limited, and there is an unmet clinical need for additional drugs. This review discusses two novel and advanced anabolic therapeutic concepts that have successfully completed phase 3 trials. Romosozumab is a monoclonal antibody that targets the Wnt inhibitor sclerostin. Two phase 3 trials (FRAME and ARCH) of romosozumab for the treatment of postmenopausal osteoporosis have been completed. Both trials successfully reached their primary endpoint by reducing vertebral fractures by 75% compared to placebo (FRAME trial) and 48% compared to alendronate (ARCH trial), respectively. Abaloparatide is a PTH-related protein (PTHrP) analog that has displayed bone anabolic activity. In the phase 3 ACTIVE trial, abaloparatide was compared to placebo and teriparatide for 18 months in postmenopausal women who had already experienced an osteoporotic fracture. Abaloparatide successfully reduced the rate of new vertebral fractures by 86% compared to placebo. Furthermore, abaloparatide achieved greater BMD increases at all measured sites compared to both placebo and teriparatide. Based on these results, abaloparatide was FDA approved in April 2017. This review discusses available data of both agents with regard to efficacy and safety as well as their possible future application.