The Impact of Obesity and Adipokines on Breast and Gynecologic Malignancies

The link between obesity and multiple disease comorbidities is well established. In 2003, Calle and colleagues presented the relationship between obesity and several cancer types, including breast, ovarian, and endometrial malignancies. Nearly, 20% of cancer-related deaths in females can be accounted for by obesity. Identifying obesity as a risk factor for cancer led to a focus on the role of fat-secreted cytokines, known as adipokines, on carcinogenesis and tumor progression. Early studies indicated that the adipokine leptin increases cell proliferation, invasion, and inhibition of apoptosis in multiple cancer types. As a greater appreciation of the obesity–cancer link has amassed, we now know that additional adipokines can impact tumorigenesis. A deeper understanding of the adipokine-activated signaling in cancer may identify new treatment strategies irrespective of obesity. Moreover, adipokines may serve as disease biomarkers, harnessing the potential of obesity-associated factors to serve as indicators of treatment response and disease prognosis. As studies investigating obesity and women\u27s cancers continue to expand, it has become evident that breast, ovarian, and uterine cancers are distinctly impacted by adipokines. While complex, these distinct interactions may provide insight into cancer progression in these organs and new opportunities for targeted therapies. This review aims to organize and present the literature from the last 5 years investigating the mechanisms and implications of adipokine signaling in breast, endometrial, and ovarian cancers with a special focus on leptin and adiponectin

Cancer Connectors: Connexins, Gap Junctions, and Communication

Despite concerted clinical and research efforts, cancer is a leading cause of death worldwide. Surgery, radiation, and chemotherapy have remained the most common standard-of-care strategies against cancer for decades. However, the side effects of these therapies demonstrate the need to investigate adjuvant novel treatment modalities that minimize the harm caused to healthy cells and tissues. Normal and cancerous cells require communication amongst themselves and with their surroundings to proliferate and drive tumor growth. It is vital to understand how intercellular and external communication impacts tumor cell malignancy. To survive and grow, tumor cells, and their normal counterparts utilize cell junction molecules including gap junctions (GJs), tight junctions, and adherens junctions to provide contact points between neighboring cells and the extracellular matrix. GJs are specialized structures composed of a family of connexin proteins that allow the free diffusion of small molecules and ions directly from the cytoplasm of adjacent cells, without encountering the extracellular milieu, which enables rapid, and coordinated cellular responses to internal and external stimuli. Importantly, connexins perform three main cellular functions. They enable direct gap junction intercellular communication (GJIC) between cells, form hemichannels to allow cell communication with the extracellular environment, and serve as a site for protein-protein interactions to regulate signaling pathways. Connexins themselves have been found to promote tumor cell growth and invasiveness, contributing to the overall tumorigenicity and have emerged as attractive anti-tumor targets due to their functional diversity. However, connexins can also serve as tumor suppressors, and therefore, a complete understanding of the roles of the connexins and GJs in physiological and pathophysiological conditions is needed before connexin targeting strategies are applied. Here, we discuss how the three aspects of connexin function, namely GJIC, hemichannel formation, and connexin-protein interactions, function in normal cells, and contribute to tumor cell growth, proliferation, and death. Finally, we discuss the current state of anti-connexin therapies and speculate which role may be most amenable for the development of targeting strategies

Mice lacking the syndecan-3 gene are resistant to diet-induced obesity

The accurate matching of caloric intake to caloric expenditure involves a complex system of peripheral signals and numerous CNS neurotransmitter systems. Syndecans are a family of membrane-bound heparan sulfate proteoglycans that modulate ligand-receptor interactions. Syndecan-3 is heavily expressed in several areas of the brain, including hypothalamic nuclei, which are known to regulate energy balance. In particular, syndecans have been implicated in modulation of the activity of the melanocortin system, which potently regulates energy intake, energy expenditure, and peripheral glucose metabolism. Our data demonstrate that syndecan-3-null mice have reduced adipose content compared with wild-type mice. On a high-fat diet, syndecan-3-null male and female mice exhibited a partial resistance to obesity due to reduced food intake in males and increased energy expenditure in females relative to that of wild-type mice. As a result, syndecan-3-null mice on a high-fat diet accumulated less adipose mass and showed improved glucose tolerance compared with wild-type controls. The data implicate syndecan-3 in the regulation of body weight and suggest that inhibition of syndecan-3 may provide a therapeutic approach for the treatment of obesity resulting from exposure to high-fat diets. Introduction Body adipose mass is regulated by matching caloric intake to caloric expenditure over time. The CNS is a critical site where signals of adipose stores are sensed and where appropriate changes in intake and/or expenditure are produced. Over the past decade, a number of proteins have been implicated in the process of sensing peripheral fuel status and the effector mechanisms that defend peripheral adipose mass (1). While most of these proteins are neurotransmitters, receptors, or intracellular signaling molecules, recent data indicate an important role for a unique family of proteins called syndecans. Syndecans are ubiquitous cell surface heparan sulfate proteoglycans (HSPGs; proteins with covalently attached, highly acidic sugar chains), unique in their ability to bind many extracellular peptides, such as hormones and growth factors. Syndecans are found on almost every cell type (2) but are differentially expressed depending on the tissue type. Evidence for the involvement of syndecans in the control of energy balance comes from mice that overexpress syndecan-1 (3). Despite using the pan-selective cytomegalovirus promoter enhancer, Reizes and colleagues showed that mice overexpressing syndecan-1 express transgenic syndecan-1 in a highly unique and circumscribed pattern including expression in regions of the hypothalamus that have long been linked to energy balance regulation, such as the paraventricular nucleus (3, 4). Quite unexpectedly, these mice also show a profound, maturity-onset obesity and type 2 diabetes (3). Although such data indicate a potential role for syndecans in the CNS control of energy balance, syndecan-1 is not normally expressed in the CNS. However, other members of the syndecan family are expressed in the CNS and, most nota

Peripheral, but not central, CB1 antagonism provides food intake-independent metabolic benefits in diet-induced obese rats.

OBJECTIVE Blockade of the CB1 receptor is one of the promising strategies for the treatment of obesity. Although antagonists suppress food intake and reduce body weight, the role of central versus peripheral CB1 activation on weight loss and related metabolic parameters remains to be elucidated. We therefore specifically assessed and compared the respective potential relevance of central nervous system (CNS) versus peripheral CB1 receptors in the regulation of energy homeostasis and lipid and glucose metabolism in diet-induced obese (DIO) rats. RESEARCH DESIGN AND METHODS Both lean and DIO rats were used for our experiments. The expression of key enzymes involved in lipid metabolism was measured by real-time PCR, and euglycemic-hyperinsulinemic clamps were used for insulin sensitivity and glucose metabolism studies. RESULTS Specific CNS-CB1 blockade decreased body weight and food intake but, independent of those effects, had no beneficial influence on peripheral lipid and glucose metabolism. Peripheral treatment with CB1 antagonist (Rimonabant) also reduced food intake and body weight but, in addition, independently triggered lipid mobilization pathways in white adipose tissue and cellular glucose uptake. Insulin sensitivity and skeletal muscle glucose uptake were enhanced, while hepatic glucose production was decreased during peripheral infusion of the CB1 antagonist. However, these effects depended on the antagonist-elicited reduction of food intake. CONCLUSIONS Several relevant metabolic processes appear to independently benefit from peripheral blockade of CB1, while CNS-CB1 blockade alone predominantly affects food intake and body weight

Mice lacking the syndecan-3 gene are resistant to diet-induced obesity

The accurate matching of caloric intake to caloric expenditure involves a complex system of peripheral signals and numerous CNS neurotransmitter systems. Syndecans are a family of membrane-bound heparan sulfate proteoglycans that modulate ligand-receptor interactions. Syndecan-3 is heavily expressed in several areas of the brain, including hypothalamic nuclei, which are known to regulate energy balance. In particular, syndecans have been implicated in modulation of the activity of the melanocortin system, which potently regulates energy intake, energy expenditure, and peripheral glucose metabolism. Our data demonstrate that syndecan-3–null mice have reduced adipose content compared with wild-type mice. On a high-fat diet, syndecan-3–null male and female mice exhibited a partial resistance to obesity due to reduced food intake in males and increased energy expenditure in females relative to that of wild-type mice. As a result, syndecan-3–null mice on a high-fat diet accumulated less adipose mass and showed improved glucose tolerance compared with wild-type controls. The data implicate syndecan-3 in the regulation of body weight and suggest that inhibition of syndecan-3 may provide a therapeutic approach for the treatment of obesity resulting from exposure to high-fat diets

Quantitative characterization of stem cell dynamics in the hypoxic microenvironment with chemotherapy using computer vision

<p>Background: The cancer stem cell hypothesis has implicated a unique subpopulation of cancer cells as the primary drivers of tumorigenesis with capabilities of self-renewal and ability to reconstitute the full spectrum of heterogeneity within a tumour. It has been noted that the proportion of cancer stem cells is increased by hypoxia, which has been implicated as playing a key causative role in metastasis and therapeutic resistance in multiple solid tumours, including breast cancer. Recently it has been also reported that that cytotoxic chemotherapeutics may also induce a stem-like state in cancer cells. The dynamics of cancer stem cell induction by these conditions, and the possibility of synergistic effects, however, have not been accurately quantified. </p><p>Methods: In this work, we present, for the first time, an analysis pipeline for the quantification of cancer stem cell dynamics using time-lapse microscopy and computer-assisted, unbiased digital image processing. The MDA-MB-231 breast cancer cell line, transduced with a NANOG promoter driven GFP reporter gene, thereby reporting a stem-like state, was cultured under varying conditions of deferoxamine (a hypoxia chemo-mimetic) and paclitaxel (a chemotherapeutic reagent). Cellular dynamics were recorded by time-lapse microscopy capturing phase contrast and fluorescent images over a four-day period. Areas of fluorescence and confluence determined from phase images were compared to obtain the time dynamics of the proportion of stem-like cells. These dynamics were then fit to a two-state ordinary differential equation model, and the underlying distribution of parameter sets was studied.</p> <p>Results: Using the obtained dynamics, the time series of the proportion of NANOG-expressing cells was elucidated, and the parameter sets obtained by fitting experimental data to the model revealed shifts in parameter value distributions for the various cases of chemotherapy and deferoxamine concentrations. These shifts indicate that there are likely non-linear effects of these drugs on key underlying biological rates, such as the rates of differentiation and dedifferentiation. </p> <p>Conclusions: Taken together, these results are indicative of a number of relationships between the parameters governing cancer stem cell dynamics when affected by both hypoxia and chemotherapy, as occurs in the setting of a patient. This underscores the need for further characterisation of these dynamics, including a more thorough exploration of the effects of differing concentrations of chemotherapy, deferoxamine, and true hypoxia. Gaining an understanding of these dynamics may ultimately provide avenues to improve the efficacy of chemotherapy and reduce the risk of tumour recurrence, by optimizing the chemotherapy regimen together with manipulating the microenvironment.</p