Eicosanoids and Adipokines in Breast Cancer: From Molecular Mechanisms to Clinical Considerations

International audienceChronic inflammation is one of the foremost risk factors for different types of malignancies, including breast cancer. Additional risk factors of this pathology in postmenopausal women are weight gain, obesity, estrogen secretion, and an imbalance in the production of adipokines, such as leptin and adiponectin. Various signaling products of transcription factor, nuclear factor-kappaB, in particular inflammatory eicosanoids, reactive oxygen species (ROS), and cytokines, are thought to be involved in chronic inflammation-induced cancer. Together, these key components have an influence on inflammatory reactions in malignant tissue damage when their levels are deregulated endogenously. Prostaglandins (PGs) are well recognized in inflammation and cancer, and they are solely biosynthesized through cyclooxygenases (COXs) from arachidonic acid. Concurrently, ROS give rise to bioactive isoprostanes from arachidonic acid precursors that are also involved in acute and chronic inflammation, but their specific characteristics in breast cancer are less demonstrated. Higher aromatase activity, a cytochrome P-450 enzyme, is intimately connected to tumor growth in the breast through estrogen synthesis, and is interrelated to COXs that catalyze the formation of both inflammatory and anti-inflammatory PGs such as PGE(2), PGF(2 alpha), PGD(2), and PGJ(2) synchronously under the influence of specific mediators and downstream enzymes. Some of the latter compounds upsurge the intracellular cyclic adenosine monophosphate concentration and appear to be associated with estrogen synthesis. This review discusses the role of COX- and ROS-catalyzed eicosanoids and adipokines in breast cancer, and therefore ranges from their molecular mechanisms to clinical aspects to understand the impact of inflammation. Antioxid. Redox Signal. 18, 323-360

Alternative in vitro models used in the main safety tests of cosmetic products and new challenges

International audienceBackground Guided by ethical considerations and regulatory requirements such as the 7th Amendment to the European Cosmetics Directive N degrees 1223/2009, the cosmetic industry has developed and evaluated alternative test strategies such as in vitro assays, in silico approaches for toxicological endpoints and efficacy of cosmetic products and cosmetics ingredients. In consequence, the European Centre for the Validation of Alternative Methods (ECVAM) has proposed a list of validated cell-based in vitro models for predicting the safety and toxicity of cosmetic ingredients. These models have been demonstrated as valuable and effective tools to overcome the limitations of animal in vivo studies. For example, 3D human skin equivalent models are used to evaluate skin irritation potential; and excised human skin is used as the gold standard for the evaluation of dermal absorption. Objective This review presents, in relation to the regulatory requirements, the main alternative in vitro models used in the safety tests of cosmetic products, focusing on skin sensitization, skin corrosion, skin irritation and skin absorption, with advantages and limitations of each model. Recent innovative 3D cell technologies such as Organ-on-a-Chip (OoC) models that can bring significant improvements for toxicology and efficacy testing are also presented. Conclusion The development of OoC technology is promising for assessing the toxicity of substances contained in cosmetics, particularly for repeated dose toxicity, for which no alternative in vitro methods are currently available. Nevertheless, aside from the challenges, the technology needs to be validated and accepted by regulatory organizations as an effective method. Collaboration between researchers, regulatory organizations and industry would be required to achieve this validation

Marine algae as attractive source to skin care

International audienceAs the largest organ in the human body, the skin has multiple functions of which one of the most important is the protection against various harmful stressors. The keratinised stratified epidermis and an underlying thick layer of collagen-rich dermal connective tissues are important components of the skin. The environmental stressors such as ultraviolet radiation (UVR) and pollution increase the levels of reactive oxygen species (ROS), contributing to clinical manifestations such as wrinkle formation and skin aging. Skin aging is related to the reduction of collagen production and decrease of several enzymatic activities including matrix metalloproteinases (MMPs), which degrade collagen structure in the dermis; and tissue inhibitor of metalloproteinases (TIMPs), which inhibit the action of MMPs. In addition to alterations of DNA, signal transduction pathways, immunology, UVR, and pollution activate cell surface receptors of keratinocytes and fibroblasts in the skin. This action leads to a breakdown of collagen in the extracellular matrix and a shutdown of new collagen synthesis. Therefore, an efficient antioxidants strategy is of major importance in dermis and epidermis layers. Marine resources have been recognised for their biologically active substances. Among these, marine algae are rich-sources of metabolites, which can be used to fight against oxidative stress and hence skin aging. These metabolites include, among others, mycosporine-like amino acids (MAAs), polysaccharides, sulphated polysaccharides, glucosyl glycerols, pigments, and polyphenols. This paper reviews the role of oxidative processes in skin damage and the action of the compounds from algae on the physiological processes to maintain skin health

Impact of enriched environment on tumor growth and adipokines secretion in a mouse model of mammary cancer

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Dietary fat without body weight gain increases in vivo MCF-7 human breast cancer cell growth and decreases natural killer cell cytotoxicity

High-calorie (HC) diet contributes to the increased incidence of obesity, which is a risk factor for breast cancer in postmenopausal women, and in particular for estrogen receptor (ER) positive tumors. This study investigated whether an HC diet increases human ER-positive breast cancer progression and modulates natural killer (NK) cell functions. Four-week-old female BALB/c athymic nude mice were fed a HC diet (5320 kcal/kg) or standard calorie diet (SC, 2820 kcal/kg) for 6 mo. After 5 mo, the mice were randomly implanted with MCF-7 breast cancer cells (SCT and HCT) or received an isovolumic injection (SC and HC) in both inguinal fat pads. Tumor growth was greater in the HCT group than in the SC group without change in body weight. The HC diet decreased the tumor expression of genes involved in the citrate cycle and in adiponectin and lipid metabolism but increased that of genes controlling glycolysis and angiogenesis. The tumor expression level of Ki67 was increased while that of the cleaved caspase 3 and the ER-beta and progesterone receptors was reduced. Tumor development in response to the HC diet was associated with smaller numbers and lower cytotoxicity of splenic NK cells. These results indicate that an HC diet without body weight gain increases ER-positive breast cancer cell proliferation and reduces tumor apoptosis. The underlying mechanisms might involve a downexpression of tumor hormonal receptor and reduced NK cell functions, and might also result in the regulation of genes involved in several cellular functions. (c) 2013 Wiley Periodicals, Inc

COX-2 expression in tumors from 12-week-old mice housed for 9 weeks in SE compare to EE.

<p>(A) Tumor excised from EE and SE mice, 21 days after the injection were cut and labeled by indirect immunofluorescence staining for COX-2 (green) and with DAPI as nuclear counterstain (blue). (B) Immunolabeled cells for COX-2 into the tumors were quantified using ImageJ software where the SE levels were set at 100% (n = 3 per group). (C) Tumor lysates were analyzed with western-blotting with the indicated antibodies. Photographs of chemiluminescent detection of the blot are shown. The relative abundance of each band to its own β-actin was quantified using ImageJ software, and the SE levels were set at 100%. (D) Tumors excised from SE and EE mice were cut and labeled by indirect immunofluorescence staining for COX-2 (green), leptin (red) and with DAPI as nuclear counterstain (blue). Right panels show overlays of the left and middle panels where the yellow shows co-localization of COX-2 and leptin. Right panels show boxed regions at high magnification. Scale bars: 100 µm. Data presented are the mean ± SEM; * = p<0.05, NS = not significant.</p

Effect of 9 weeks of SE and EE housing on body weight and body composition.

<p>(A) Schematic diagram illustrating the experimental protocol. (B) EE and SE cages (see additional supplementation video 1). (C) Mean body weight growth per housing condition (n = 25 per group). <i>Ad-libitum–fed mice</i> were housed in the EE or SE cages for 9 weeks prior to tumor injection. (D) Levels of weight gained by 9 and 12-week-old EE and SE mice since the fifth postnatal week (n = 25 per group). (E) Left panel: Analysis of total fat mass by magnetic resonance spectroscopy and normalized to total body mass of 12-week-old mice. Right panel: Analysis of excised visceral fat mass normalized to total body mass of 12-week-old (n = 6 per group). (F) Left panel: Representative hematoxylin and eosin-stained visceral fat sections from 12-week-old EE and SE mice. Right panel: Adipocyte area was measured using images of visceral fat sections and ImageJ software (n = 3 per group). (G) Left panel: Measurement of lean mass by magnetic resonance spectroscopy of 12-week-old mice (n = 7 per group). Right panel: Measurement of percent of lean mass by magnetic resonance spectroscopy, normalized to total body mass of 12-week-old (n = 7 per group). (H) Relative weight of soleus, gastrocnemius, spleen and liver of 12-week-old (n = 7). The SE levels were set at 100%. Data presented are the mean ± SEM; * = p<0.05, ** = p<0.01, *** = p<0.001, NS = not significant.</p

Effets of leptin and serum from 12-week-old mice housed in EE and SE for 9 weeks on EO771 cell proliferation.

<p>(A) EO771cells proliferation in response to leptin treatment at 0, 10, 25, 50, 100 and 200 ng/ml for 24 h (n = 3). Control levels (0 ng/ml) were set to 100%. (B) EO771 cells were cultured for 24 h with 1% of serum alone from 12-week-old mice housed in EE or SE cages for 9 weeks, or with 1% of serum pretreated with leptin-neutralizing antibody (n = 6 per group). Control levels (serum from SE mice) were set to 100%. Data presented are the mean ± SEM; * = p<0.05, ** = p<0.01, NS = not significant.</p

Analysis of normal mammary gland of 12-week-old mice housed in SE and EE cages for 9 weeks.

<p>(A, B) Carmine whole mount staining of the fourth mammary gland isolated from EE and SE mice. Lower panels show higher magnification of upper panels. (n = 6; scale bars; upper panels: 5 mm, lower panels: 250 µm). (C) Quantification of epithelial growth that corresponds to the distance from the lymph node to the end of epithelial tree, measured using a ruler in millimeters (mm) (n = 6). (D) Quantification of primary branches were defined as ducts extending from the nipple and terminating in an end bud (n = 6). (E) Quantification of the side-branching that corresponds to the number of branch points along the terminal ductal tips (n = 6). (F) Ductal epithelium observed in the mammary gland isolated from SE mice labeled by indirect immunofluorescence for keratin 14 (K14, green) and with DAPI as nuclear counterstain (blue). (G) Alveolar epithelium observed in the mammary gland isolated from EE mice labeled by indirect immunofluorescence for keratin 14 (K14, green) and with DAPI as nuclear counterstain (blue). (H–I) Normal mammary gland isolated from EE and SE mice labeled by indirect immunofluorescence for Ki-67 (red) and with DAPI as nuclear counterstain (blue). (J–K) Normal mammary gland isolated from SE mice labeled by indirect immunofluorescence for leptin (red), keratin 14 (K14, green) and DAPI (blue). (J) The staining pattern of leptin is showed in red. (K) The three color overlays are shown. (L–M) Normal mammary gland isolated from SE mice labeled by indirect immunofluorescence for leptin receptor (Ob-R, red), K14 (green) and DAPI (blue). (L) The staining pattern of leptin receptor is showed in red. (M) The three color overlays are shown. Scale bars: 50 µm. Data presented are the mean ± SEM; * = p<0.05, ** = p<0.01.</p