Anticancer Active Ingredient From Guiera Senegalensis

Anticancer Active Ingredient From Guiera Senegalensi

The Impact of Obesity, Adipose Tissue, and Tumor Microenvironment on Macrophage Polarization and Metastasis

International audienceTumor metastasis is a major cause of death in cancer patients. It involves not only the intrinsic alterations within tumor cells, but also crosstalk between these cells and components of the tumor microenvironment (TME). Tumorigenesis is a complex and dynamic process, involving the following three main stages: initiation, progression, and metastasis. The transition between these stages depends on the changes within the extracellular matrix (ECM), in which tumor and stromal cells reside. This matrix, under the effect of growth factors, cytokines, and adipokines, can be morphologically altered, degraded, or reorganized. Many cancers evolve to form an immunosuppressive TME locally and create a pre-metastatic niche in other tissue sites. TME and pre-metastatic niches include myofibroblasts, immuno-inflammatory cells (macrophages), adipocytes, blood, and lymphatic vascular networks. Several studies have highlighted the adipocyte-macrophage interaction as a key driver of cancer progression and dissemination. The following two main classes of macrophages are distinguished: M1 (pro-inflammatory/anti-tumor) and M2 (anti-inflammatory/pro-tumor). These cells exhibit distinct microenvironment-dependent phenotypes that can promote or inhibit metastasis. On the other hand, obesity in cancer patients has been linked to a poor prognosis. In this regard, tumor-associated adipocytes modulate TME through the secretion of inflammatory mediators, which modulate and recruit tumor-associated macrophages (TAM). Hereby, this review describes the cellular and molecular mechanisms that link inflammation, obesity, and cancer. It provides a comprehensive overview of adipocytes and macrophages in the ECM as they control cancer initiation, progression, and invasion. In addition, it addresses the mechanisms of tumor anchoring and recruitment for M1, M2, and TAM macrophages, specifically highlighting their origin, classification, polarization, and regulatory networks, as well as their roles in the regulation of angiogenesis, invasion, metastasis, and immunosuppression, specifically highlighting the role of adipocytes in this process

3D Cell Culture Systems: Tumor Application, Advantages, and Disadvantages

International audienceThe traditional two-dimensional (2D) in vitro cell culture system (on a flat support) has long been used in cancer research. However, this system cannot be fully translated into clinical trials to ideally represent physiological conditions. This culture cannot mimic the natural tumor microenvironment due to the lack of cellular communication (cell-cell) and interaction (cell-cell and cell-matrix). To overcome these limitations, three-dimensional (3D) culture systems are increasingly developed in research and have become essential for tumor research, tissue engineering, and basic biology research. 3D culture has received much attention in the field of biomedicine due to its ability to mimic tissue structure and function. The 3D matrix presents a highly dynamic framework where its components are deposited, degraded, or modified to delineate functions and provide a platform where cells attach to perform their specific functions, including adhesion, proliferation, communication, and apoptosis. So far, various types of models belong to this culture: either the culture based on natural or synthetic adherent matrices used to design 3D scaffolds as biomaterials to form a 3D matrix or based on non-adherent and/or matrix-free matrices to form the spheroids. In this review, we first summarize a comparison between 2D and 3D cultures. Then, we focus on the different components of the natural extracellular matrix that can be used as supports in 3D culture. Then we detail different types of natural supports such as matrigel, hydrogels, hard supports, and different synthetic strategies of 3D matrices such as lyophilization, electrospiding, stereolithography, microfluid by citing the advantages and disadvantages of each of them. Finally, we summarize the different methods of generating normal and tumor spheroids, citing their respective advantages and disadvantages in order to obtain an ideal 3D model (matrix) that retains the following characteristics: better biocompatibility, good mechanical properties corresponding to the tumor tissue, degradability, controllable microstructure and chemical components like the tumor tissue, favorable nutrient exchange and easy separation of the cells from the matrix

Contribution of adipose stem cells from obese subjects to hepato-or breast-carcinoma tumorogenesis, through promotion of Th17 cells

Introduction:As opposed with lean adipose tissues (AT), obese AT are heavily infiltrated with variety of inflammatory cells. Among them, Th17 cells are found not only within AT, but also in the periphery in obese subjects. We have demonstrated that AT-derived stem cells (ASC), or their progenitors, contribute to inflammation through promotion of Th-17 cells, provided that they are issued from obese-, but not lean-AT (Diabetes, 2015; Adipocyte, 2016). Because obesity is associated with increased prevalence of various cancers, including hepatic or breast cancer, we postulated herein that ASC-mediated promotion of Th17 cells might result in tumorogenesis progression.Materials and Methods:Human ASC were isolated from WAT of obese donors (obASC). Mononuclear cells (MNC) were collected from blood donors. PHA-activated co-cultures of obASC/MNC, which increase secretion of IL-17A, IL--6, were performed. Conditioned media (CM) were collected from such cultures, and added to HuH7 (hepato-carcinoma cell line) or MCF-7 / MDA-MB-231 (breast carcinoma cell line) cultures for 24h. mRNA profiles were measured by qRT-PCR. Expression of CXCR4 was measured by flow cytometry.Results:CM from 48 hr PHA-activated-ASC/MNC co-cultures enhanced IL--8 TNF-IL-6 mRNA expression in HUH7 by almost 700, 2, 3, 3, and 6-fold, respectively. A putative effect of CM on HUH7 invasiveness was supported by 2a –fold, and 3-fold increase in MMP9, and CXCR4 expression, respectively. In addition, CM also increased IL--6, IL-8 and VEGF-in both MCF-7 and MDA-MB-231 cell lines.Conclusion:Our results suggest that the interaction of ob ASC with immune cells contribute to an inflammatory environment, able to impact hepato- or breast-carcinoma cell secretion profile, and/or invasiveness, either through propagation of inflammatory cytokines outside adipose tissues, or ASC migration inside tumor

New Insights into Anticarcinogenic Properties of Adiponectin: A Potential Therapeutic Approach in Breast Cancer?

Document Type : Book ChapterInternational audienceObesity is a recognized breast cancer risk factor in postmenopausal women. A recent hypothesis suggests a major role for adipose tissue in carcinogenesis. During many years, the adipose tissue was only considered as a fat storage of energy. This tissue is now described as an endocrine organ secreting a large range of molecules called adipokines. Among these adipokines, adiponectin may play a major role in breast cancer. Plasma adiponectin levels were found to be decreased in cases of breast cancer and in obese patients. Adiponectin may act directly on breast cancer cells by inhibiting proliferation and angiogenesis or by stimulating apoptosis. Increasing adiponectin levels may be of major importance in the prevention and/or the treatment of breast cancer. This therapeutic approach may be of particular significance for obese patients. The beneficial effects of adiponectin and its possible therapeutic applications will be discussed in this review

Targeting Adiponectin in Breast Cancer

International audienceObesity and breast cancer are two major health issues that could be categorized as sincere threats to human health. In the last few decades, the relationship between obesity and cancer has been well established and extensively investigated. There is strong evidence that overweight and obesity increase the risk of postmenopausal breast cancer, and adipokines are the central players in this relationship. Produced and secreted predominantly by white adipose tissue, adiponectin is a bioactive molecule that exhibits numerous protective effects and is considered the guardian angel of adipokine. In the obesity–cancer relationship, more and more evidence shows that adiponectin may prevent and protect individuals from developing breast cancer. Recently, several updates have been published on the implication of adiponectin in regulating tumor development, progression, and metastases. In this review, we provide an updated overview of the metabolic signaling linking adiponectin and breast cancer in all its stages. On the other hand, we critically summarize all the available promising candidates that may reactivate these pathways mainly by targeting adiponectin receptors. These molecules could be synthetic small molecules or plant-based proteins. Interestingly, the advances in genomics have made it possible to create peptide sequences that could specifically replace human adiponectin, activate its receptor, and mimic its function. Thus, the obvious anti-cancer activity of adiponectin on breast cancer should be better exploited, and adiponectin must be regarded as a serious biomarker that should be targeted in order to confront this threatening disease

Obésité et cellules myoépithéliales : nouveau tandem impliqué dans la cancérogenèse mammaire ?

International audienceLe cancer du sein est le cancer le plus fréquent chez les femmes dans le monde. La surcharge pondérale et l'obésité sont désormais reconnues comme des facteurs de risque établis de cette pathologie chez les femmes ménopausées et sont également considérées comme responsables de taux de récurrence et de mortalité plus élevés. Des interactions réciproques ont été décrites entre les cellules adipeuses et cancéreuses, favorisant une plus grande prolifération des cellules cancéreuses, leur invasion et même leur résistance aux traitements anticancéreux. En outre, l'inflammation chronique de bas grade observée chez les personnes obèses amplifierait ces processus. Parmi l’ensemble des types cellulaires présents dans le sein, les cellules myoépithéliales (CME), situées à l'interface des cellules épithéliales et du stroma, sont considérées comme des cellules "suppressives de tumeurs". Lors de la transition d'un carcinome canalaire in situ à un cancer invasif, une désorganisation voire une disparition des CME est observée, renforçant la capacité des cellules cancéreuses à migrer. Le microenvironnement adipeux étant un acteur central dans la progression du cancer du sein, notre objectif était d'évaluer s'il pouvait être impliqué dans les modifications fonctionnelles des CME en particulier chez les patients obèses. Grâce à un modèle de co-culture, nous avons étudié l'impact des cellules souches adipeuses humaines (hASC) (lignée hMAD ou hASC provenant de femmes de poids normal (hASC20) ou obèses (hASC30)), différenciées ou non en adipocytes matures (AM20, AM30), sur la fonctionnalité des CME (lignée Hs578Bst) en mesurant les modifications de la prolifération, de l'apoptose, de l'expression des gènes (32 gènes, n=6) et des miARN (384 miRNA). En présence des hASC et des AM, une diminution de la viabilité des CME est observée (-23%,-10% avec hMAD et hASC respectivement, p<0,05;-11% avec AM, p<0,01) associée à une légère augmentation de l'apoptose. Les cellules adipeuses extraites de femmes normopondérées semblent favoriser la viabilité des CME par rapport à celles provenant de femmes obèses (-13% avec hASC20;-8% avec hASC30;-16% avec AM20,p<0,01;-8% avec AM30,ns). Le microenvironnement adipeux a également entrainé de nombreuses modifications d'expression de gènes impliqués dans le maintien de la matrice extracellulaire et amplifié l'expression de la leptine et des marqueurs inflammatoires (IL6, COX2, TNF). Enfin, 2 miRNA apparaissent comme des cibles potentielles des cellules adipeuses : miR-122-5p et miR-132-3p. Ces résultats confirment l’implication des cellules adipeuses et de leur sécrétome dans la perte de fonctionnalité des CME. Toutes ces perturbations pourraient donc être responsables de la perte du statut de suppresseur de tumeur des CME et favoriser le passage d'un carcinome in situ à un carcinome invasif particulièrement chez les patientes obèses.Projet financé par la Fondation ARC pour la recherche sur le cance

Differential Expression of Genes Induced by Resveratrol in Human Breast Cancer Cell Lines

International audienceThe phytoalexin, trans-resveratrol (RES), is a polyphenolic compound found in plants and fruits that seems to have a wide spectrum of biological activities. It has been found to possess cancer chemopreventive effects by inhibiting diverse cellular events associated with tumor initiation, promotion, and progression. RES is also a phytoestrogen, which binds to and activates estrogen receptors (ERs) that regulate the transcription of estrogen-responsive target genes. We used two human breast tumor cell lines (MCF7 and MBA-MB-231) and one fibrocystic breast cell line (MCF10a) to examine whether RES altered mRNA expression of genes that are involved in biological pathway frequently altered during carcinogenesis. Two GEarray systems were used to screen the differentially expressed genes between RES-treated cells and control cells. The differentially expressed genes were analyzed further by quantitative reverse transcriptase polymerase chain reaction. Here, we demonstrate that RES regulates mRNA expression of several genes involved in cell cycle control, apoptosis, metastasis, cell-cell adhesion, and ER signaling pathway. This effect of RES on the gene expression appears in correlation with chemoprevention activities of RES described previously. RES is also found to be more active in ER+ than ER- cells

Leptin, adipocytes and breast cancer: Focus on inflammation and anti-tumor immunity

International audienceMore than one million new cases of breast cancer are diagnosed worldwide each year and more than 400,000 deaths are caused by the disease. The origin of this pathology is multifactorial and involved genetic, hormonal, environmental and nutritional factors including obesity in postmenopausal women. The role played by the adipose tissue and their secretions, ie adipokines, is beginning to be recognized. Plasma adipokine levels, which are modulated during obesity, could have "remote" effects on mammary carcinogenesis. Breast cancer cells are surrounded and locally influenced by an adipocyte microenvironment, which is probably more extensive in obese people. Hence, leptin appears to be strongly involved in mammary carcinogenesis and may contribute to the local pro-inflammatory mechanisms, especially in obese patients, who have increased metastatic potential and greater risk of mortality. This review presents the multifaceted role of leptin in breast cancer development and the different molecular pathways involved such as inflammation, oxidative stress and antitumor immunity

Contribution of obese adipose tissue-derived stem cells to hepato-or breast-carcinoma inflammation, through promotion of Th17 cells and activation of IL-1b by monocytes

Background and aims:As opposed with lean adipose tissues (AT), obese AT are heavily infiltrated with variety of inflammatory cells such as macrophages and Th17 cells. Obesity-mediated chronic low-grade inflammation is known to contribute to tumor progression in various cancers, including hepatic and breast cancers. Because we have previous-ly demonstrated, using co-culture experiments, that obese AT-derived stem cells (obASC) contribute to AT inflammation through promotion of Th17 cells, and activation of IL-1β-secreting monocytes, we postulated herein that such inflammatory environment could contribute to tumor progression in cancer-suffering obese patients.Materials and methods:Human ASC were isolated from AT of obese donors. Mononuclear cells (MNC) were collected from healthy blood donors. Co-cultures of obASC and MNC were activated for 48 hours with phytohemagglutinin A ( PHA), a T cell mitogen, or not. Conditionned media (CM) were collected, and added for 24h to cultures of HuH7 (hepatocarinoma cell line) or of two breast carcinoma cell lines, i.e MCF-7, or MDA-MB-231. Levels of inflammatory or angiogenic gene expression were evaluated by qRT-PCR. Expression of CXCR4 (a marker of invasiveness) was measured by flow cytometry in the HuH7 cell line.Results:CM from PHA-activated-obASC/MNC co-cultures enhanced IL-1 β ,IL-8andVEGF α mRNA expression in HuH7 cells by 1942.2, 45.7 and 6.1 -fold, respectively, as compared with no treatment. A putative effect of CM on HuH7 invasiveness was supported by a 2- and 3-fold increase in MMP-9, and CXCR4 expression, respectively. In addition, IL-1β, IL-8 and VEGF-α mRNA expression were increased by 34.3, 33.2, and 2.97 fold respectively in MCF-7 cells, and by 85.8, 52.0 , and 1.34 fold respectively, in MDA-MB-231 cells. These results indicated thus a differential sensitivity of cancer cell lines to CM from PHA-activated-ob ASC/MNC co-cultures, with a preponderant increase of IL-1 β mRNA levels in hepatocarcinoma cells versus a similar increase of IL-1β and IL-8 gene expression in breast carcinoma cells.Conclusion:Our results suggest that in cancer-suffering obese patients, interaction of obASC with AT-infiltrating immune cells contribute to the establishment of an inflammatory environment, propitious to tumor inflammation and/or tumor migration. Whether this inflammation could occur through propagation of obese AT inflammatory environment towards tumors, or through migration of ASC inside tumors and then inter-action with tumor infiltrating immune cells, remain to be explored