Implications of adrenomedullin secreted by cancer-associated fibroblasts in tumor growth

Le cancer du sein est la première cause de mortalité chez la femme par cancer. Différents travaux ont montré l’implication des fibroblastes associés au cancer (CAFs) dans la résistance thérapeutique, ainsi que leur rôle dans le développement de cancer du sein. L’adrénomédulline (AM) joue un rôle crucial dans la croissance des tumeurs. Dans notre étude, nous nous sommes interrogés sur l’apport de l’AM sécrétée par la composante majeure du stroma tumoral les CAFs, dans le développement du cancer du sein. Dans cette étude nous avons montré que les CAFs isolés à partir des tumeurs issues du cancer du sein, présentent une augmentation de l’expression du système d’AM (AM et ses récepteurs) par rapport aux fibroblastes non activés (NHDFs). Nos études dans le modèle d’angiogenèse in vivo montrent que les CAFs sont plus compétents à mettre en place une vascularisation stable et fonctionnelle par rapport aux NHDFs. Cependant, le traitement des souris avec des anticorps anti récepteurs de l’AM (αAMRs) bloque la vascularisation. De plus, les xénogreffes issues du mélange MCF-7/CAFs génèrent des tumeurs plus importantes par rapport aux tumeurs issues de MCF-7 seules ou combinées aux NHDFs. Les souris traitées par voie i.p. avec des αAMRs ou l’antagoniste AM22-52, montrent une inhibition de la croissance tumorale des xénogreffes. Les études immunohistochimiques montrent une vascularisation bien établie chez le groupe MCF-7/CAFs, qui est altérée suite au blocage du système de l’AM.Notre étude montre le rôle important de l’AM sécrétée par les CAFs dans le processus de la tumorigenèse du cancer du sein.Breast cancer is the leading cause of death among women with cancer. Various studies have shown the involvement of cancer associated fibroblasts (CAFs) in this therapeutic resistance and their role in the development of the tumor. Adrenomedullin (AM) plays a critical role in tumor growth. In our study, we asked about the contribution of AM secreted by the major component of the tumor stroma CAFs in breast cancer development. In this study, we demonstrate that CAFs isolated from tumors derived from breast cancer, showed an increase in the expression of AM (AM and its receptors) compared to non-activated fibroblasts (NHDFs). Our studies in vivo angiogenesis model shows that CAFs are more competent to set-up a stable and functional vasculature compared to NHDFs. However, treatment of mice with antibodies anti AM receptor (αAMRs) blocks vascularization, indicating the role of AM secreted by CAFs in the establishment of neovascularization. Additionally, xenografts from MCF-7 mixture / CAFs generate larger tumors compared to tumors from MCF-7 alone or combined with NHDFs. Mice treated, mice treated by intra-peritoneal (i.p.) injection with αAMRs or antagonist AM22-52, show inhibition of tumor growth of xenografts. Immunohistochemical studies show an established vasculature in the MCF-7 / CAFs group, which is impaired due to the blocking of the AM system.Our study shows the important role of the AM secreted by CAFs in the process of breast cancertumorigenesis. It provides an evidence of the effectiveness of a therapy anti-AM, which will target as one of the most predominant components of breast cancer tumor microenvironment

In Vitro and In Vivo Characterization of MCT1 Inhibitor AZD3965 Confirms Preclinical Safety Compatible with Breast Cancer Treatment

To survive and proliferate in solid tumors, cancer cells adapt and evolve rapidly in microenvironments where oxygen and substrate bioavailability fluctuates over time and space. This creates metabolic heterogeneity. Cancer cells can further cooperate metabolically, for example by swapping glycolytic end-product lactate for blood-borne glucose. This type of cooperation can be targeted therapeutically, since transmembrane lactate exchanges are facilitated by lactate-proton symporters of the monocarboxylate (MCT) family. Among new drugs, AZD3965 is a first-in-class selective MCT1 inhibitor currently tested in Phase I/II clinical trials for patients with different types of cancers. Because MCT1 can function bidirectionally, we tested here whether and how malignant and nonmalignant cells adapt their metabolism and MCT repertoire when AZD3965 inhibits either lactate import or export. Using breast-associated malignant and nonmalignant cell lines as models, we report that AZD3965 is not directly cytotoxic. In the presence of glucose and glutamine, oxidative cells can survive when lactate uptake is blocked, and proliferating cells compensate MCT1 inhibition by overexpressing MCT4, a specialized facilitator of lactate export. Phenotypic characterization of mice focusing on metabolism, muscle and brain physiology found partial and transient memory retention defect as sole consequence of MCT1 inhibition by AZD3965. We therefore conclude that AZD3965 is compatible with anticancer therapy

Poetics of the female detective novel : the case of Catherine Simon, Nicole Ben Youssef and Azza Filali

La littérature féminine est récente au Maghreb. Le genre policier, qui a fait son apparition sous la plume d’auteures non maghrébines, est également récent dans cette sphère littéraire. Notre recherche porte sur l’étude du roman policier écrit par des auteures françaises et maghrébines confondues, et se répartit en trois volets. Il s’agit ici d’examiner la structure de chaque roman du corpus ainsi que les caractéristiques, les enjeux esthétiques et politiques de cette écriture francophone et féminine. Le contexte d’émergence de ces récits correspond à la fin des années 1990, une période d’instabilité et de violence socio-politiques en Algérie. Aussi, les œuvres algériennes publiées par Catherine Simon ne se détachent pas de ce climat de turbulence, qu’ils dépeignant cette phase sous forme de fiction policière. Les romans tunisiens de Nicole Ben Youssef, quant à eux, s’éloignent de toute actualité politique ou événements socio-historiques, et confirment leur appartenance au récit policier ludique. Par ailleurs, le récit d’Azza Filali emprunte au genre policier quelques caractéristiques, sans pour autant y appartenir de manière explicite ou exclusive. Il est question dans ce roman d’une fiction où plusieurs genres s’entremêlent : fiction fantastique, conte absurde et récit policier. Cette étude a pour objectif d’explorer et d’interpréter les singularités de l’écriture féminine policière au Maghreb. Nous mobiliserons, tout au long de ce travail, les études poétiques menées sur le roman policier, la théorie de la littérature, mais également les études francophones et postcoloniales, ainsi que les critiques sur le genre. Par ailleurs, nous étendrons notre réflexion aux analyses sur le nouveau roman.Women's literature is recent in the Maghreb. The detective’s feminine novel, which first appeared in the Maghreb area under the pen of non-North African authors, is also recent in this literary sphere. Our research focuses on the study of detective novels written by French and North African authors, and is divided into three parts. The aim here is to examine the structure of each novel in the corpus as well as the characteristics, the aesthetic and political issues of this francophone and feminine writing. The context of the emergence of these novels corresponds to the end of the 1990s, this period represents a socio-political instability and violence in Algeria. The reason why the algerian novels published by Catherine Simon don’t stand out from this climate of turbulence, as they reflect the socio-political problems in the form of detective fiction. The Tunisian novels of Nicole Ben Youssef, meanwhile, keep a distance from any political news or socio-historical events, and confirm their belonging to the playful detective story. However, Azza Filali's novel borrows some characteristics from the detective genre, without however belonging to them explicitly or exclusively. This novel is about a fiction where several genres intermingle: fantasy fiction, absurd tale and detective story. Our study aims to explore and interpret the particularities of feminine criminal writing in the Maghreb area. We will focus, throughout of our research on the poetic studies, carried out on the detective novel, the theory of literature, but also francophone and postcolonial studies, as well as the critiques on the gender. Finally, we will extend our reflection to the analyzes on the new novel

Poetics of the female detective novel : the case of Catherine Simon, Nicole Ben Youssef and Azza Filali

La littérature féminine est récente au Maghreb. Le genre policier, qui a fait son apparition sous la plume d’auteures non maghrébines, est également récent dans cette sphère littéraire. Notre recherche porte sur l’étude du roman policier écrit par des auteures françaises et maghrébines confondues, et se répartit en trois volets. Il s’agit ici d’examiner la structure de chaque roman du corpus ainsi que les caractéristiques, les enjeux esthétiques et politiques de cette écriture francophone et féminine. Le contexte d’émergence de ces récits correspond à la fin des années 1990, une période d’instabilité et de violence socio-politiques en Algérie. Aussi, les œuvres algériennes publiées par Catherine Simon ne se détachent pas de ce climat de turbulence, qu’ils dépeignant cette phase sous forme de fiction policière. Les romans tunisiens de Nicole Ben Youssef, quant à eux, s’éloignent de toute actualité politique ou événements socio-historiques, et confirment leur appartenance au récit policier ludique. Par ailleurs, le récit d’Azza Filali emprunte au genre policier quelques caractéristiques, sans pour autant y appartenir de manière explicite ou exclusive. Il est question dans ce roman d’une fiction où plusieurs genres s’entremêlent : fiction fantastique, conte absurde et récit policier. Cette étude a pour objectif d’explorer et d’interpréter les singularités de l’écriture féminine policière au Maghreb. Nous mobiliserons, tout au long de ce travail, les études poétiques menées sur le roman policier, la théorie de la littérature, mais également les études francophones et postcoloniales, ainsi que les critiques sur le genre. Par ailleurs, nous étendrons notre réflexion aux analyses sur le nouveau roman.Women's literature is recent in the Maghreb. The detective’s feminine novel, which first appeared in the Maghreb area under the pen of non-North African authors, is also recent in this literary sphere. Our research focuses on the study of detective novels written by French and North African authors, and is divided into three parts. The aim here is to examine the structure of each novel in the corpus as well as the characteristics, the aesthetic and political issues of this francophone and feminine writing. The context of the emergence of these novels corresponds to the end of the 1990s, this period represents a socio-political instability and violence in Algeria. The reason why the algerian novels published by Catherine Simon don’t stand out from this climate of turbulence, as they reflect the socio-political problems in the form of detective fiction. The Tunisian novels of Nicole Ben Youssef, meanwhile, keep a distance from any political news or socio-historical events, and confirm their belonging to the playful detective story. However, Azza Filali's novel borrows some characteristics from the detective genre, without however belonging to them explicitly or exclusively. This novel is about a fiction where several genres intermingle: fantasy fiction, absurd tale and detective story. Our study aims to explore and interpret the particularities of feminine criminal writing in the Maghreb area. We will focus, throughout of our research on the poetic studies, carried out on the detective novel, the theory of literature, but also francophone and postcolonial studies, as well as the critiques on the gender. Finally, we will extend our reflection to the analyzes on the new novel

Metabolic and non-metabolic pathways that control cancer resistance to anthracyclines.

Anthracyclines Doxorubicin, Epirubicin, Daunorubicin and Idarubicin are used to treat a variety of tumor types in the clinics, either alone or, most often, in combination therapies. While their cardiotoxicity is well known, the emergence of chemoresistance is also a major issue accounting for treatment discontinuation. Resistance to anthracyclines is associated to the acquisition of multidrug resistance conferred by overexpression of permeability glycoprotein-1 or other efflux pumps, by altered DNA repair, changes in topoisomerase II activity, cancer stemness and metabolic adaptations. This review further details the metabolic aspects of resistance to anthracyclines, emphasizing the contributions of glycolysis, the pentose phosphate pathway and nucleotide biosynthesis, glutathione, lipid metabolism and autophagy to the chemoresistant phenotype

Cognitive trajectories in relapsing-remitting multiple sclerosis: Evidence of multiple evolutionary trends.

Cognitive impairment (CI) frequently occurs in multiple sclerosis (MS) and is assumed to increase over time. However, recent studies have suggested that the evolution of cognitive status in patients with MS may be more heterogeneous than expected. Predicting CI remains also challenging, and longitudinal studies exploring the baseline determinants of cognitive performances are limited. No studies have explored the predictive value of patient-reported outcome measures (PROMs) regarding future CI. To explore the evolutionary patterns of cognitive status in a cohort of RRMS patients initiating a new disease modifying treatment (DMT), and to determine whether PROMs may have a predictive value for future CI. The present prospective study is a 12-month follow-up of a cohort of 59 RRMS patients who underwent yearly a comprehensive, multiparametric assessment combining clinical (with EDSS assessment), neuropsychological (BVMT-R, SDMT, CVLT-II), MRI-derived metrics and a set of self-reported questionnaires. Lesion and brain volumes were analyzed and processed by the automated MSmetrix® software (Icometrix®, Leuven, Belgium). Spearman's correlation coefficient was used to evaluate the association of collected variables. A longitudinal logistic regression analysis was performed to find baseline correlates of CI at 12 months (T1). A total of 33 patients (56%) were defined as cognitively impaired at baseline, and 20 (38%) were defined as impaired at follow-up after 12 months. The mean raw scores and Z-scores of all the cognitive tests were significantly improved at T1 (p < 0.05). There was a statistically significant improvement in most PROM scores at T1 (p < 0.05) in comparison with baseline scores. Among the variables assessed, lower education and physical disability level at baseline correlated with impaired SDMT (OR: 1.68, p = 0.01; OR: 3.10, p = 0.02, respectively) and impaired BVMT-R (OR: 4.08, p=<0.001; OR: 4.82, p = 0.001, respectively) at T1. Neither baseline PROMs nor MRI volumetric parameters were predictive of cognitive performances at T1. These findings provide additional evidence that evolution of CI in MS may be a dynamic phenomenon and will not usually follow an inevitable, declining trajectory, and do not support the utility of PROMs in predicting CI in RRMS. The present study is still ongoing to determine whether our findings are confirmed at 2 and 3 years of follow-up

Patient-reported outcome measurements in a selective cohort of relapsing-remitting multiple sclerosis patients: relationships with physical disability, cognitive impairment, and MRI-derived metrics.

The added value of patient-reported outcome measures (PROMs) in addition to standard clinical outcome tools in the assessment of relapsing-remitting multiple sclerosis (RRMS) patients' status is increasingly recognized. PROMs facilitate the detection of hidden aspects of MS and help to integrate the patient's subjective experience of health-related quality of life (HRQoL) status and treatment satisfaction in a holistic way. However, the relationship between PROMs and clinical and cognitive status has been scarcely investigated up to now. To investigate the association of PROMs with physical and cognitive disability in a cohort of RRMS patients at initiation of a new disease-modifying treatment. In this cross-sectional bicenter study, 59 consecutive RRMS patients underwent neurological examination with EDSS assessment, comprehensive cognitive tests (BVMT-R, SDMT, CVLT-II) and a set of self-reported questionnaires. Lesion and brain volumes were analyzed and processed by the automated MSmetrix software (Icometrix, Leuven, Belgium). Spearman's correlation coefficient was used to evaluate the association of collected variables. A cross-sectional logistic regression analysis was performed to find baseline correlates of cognitive impairment. Of the 59 RRMS patients (mean age 39 ± 9.8 years, 79.7% female, median EDSS 2.0), 33 (56%) had cognitive impairment. While almost all dimensions of health, explored by PROMs, were impacted in the overall sample, no significant difference was observed in patients with and without cognitive impairment. All PROMs were significantly associated with EDSS (R = 0.37-0.55; p < 0.05), except for the psychological component of MSIS-29, BDI and DEX-Q scores. No significant correlation was found between PROMs and cognitive performances. The cross-sectional logistic regression analysis included age, gender (female), education, EDSS, hippocampus and FLAIR lesion volumes as significant predictors of cognitive impairment. The data highlight that PROMs provide valuable information on the well-being of PwMS closely paralleling the extent of MS-related disability, as measured by the EDSS. Additional research should determine the relevance of PROMs as longitudinal outcome measures

A Distinct Anti-EBV DNase Profile in Patients with Undifferentiated Nasopharyngeal Carcinoma Compared to Classical Antigens

Nasopharyngeal cancer (NPC) is a prevalent type of cancer that often takes the form of undifferentiated carcinoma in the Maghreb region. It affects people of all ages. NPC diagnosis, mainly based on detecting Epstein-Barr virus (EBV), has not been well evaluated in North Africa. We compared the classical EBV serological tests using indirect immunofluorescence to the detection of EBV DNase antibodies by immunoblot in Algerian NPC patients. Significant variations were observed among different age groups of patients regarding the presence of VCA-IgA antibodies (0–14 and ≥30 years old, p p p p < 0.05). Differences were also noted in the titers of IgA anti-VCA and anti-EA antibodies across the three age groups. Some patients under the age of 30 with detectable IgG anti-VCA antibodies had undetectable IgA anti-VCA antibodies. These patients had a strong anti-DNase IgA response. However, older individuals had a higher level of anti-DNase IgG. Before treatment, children had strong DNase reactivity as indicated by specific IgA antibodies. Young adults had high IgA anti-DNase response, but the elderly (90.9%) had a lower response for these antibodies. Following therapy, the children retained high levels of IgA anti-DNase antibodies, and 66% of the young adults demonstrated robust antibody reactivity against DNase. In contrast, IgG responses to anti-DNase were low in children. This study demonstrated the utility of anti-DNase responses in the diagnosis and prognosis of NPC

In Vitro and In Vivo Characterization of MCT1 Inhibitor AZD3965 Confirms Preclinical Safety Compatible with Breast Cancer Treatment

To survive and proliferate in solid tumors, cancer cells adapt and evolve rapidly in microenvironments where oxygen and substrate bioavailability fluctuates over time and space. This creates metabolic heterogeneity. Cancer cells can further cooperate metabolically, for example by swapping glycolytic end-product lactate for blood-borne glucose. This type of cooperation can be targeted therapeutically, since transmembrane lactate exchanges are facilitated by lactate-proton symporters of the monocarboxylate (MCT) family. Among new drugs, AZD3965 is a first-in-class selective MCT1 inhibitor currently tested in Phase I/II clinical trials for patients with different types of cancers. Because MCT1 can function bidirectionally, we tested here whether and how malignant and nonmalignant cells adapt their metabolism and MCT repertoire when AZD3965 inhibits either lactate import or export. Using breast-associated malignant and nonmalignant cell lines as models, we report that AZD3965 is not directly cytotoxic. In the presence of glucose and glutamine, oxidative cells can survive when lactate uptake is blocked, and proliferating cells compensate MCT1 inhibition by overexpressing MCT4, a specialized facilitator of lactate export. Phenotypic characterization of mice focusing on metabolism, muscle and brain physiology found partial and transient memory retention defect as sole consequence of MCT1 inhibition by AZD3965. We therefore conclude that AZD3965 is compatible with anticancer therapy

Stromal fibroblasts present in breast carcinomas promote tumor growth and angiogenesis through adrenomedullin secretion

International audienceTumor-or cancer-associated fibroblasts (TAFs or CAFs) are active players in tumorigenesis and exhibit distinct angiogenic and tumorigenic properties. Adrenomedullin (AM), a multifunctional peptide plays an important role in angiogenesis and tumor growth through its receptors calcitonin receptor-like receptor/receptor activity modifying protein-2 and-3 (CLR/RAMP2 and CLR/RAMP3). We show that AM and AM receptors mRNAs are highly expressed in CAFs prepared from invasive breast carcinoma when compared to normal fibroblasts. Immunostaining demonstrates the presence of immunoreactive AM and AM receptors in the CAFs (n = 9). The proliferation of CAFs is decreased by anti-AM antibody (αAM) and anti-AM receptors antibody (aAMR) treatment, suggesting that AM may function as a potent autocrine/paracrine growth factor. Systemic administration of aAMR reduced neovascularization of in vivo Matrigel plugs containing CAFs as demonstrated by reduced numbers of the vessel structures, suggesting that AM is one of the CAFs-derived factors responsible for endothelial cell-like and pericytes recruitment to built a neovascularization. We show that MCF-7 admixed with CAFs generated tumors of greater volume significantly different from the MCF-7 xenografts in nude mice due in part to the induced angiogenesis. aAMR and AM 22-52 therapies significantly suppressed the growth of CAFs/MCF-7 tumors. Histological examination of tumors treated with AM 22-52 and aAMR showed evidence of disruption of tumor vasculature with depletion of vascular endothelial cells, induced apoptosis and decrease of tumor cell proliferation. Our findings highlight the importance of CAFs-derived AM pathway in growth of breast carcinoma and in neovascularization by supplying and amplifying signals that are essential for pathologic angiogenesis