[Ethical principles for the design of a clinical trial in oncology]. / Règles éthiques pour la conception d'un essai clinique en oncologie.

Clinical research in the area of cancer is of utmost importance in order to improve patient care, both in terms of overall survival and quality of life. The implementation of clinical trials on medicinal products, now falling under EU Regulation 536/2014, is conditioned on prior scientific authorisation from the French National Agency for the Safety of Medicines and Health Products and a favorable ethical opinion from a Research Ethics Committee (REC). OBJECTIVE: The objective of this work is to report on the main problematic issues identified during the evaluation of oncology dossiers by the REC in order to present the expected elements and thus optimise the evaluation procedures. METHODS: The National Conference of the Research Ethics Committees analysed the questions raised by the REC during their evaluation of clinical trials of oncology drugs submitted to the European information system in 2022. RESULTS: Out of a total of fourteen dossiers, nine were subject to ethical questions on the protocol and all dossiers required modifications to the information documents. DISCUSSION: The heterogeneous quality of the dossiers reminds the need to submit well-argued, methodologically robust protocols with supervised research procedures that are safe for the participants. The drafting of information documents needs to be thoroughly reconsidered in order to present clear, concise, loyal and respectful documents for patients' rights.

[The role of physicians in patient and family adherence to genetic testing]. / Rôle des médecins dans l'adhésion des patients et des familles à la réalisation d'analyses de caractéristiques génétiques.

INTRODUCTION: More and more French cancer patients are offered by their physicians having their genetic characteristics analyzed (diagnosis, adaptation of treatment plans, etc.). In oncology, considering the development of personalized medicine, these analyses are commonplace. Analyses of germline (hereditary) genetic characteristics require information from patients who must sign an informed consent (article 16.10 of the Civil Code and articles L. 1131-3 and L. 1122-1-1 of the Public Health Code). However, prescribing physicians are rarely geneticists and have little training in genetics. Patients report that few are able to answer their questions and often sign a consent that is not truly informed. METHODS: To identify the genetic knowledge and training needs of prescribers, we conducted an online survey of physicians prescribing genetic testing in oncology between January and March 2020. The survey consisted of 17 closed questions and 3 open questions. RESULTS: We obtained 35 usable questionnaires which show that 50% of the prescribing physicians questioned lack knowledge of genetics, but do not express a need for training. They were interested in the provision of a digital teaching aid for patients. DISCUSSION: We have therefore made a film for patients, available in free access, which aims to shed light on the analysis of genetic characteristics. The film helps physicians to explain the offered analyses and their consequences (https://youtu.be/5lWUSsteavs).

PPARγ activation modulates the balance of peritoneal macrophage populations to suppress ovarian tumor growth and tumor-induced immunosuppression.

BACKGROUND: Ovarian adenocarcinoma (OVAD) frequently metastasizes to the peritoneal cavity and manifests by the formation of ascites, which constitutes a tumor-promoting microenvironment. In the peritoneal cavity, two developmentally, phenotypically and functionally distinct macrophage subsets, immunocompetent large peritoneal macrophages (LPM) and immunosuppressive small peritoneal macrophages (SPM), coexist. Because peroxisome proliferator-activated receptor γ (PPARγ) is a critical factor participating in macrophage differentiation and cooperates with CCAAT/enhancer binding protein ß (C/EBPß), a transcription factor essential for SPM-to-LPM differentiation, PPARγ could be also involved in the regulation of SPM/LPM balance and could be a promising therapeutic target. METHODS: To evaluate the 15(S)-hydroxyeicosatetraenoic acid (HETE), a PPARγ endogenous ligand, impact on ovarian tumor growth, we intraperitoneally injected 15(S)-HETE into a murine ovarian cancer model. This experimental model consists in the intraperitoneally injection of ID8 cells expressing luciferase into syngeneic C57BL/6 female mice. This ID8 orthotopic mouse model is a well-established experimental model of end-stage epithelial OVAD. Tumor progression was monitored using an in vivo imaging system. Peritoneal immune cells in ascites were analyzed by flow cytometry and cell sorting. To determine whether the impact of 15(S)-HETE in tumor development is mediated through the macrophages, these cells were depleted by injection of liposomal clodronate. To further dissect how 15(S)-HETE mediated its antitumor effect, we assessed the tumor burden in tumor-bearing mice in which the PPARγ gene was selectively disrupted in myeloid-derived cells and in mice deficient of the recombination-activating gene Rag2. Finally, to validate our data in humans, we isolated and treated macrophages from ascites of individuals with OVAD. RESULTS: Here we show, in the murine experimental model of OVAD, that 15(S)-HETE treatment significantly suppresses the tumor growth, which is associated with the differentiation of SPM into LPM and the LPM residency in the peritoneal cavity. We demonstrate that C/EBPß and GATA6 play a central role in SPM-to-LPM differentiation and in LPM peritoneal residence through PPARγ activation during OVAD. Moreover, this SPM-to-LPM switch is associated with the increase of the effector/regulatory T-cell ratio. Finally, we report that 15(S)-HETE attenuates immunosuppressive properties of human ovarian tumor-associated macrophages from ascites. CONCLUSION: Altogether, these results promote PPARγ as a potential therapeutic target to restrain OVAD development and strengthen the use of PPARγ agonists in anticancer therapy.

[Requests for genetic characteristics analysis by sequencing in clinical research: Legal and ethical considerations]. / Les demandes d'analyses des caractéristiques génétiques par séquençage dans les recherches cliniques : considérations juridiques et éthiques.

More and more practitioners are being led to propose to their patients an analysis of their genetic characteristics (structural or functional genomics) either to confirm a diagnosis or to adapt a treatment (personalized medicine). Patients treated in hospitals are also offered analyses of their genetic characteristics either because they have not objected to their biological samples taken during care being used for research, or because they are included in a clinical study. The revised bioethics laws for application on 1/1/2021 provide a complete and clear framework for practices concerning genetics. However, most patients or healthy volunteers who have agreed (or not objected) to genetic testing are not aware of the potential consequences for them and their families. This is mostly due to a lack of information (inclusion of a sample without seeking express consent) or partial information due to either a lack of training of the prescriber himself or, in the context of clinical trials, an inadequate information leaflet. In order to help prescribers and evaluators of clinical trial applications to propose fair and clear information and consent letters to patients and thus ensure patient protection, we have produced an exegesis of the legal and ethical elements on which to base a proposal for genetic characteristics analysis. We include examples of requests for analysis of genetic characteristics, specifying the cases in which the research is authorized or not and mentioning the corresponding legal texts. We have generated here a useful pedagogical tool for all prescribers, researchers or simply French citizens.

Monoamine Oxidase Inhibitors Prevent Glucose-Dependent Energy Production, Proliferation and Migration of Bladder Carcinoma Cells.

Bladder cancer is the 10th most common cancer in the world and has a high risk of recurrence and metastasis. In order to sustain high energetic needs, cancer cells undergo complex metabolic adaptations, such as a switch toward aerobic glycolysis, that can be exploited therapeutically. Reactive oxygen species (ROS) act as key regulators of cancer metabolic reprogramming and tumorigenesis, but the sources of ROS remain unidentified. Monoamine oxidases (MAOs) are mitochondrial enzymes that generate H2O2 during the breakdown of catecholamines and serotonin. These enzymes are particularly important in neurological disorders, but recently, a new link between MAOs and cancer has been uncovered, involving their production of ROS. At present, the putative role of MAOs in bladder cancer has never been evaluated. We observed that human urothelial tumor explants and the bladder cancer cell line AY27 expressed both MAO-A and MAO-B isoforms. Selective inhibition of MAO-A or MAO-B limited mitochondrial ROS accumulation, cell cycle progression and proliferation of bladder cancer cells, while only MAO-A inhibition prevented cell motility. To test whether ROS contributed to MAO-induced tumorigenesis, we used a mutated form of MAO-A which was unable to produce H2O2. Adenoviral transduction of the WT MAO-A stimulated the proliferation and migration of AY27 cells while the Lys305Met MAO-A mutant was inactive. This was consistent with the fact that the antioxidant Trolox strongly impaired proliferation and cell cycle progression. Most interestingly, AY27 cells were highly dependent on glucose metabolism to sustain their growth, and MAO inhibitors potently reduced glycolysis and oxidative phosphorylation, due to pyruvate depletion. Accordingly, MAO inhibitors decreased the expression of proteins involved in glucose transport (GLUT1) and transformation (HK2). In conclusion, urothelial cancer cells are characterized by a metabolic shift toward glucose-dependent metabolism, which is important for cell growth and is under the regulation of MAO-dependent oxidative stress.

Imprinting of Mesenchymal Stromal Cell Transcriptome Persists even after Treatment in Patients with Multiple Myeloma.

INTRODUCTION: Multiple myeloma (MM) is a B-cell neoplasm characterized by clonal expansion of malignant plasma cells (MM cells) in the bone-marrow (BM) compartment. BM mesenchymal stromal cells (MSC) from newly diagnosed MM patients were shown to be involved in MM pathogenesis and chemoresistance. The patients displayed a distinct transcriptome and were functionally different from healthy donors' (HD) MSC. Our aim was to determine whether MM-MSC also contributed to relapse. METHODS: We obtained and characterized patients' MSC samples at diagnosis, two years after intensive treatment, without relapse and at relapse. RESULTS: Transcriptomic analysis revealed differences in gene expression between HD and MM-MSC, whatever the stage of the disease. An easier differentiation towards adipogenesis at the expense of osteoblatogeneis was observed, even in patients displaying a complete response to treatment. Although their transcriptome was similar, we found that MSC from relapsed patients had an increased immunosuppressive ability, compared to those from patients in remission. CONCLUSION: We demonstrated that imprinting of MSC transcriptome demonstrated at diagnosis of MM, persisted even after the apparent disappearance of MM cells induced by treatment, suggesting the maintenance of a local context favorable to relapse.

Circulating CD14high CD16low intermediate blood monocytes as a biomarker of ascites immune status and ovarian cancer progression.

BACKGROUND: Besides the interest of an early detection of ovarian cancer, there is an urgent need for new predictive and prognostic biomarkers of tumor development and cancer treatment. In healthy patients, circulating blood monocytes are typically subdivided into classical (85%), intermediate (5%) and non-classical (10%) populations. Although these circulating monocyte subsets have been suggested as biomarkers in several diseases, few studies have investigate their potential as a predictive signature for tumor immune status,tumor growth and treatment adaptation. METHODS: In this study, we used a homogeneous cohort of 28 chemotherapy-naïve patients with ovarian cancer to evaluate monocyte subsets as biomarkers of the ascites immunological status. We evaluated the correlations between circulating monocyte subsets and immune cells and tumor burden in peritoneal ascites. Moreover, to validate the use of circulating monocyte subsets tofollow tumor progression and treatment response, we characterized blood monocytes from ovarian cancer patients included in a phase 1 clinical trial at baseline and following murlentamab treatment. RESULTS: We demonstrate here a robust expansion of the intermediate blood monocytes (IBMs) in ovarian cancer patients. We establish a significant positive correlation between IBM percentage and tumor-associate macrophages with a CCR2high/CD163high/CD206high/CD86lowprofile. Moreover, IBM expansion is associated with a decreased effector/regulatory T-cell ratio in ascites and with the presence of soluble immunosuppressive mediators. We also establish that IBM proportion positively correlates with the peritoneum tumor burden. Finally, the study of IBMs in patients with ovarian cancer under immunotherapy during the phase clinical trial supports IBMs to follow the evolution of tumor development and the treatment adaptation. CONCLUSIONS: This study, which links IBM level with immunosuppression and tumor burden in peritoneum, identifies IBMs as apotential predictive signature of ascites immune status and as a biomarker ofovarian cancer development and treatment response. TRIAL REGISTRATION NUMBER: EudraCT: 2015-004252-22 NCT02978755.

[George Lucas: prophet of transhumanism?] / George Lucas : Prophète du transhumanisme ?

Star Wars, a "general public" film saga, raises questions about human nature and transhumanism. It features different characters who are neither "real" humans nor robots; there are creatures that can be likened to advanced humans (cyborgs, chimeras or genetically-modified humans). Based on the "Star Wars" movie, we will approach some ways of modifying the human person both in his body and in his consciousness and we will wonder about the man of tomorrow by asking ourselves if George Lucas (director of the first film released) might have not been a visionary of the men of tomorrow.

TITLE: George Lucas : Prophète du transhumanisme ? ABSTRACT: La Guerre des étoiles, saga cinématographique « grand public ¼, permet de se questionner sur la nature humaine et sur le transhumanisme. Elle met en effet en scène différents personnages qui ne sont ni de « vrais ¼ humains, ni des robots, des créatures pouvant être assimilées à des humains évolués (des cyborgs, des chimères ou des humains génétiquement modifiés). À partir de cette approche cinématographique, nous aborderons certains moyens de modification de la personne humaine à la fois dans son corps et dans sa conscience, et nous nous interrogerons sur l'homme de demain, en se demandant si George Lucas (réalisateur du premier film) n'était pas un visionnaire des hommes de demain.

Tumor cells educate mesenchymal stromal cells to release chemoprotective and immunomodulatory factors.

Factors released by surrounding cells such as cancer-associated mesenchymal stromal cells (CA-MSCs) are involved in tumor progression and chemoresistance. In this study, we characterize the mechanisms by which naïve mesenchymal stromal cells (MSCs) can acquire a CA-MSCs phenotype. Ovarian tumor cells trigger the transformation of MSCs to CA-MSCs by expressing pro-tumoral genes implicated in the chemoresistance of cancer cells, resulting in the secretion of high levels of CXC chemokine receptors 1 and 2 (CXCR1/2) ligands such as chemokine (C-X-C motif) ligand 1 (CXCL1), CXCL2, and interleukin 8 (IL-8). CXCR1/2 ligands can also inhibit the immune response against ovarian tumor cells. Indeed, through their released factors, CA-MSCs promote the differentiation of monocytes towards M2 macrophages, which favors tumor progression. When CXCR1/2 receptors are inhibited, these CA-MSC-activated macrophages lose their M2 properties and acquire an anti-tumoral phenotype. Both ex vivo and in vivo, we used a CXCR1/2 inhibitor to sensitize ovarian tumor cells to carboplatin and circumvent the pro-tumoral effects of CA-MSCs. Since high concentrations of CXCR1/2 ligands in patients' blood are associated with chemoresistance, CXCR1/2 inhibition could be a potential therapeutic strategy to revert carboplatin resistance.

Latest Advances in Targeting the Tumor Microenvironment for Tumor Suppression.

The tumor bulk is composed of a highly heterogeneous population of cancer cells, as well as a large variety of resident and infiltrating host cells, extracellular matrix proteins, and secreted proteins, collectively known as the tumor microenvironment (TME). The TME is essential for driving tumor development by promoting cancer cell survival, migration, metastasis, chemoresistance, and the ability to evade the immune system responses. Therapeutically targeting tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), regulatory T-cells (T-regs), and mesenchymal stromal/stem cells (MSCs) is likely to have an impact in cancer treatment. In this review, we focus on describing the normal physiological functions of each of these cell types and their behavior in the cancer setting. Relying on the specific surface markers and secreted molecules in this context, we review the potential targeting of these cells inducing their depletion, reprogramming, or differentiation, or inhibiting their pro-tumor functions or recruitment. Different approaches were developed for this targeting, namely, immunotherapies, vaccines, small interfering RNA, or small molecules.

IL13-Mediated Dectin-1 and Mannose Receptor Overexpression Promotes Macrophage Antitumor Activities through Recognition of Sialylated Tumor Cells.

Macrophage-mediated cytotoxicity is controlled by surface receptor expression and activation. Despite the numerous studies documenting the role of macrophage C-type lectin receptors (CLR) in pathogen elimination, little is known about their contribution to antitumor responses. Here, we report that IL13 inhibits T-cell lymphoma and ovarian adenocarcinoma development in tumor-bearing mice through the conversion of tumor-supporting macrophages to cytotoxic effectors, characterized by a CLR signature composed of dectin-1 and mannose receptor (MR). We show that dectin-1 and MR are critical for the recognition of tumor cells through sialic acid-specific glycan structure on their surface and for the subsequent activation of macrophage tumoricidal response. Finally, we validated that IL13 antitumor effect mediated by dectin-1 and MR overexpression on macrophages can extend to various types of human tumors. Therefore, these results identify these CLRs as potential targets to promote macrophage antitumor response and represent an attractive approach to elicit tumor-associated macrophage tumoricidal properties.

DEBIO 1143, an IAP inhibitor, reverses carboplatin resistance in ovarian cancer cells and triggers apoptotic or necroptotic cell death.

The poor prognosis of ovarian cancer (it is the leading cause of death from gynecological cancers) is mainly due to the acquisition of resistance to carboplatin. Among the possible resistance pathways, resistance to apoptosis and especially the overexpression of inhibitor of apoptosis proteins (IAP) cIAP1 and X-linked IAP (XIAP), have been implicated. DEBIO 1143, a SMAC (second mitochondria-derived activator of caspase) mimetic, belongs to a new class of targeted agents currently being evaluated in clinical trials, which activate apoptotic cell death and block pro-survival signaling in cancer cells. Here, we demonstrate that DEBIO 1143 in vitro inhibits the cell viability of two carboplatin-sensitive cell lines (IGROV-1 and A2780S) as well as three carboplatin-resistant cell lines (A2780R, SKOV-3 and EFO-21). Of note, DEBIO 1143 is able to reverse resistance to carboplatin by inducing cell death either by apoptosis or necroptosis depending on the cell lines. To identify a biomarker able to predict the sensitivity of the cell lines to DEBIO 1143 treatment we analyzed the expression of the DEBIO 1143 targets cIAP1 and XIAP, and one of their downstream targets, caspase 9. These proteins did not constitute a marker of DEBIO 1143 sensitivity/resistance. Importantly, we confirmed these findings in vivo in SKOV-3 xenograft models where DEBIO 1143 highly potentiated carboplatin treatment.

Effect of combined inhibition of p110 alpha PI3K isoform and STAT3 pathway in ovarian cancer platinum-based resistance.

BACKGROUND: Ovarian cancer is associated with poor prognostic outcome due to late diagnosis and to intrinsic and acquired resistance to platinum-based chemotherapy in a large number of patients. This chemoresistance is acquired through the peritoneal and ascites microenvironment by several released factors, such as IL-6,. Preclinical studies have implicated the activation of PI3K pathway in chemoresistance, showing it to extend tumor cell survival and modulate multidrug resistance. We aimed to evaluate the implication of the p110 alpha PI3K subunit in ovarian cancer chemoresistance acquisition, and to evaluate whether the STAT3 pathway can mediate resistance to PI3K inhibitors through secretion of IL6. RESULTS: Human ovarian adenocarcinoma IGROV-1 and JHOC-5 cells cultured in ascites showed an increase in carboplatinum-based resistance. Level of chemoresistance was associated to IL6 concentration in ascites. Activation of PI3K/Akt, STAT and MAPK pathways was observed after IGROV-1 incubation with ascites and treatment with carboplatin. Neither IGROV-1 nor JHOC-5 cells exposed to ascites treated with additional IL-6 directed antibody showed any reversion of the chemoresistance. CONCLUSION: IL6-related resistance was not abolished by the selective inhibition of PI3K alpha subunit coupled with the anti-IL6-receptor antibody tocilizumab. This dual inhibition requires further exploration in other ovarian cancer models such as clear cell carcinoma.

Fluorescence-guided surgery for cancer patients: a proof of concept study on human xenografts in mice and spontaneous tumors in pets.

Surgery is often the first treatment option for patients with cancer. Patient survival essentially depends on the completeness of tumor resection. This is a major challenge, particularly in cases of peritoneal carcinomatosis, where tumors are widely disseminated in the large peritoneal cavity. Any development to help surgeons visualize these residual cells would improve the completeness of the surgery. For non-disseminated tumors, imaging could be used to ensure that the tumor margins and the draining lymph nodes are free of tumor deposits. Near-infrared fluorescence imaging has been shown to be one of the most convenient imaging modalities. Our aim was to evaluate the efficacy of a near-infrared fluorescent probe targeting the αvß3 integrins (Angiostamp™) for intraoperative detection of tumors using the Fluobeam® device. We determined whether different human tumor nodules from various origins could be detected in xenograft mouse models using both cancer cell lines and patient-derived tumor cells. We found that xenografts could be imaged by fluorescent staining irrespective of their integrin expression levels. This suggests imaging of the associated angiogenesis of the tumor and a broader potential utilization of Angiostamp™. We therefore performed a veterinary clinical trial in cats and dogs with local tumors or with spontaneous disseminated peritoneal carcinomatosis. Our results demonstrate that the probe can specifically visualize both breast and ovarian nodules, and suggest that Angiostamp™ is a powerful fluorescent contrast agent that could be used in both human and veterinary clinical trials for intraoperative detection of tumors.

Oxidative Stress by Monoamine Oxidase-A Impairs Transcription Factor EB Activation and Autophagosome Clearance, Leading to Cardiomyocyte Necrosis and Heart Failure.

AIMS: In heart failure (HF), mitochondrial quality control and autophagy are progressively impaired, but the role of oxidative stress in this process and its underlying mechanism remain to be defined. By degrading norepinephrine and serotonin, the mitochondrial enzyme, monoamine oxidase-A (MAO-A), is a potent source of reactive oxygen species (ROS) in the heart and its activation leads to the persistence of mitochondrial damage. In this study, we analyzed the consequences of ROS generation by MAO-A on the autophagy-lysosome pathway in the heart. RESULTS: Cardiomyocyte-driven expression of MAO-A in mice led to mitochondrial fission and translocation of Drp1 and Parkin in the mitochondrial compartment. Ventricles from MAO-A transgenic mice displayed accumulation of LC3-positive autophagosomes, together with p62 and ubiquitylated proteins, indicating impairment of autophagy. In vitro adenoviral delivery of MAO-A in cardiomyocytes and the consequent generation of ROS blocked autophagic flux with accumulation of LC3II, p62, and ubiquitylated proteins, leading to mitochondrial fission and cell necrosis. In addition, MAO-A activation induced accumulation of lysosomal proteins, cathepsin D and Lamp1, reduced lysosomal acidification, and blocked the nuclear translocation of transcription factor-EB (TFEB), a master regulator of autophagy and lysosome biogenesis. Most interestingly, overexpression of TFEB attenuated autophagosome buildup, mitochondrial fission, cardiomyocyte death, and HF associated with MAO-A activation. INNOVATION AND CONCLUSION: This study unravels a new link between MAO-dependent H2O2 production and lysosomal dysfunction. Altogether, our findings demonstrate that the MAO-A/H2O2 axis has a negative impact on the elimination and recycling of mitochondria through the autophagy-lysosome pathway, which participates in cardiomyocyte death and HF. Antioxid. Redox Signal. 25, 10-27.

Periprostatic adipocytes act as a driving force for prostate cancer progression in obesity.

Obesity favours the occurrence of locally disseminated prostate cancer in the periprostatic adipose tissue (PPAT) surrounding the prostate gland. Here we show that adipocytes from PPAT support the directed migration of prostate cancer cells and that this event is strongly promoted by obesity. This process is dependent on the secretion of the chemokine CCL7 by adipocytes, which diffuses from PPAT to the peripheral zone of the prostate, stimulating the migration of CCR3 expressing tumour cells. In obesity, higher secretion of CCL7 by adipocytes facilitates extraprostatic extension. The observed increase in migration associated with obesity is totally abrogated when the CCR3/CCL7 axis is inhibited. In human prostate cancer tumours, expression of the CCR3 receptor is associated with the occurrence of aggressive disease with extended local dissemination and a higher risk of biochemical recurrence, highlighting the potential benefit of CCR3 antagonists in the treatment of prostate cancer.

F14512, a polyamine-vectorized inhibitor of topoisomerase II, exhibits a marked anti-tumor activity in ovarian cancer.

Epithelial ovarian cancer is the fourth cause of death among cancer-bearing women and frequently associated with carboplatin resistance, underlining the need for more efficient and targeted therapies. F14512 is an epipodophylotoxin-core linked to a spermine chain which enters cells via the polyamine transport system (PTS). Here, we investigate this novel concept of vectorization in ovarian cancer. We compared the effects of etoposide and F14512 on a panel of five carboplatin-sensitive or resistant ovarian cancer models. We assessed the incorporation of F17073, a spermine-linked fluorescent probe, in these cells and in 18 clinical samples. We then showed that F14512 exhibits a high anti-proliferative and pro-apoptotic activity, particularly in cells with high levels of F17073 incorporation. Consistently, F14512 significantly inhibited tumor growth compared to etoposide, in a cisplatin-resistant A2780R subcutaneous model, at a dose of 1.25 mg/kg. In addition, ex vivo analysis indicated that 15 out of 18 patients presented a higher F17073 incorporation into tumor cells compared to normal cells. Overall, our data suggest that F14512, a targeted drug with a potent anti-tumor efficacy, constitutes a potential new therapy for highly PTS-positive and platinum-resistant ovarian cancer-bearing patients.

SDF-1alpha concentration dependent modulation of RhoA and Rac1 modifies breast cancer and stromal cells interaction.

BACKGROUND: The interaction of SDF-1alpha with its receptor CXCR4 plays a role in the occurrence of distant metastasis in many solid tumors. This interaction increases migration from primary sites as well as homing at distant sites. METHODS: Here we investigated how SDF-1α could modulate both migration and adhesion of cancer cells through the modulation of RhoGTPases. RESULTS: We show that different concentrations of SDF-1α modulate the balance of adhesion and migration in cancer cells. Increased migration was obtained at 50 and 100 ng/ml of SDF-1α; however migration was reduced at 200 ng/ml. The adhesion between breast cancer cells and BMHC was significantly increased by SDF-1α treatment at 200 ng/ml and reduced using a blocking monoclonal antibody against CXCR4. We showed that at low SDF-1α concentration, RhoA was activated and overexpressed, while at high concentration Rac1 was promoting SDF-1α mediating-cell adhesion. CONCLUSION: We conclude that SDF-1α concentration modulates migration and adhesion of breast cancer cells, by controlling expression and activation of RhoGTPases.

LRH-1 mediates anti-inflammatory and antifungal phenotype of IL-13-activated macrophages through the PPARγ ligand synthesis.

Liver receptor homologue-1 (LRH-1) is a nuclear receptor involved in the repression of inflammatory processes in the hepatointestinal tract. Here we report that LRH-1 is expressed in macrophages and induced by the Th2 cytokine IL-13 via a mechanism involving STAT6. We show that loss-of-function of LRH-1 in macrophages impedes IL-13-induced macrophage polarization due to impaired generation of 15-HETE PPARγ ligands. The incapacity to generate 15-HETE metabolites is at least partially caused by the compromised regulation of CYP1A1 and CYP1B1. Mice with LRH-1-deficient macrophages are, furthermore, highly susceptible to gastrointestinal and systemic Candida albicans infection. Altogether, these results identify LRH-1 as a critical component of the anti-inflammatory and fungicidal response of alternatively activated macrophages that acts upstream from the IL-13-induced 15-HETE/PPARγ axis.

Pancreatic cell plasticity and cancer initiation induced by oncogenic Kras is completely dependent on wild-type PI 3-kinase p110α.

Increased PI 3-kinase (PI3K) signaling in pancreatic ductal adenocarcinoma (PDAC) correlates with poor prognosis, but the role of class I PI3K isoforms during its induction remains unclear. Using genetically engineered mice and pharmacological isoform-selective inhibitors, we found that the p110α PI3K isoform is a major signaling enzyme for PDAC development induced by a combination of genetic and nongenetic factors. Inactivation of this single isoform blocked the irreversible transition of exocrine acinar cells into pancreatic preneoplastic ductal lesions by oncogenic Kras and/or pancreatic injury. Hitting the other ubiquitous isoform, p110ß, did not prevent preneoplastic lesion initiation. p110α signaling through small GTPase Rho and actin cytoskeleton controls the reprogramming of acinar cells and regulates cell morphology in vivo and in vitro. Finally, p110α was necessary for pancreatic ductal cancers to arise from Kras-induced preneoplastic lesions by increasing epithelial cell proliferation in the context of mutated p53. Here we identify an in vivo context in which p110α cellular output differs depending on the epithelial transformation stage and demonstrate that the PI3K p110α is required for PDAC induced by oncogenic Kras, the key driver mutation of PDAC. These data are critical for a better understanding of the development of this lethal disease that is currently without efficient treatment.