Platelet-derived growth factor negatively regulates the insulin-like growth factor signaling pathway through the coordinated action of phosphatidylinositol 3-kinase and protein kinase C beta I

AbstractWe recently described that epidermal and fibroblast growth factors (EGF and FGF) regulate the IGF-I signaling pathway at the level of IRS-1 through the cooperative action of two independent signaling pathways; one dependent on phosphatidylinositol 3-kinase (PI 3-kinase) and the other on protein kinase D1 (PKD1) (Karam et al. [22]). To determine whether this mechanism could be generalized to another tyrosine kinase receptor-dependent growth factor, the effect of platelet-derived growth factor (PDGF) on the IGF-I signaling pathway was studied. PDGF inhibited IGF-I-stimulated IRS-1 tyrosine phosphorylation and subsequent IGF-I-induced PI 3-kinase activity, and stimulated IRS-1 serine 307 phosphorylation. These effects were mediated through a PI 3-kinase-dependent but extracellular signal-regulated kinase (ERK)-independent signaling pathway. However, PDGF-induced IRS-1 serine 307 phosphorylation was not sufficient per se to inhibit the IGF-I signaling but required another independent pathway. Noteworthy, although acutely stimulated by PDGF, and contrary to what we previously described (Karam et al. [22]), PKD1 did not associate with IRS-1and did not inhibit the IGF-I signaling in response to PDGF. However, we identified PKCβI as a new regulatory partner of PI 3-kinase for PDGF-induced inhibition of the IGF-I signaling pathway. Therefore, our results reinforce the idea that a coordinated action of two independent pathways seems absolutely necessary to negatively regulate IRS-1. Moreover, they also demonstrated that, depending of the cross-talk considered, subtle and specific regulatory mechanisms occur at the level of IRS-1 and that a unique regulatory model is not conceivable

Studying the role of protein kinase D1 in the control of IGF-I signal transduction pathway and MCF-7 breast cancer cell proliferation

La protéine kinase D1, PKD1, est une nouvelle sérine/thréonine kinase activée par de nombreux mitogènes et dérégulée dans de nombreux types de cancers dont le cancer du sein, ce qui suggère un rôle de cette kinase dans la prolifération cellulaire et la tumorigenèse. Cependant, le rôle précis et les cibles de PKD1 ne sont pas encore bien connus. Au cours de ce travail, nous avons tout d’abord démontré que PKD1 est activée par les facteurs de croissance épidermique (EGF) et fibroblastique (FGF) et qu’elle régule la voie de signalisation de l’insulin-like Growth Factor-I (IGF-I). D’autre part, nos résultats démontrent que PKD1 favorise les propriétés pro-prolifératives et pro-tumorales des cellules MCF-7 dérivées d’un adénocarcinome mammaire humain estrogéno-dépendant. Ces mécanismes mettent en jeu des voies de signalisation dépendantes de protéines kinases (la voie MEK/ERK) et hormonales (la voie estrogène/REα). Ainsi, l’ensemble de ce travail fait apparaître PKD1 comme une nouvelle cible thérapeutique anti-tumorale potentielle.Protein kinase D1, PKD1, is a novel serine/threonine kinase which can be activated by mitogens and whose expression is altered in many tumors such as breast cancer, suggesting a role for this kinase in cancer development. However, its precise role and targets are still unclear. Our study identified PKD1 as a new regulatory kinase implicated in the control of IGF-I signal transduction pathway. Furthermore, we showed that PKD1 enhances estrogen-dependent MCF-7 breast cancer cell proliferation and tumorigenesis through the regulation of MEK/ERK and estrogen/ERα pathways. Thus, this work may define PKD1 as a novel potential anti-tumor therapeutic target

Is Sphingosine-1-Phosphate a Regulator of Tumor Vascular Functionality?

Increasing evidence indicates that tumor vasculature normalization could be an appropriate strategy to increase therapies’ efficacy in solid tumors by decreasing hypoxia and improving drug delivery. We searched for a novel approach that reduces hypoxia and enhances chemotherapy efficacy in pancreatic adenocarcinoma which is characterized by disrupted blood vasculature associated with poor patient survival. Clinical significance of plasma levels of the angiogenic lipid sphingosine-1-phosphate (S1P) was assessed at baseline in 175 patients. High plasma S1P concentration was found to be a favorable prognostic/predictive marker in advanced/metastatic pancreatic adenocarcinoma patients treated by gemcitabine alone but not in patients receiving a combination gemcitabine and PDGFR-inhibitor. In pancreatic adenocarcinoma PDX models, oral administration of an S1P lyase inhibitor (LX2931) significantly increased plasma S1P levels, decreased tumor expression of the hypoxia marker (CA IX), and enhanced chemotherapy efficacy when combined with gemcitabine treatment. The direct effect of S1P on tumor oxygenation was assessed by administration of S1P onto tumor-grafted CAM model and measuring intra-tumoral pO2 using a tissue oxygen monitor. S1P increased pO2 in a tumor-CAM model. Thus, increasing plasma S1P is a promising strategy to decrease tumor hypoxia and enhance therapy efficacy in solid tumors. S1P may act as a tumor vasculature normalizer

Etude du rôle de la protéine kinase D1 dans les intercommunications entre les voies de signalisation des récepteurs à activité tyrosine kinase et dans la prolifération des cellules tumorales mammaires MCF-7

La protéine kinase D1, PKD1, est une nouvelle sérine/thréonine kinase activée par de nombreux mitogènes et dérégulée dans de nombreux types de cancers dont le cancer du sein, ce qui suggère un rôle de cette kinase dans la prolifération cellulaire et la tumorigenèse. Cependant, le rôle précis et les cibles de PKD1 ne sont pas encore bien connus. Au cours de ce travail, nous avons tout d abord démontré que PKD1 est activée par les facteurs de croissance épidermique (EGF) et fibroblastique (FGF) et qu elle régule la voie de signalisation de l insulin-like Growth Factor-I (IGF-I). D autre part, nos résultats démontrent que PKD1 favorise les propriétés pro-prolifératives et pro-tumorales des cellules MCF-7 dérivées d un adénocarcinome mammaire humain estrogéno-dépendant. Ces mécanismes mettent en jeu des voies de signalisation dépendantes de protéines kinases (la voie MEK/ERK) et hormonales (la voie estrogène/REa). Ainsi, l ensemble de ce travail fait apparaître PKD1 comme une nouvelle cible thérapeutique anti-tumorale potentielle.Protein kinase D1, PKD1, is a novel serine/threonine kinase which can be activated by mitogens and whose expression is altered in many tumors such as breast cancer, suggesting a role for this kinase in cancer development. However, its precise role and targets are still unclear. Our study identified PKD1 as a new regulatory kinase implicated in the control of IGF-I signal transduction pathway. Furthermore, we showed that PKD1 enhances estrogen-dependent MCF-7 breast cancer cell proliferation and tumorigenesis through the regulation of MEK/ERK and estrogen/ERa pathways. Thus, this work may define PKD1 as a novel potential anti-tumor therapeutic target.PARIS11-SCD-Bib. électronique (914719901) / SudocSudocFranceF

Is Sphingosine-1-Phosphate a Regulator of Tumor Vascular Functionality?

Increasing evidence indicates that tumor vasculature normalization could be an appropriate strategy to increase therapies’ efficacy in solid tumors by decreasing hypoxia and improving drug delivery. We searched for a novel approach that reduces hypoxia and enhances chemotherapy efficacy in pancreatic adenocarcinoma which is characterized by disrupted blood vasculature associated with poor patient survival. Clinical significance of plasma levels of the angiogenic lipid sphingosine-1-phosphate (S1P) was assessed at baseline in 175 patients. High plasma S1P concentration was found to be a favorable prognostic/predictive marker in advanced/metastatic pancreatic adenocarcinoma patients treated by gemcitabine alone but not in patients receiving a combination gemcitabine and PDGFR-inhibitor. In pancreatic adenocarcinoma PDX models, oral administration of an S1P lyase inhibitor (LX2931) significantly increased plasma S1P levels, decreased tumor expression of the hypoxia marker (CA IX), and enhanced chemotherapy efficacy when combined with gemcitabine treatment. The direct effect of S1P on tumor oxygenation was assessed by administration of S1P onto tumor-grafted CAM model and measuring intra-tumoral pO2 using a tissue oxygen monitor. S1P increased pO2 in a tumor-CAM model. Thus, increasing plasma S1P is a promising strategy to decrease tumor hypoxia and enhance therapy efficacy in solid tumors. S1P may act as a tumor vasculature normalizer

The 'Holy Grail' in Immuno-Oncology: AC BioScience SA is Aiming to Potentiate Anti-PD-1 Therapy Efficacy through Tumor Cell Conditioning Strategy

AC BioScience is a Swiss biotech company based at the EPFL Innovation Park and Biopôle, dedicated to developing groundbreaking therapies to fight a range of cancers and infectious diseases. We are about to start clinical trials with two of four leading-edge cancer drugs mainly focusing on immune-oncology and tumor vascular normalization with multi-billion $ sales potential. Here, we present our strategy and one of our pioneering drug candidates that has already shown exceptional results with tumor cell conditioning to improve the efficacy of immune checkpoint inhibitors

Correction to: Enhanced differentiation of human pluripotent stem cells into pancreatic progenitors co-expressing PDX1 and NKX6.1

The original article [1] contains a number of small errors which the authors would like to clarify

Enhanced differentiation of human pluripotent stem cells into pancreatic progenitors co-expressing PDX1 and NKX6.1

Abstract Background Pancreatic progenitors (PPs) co-expressing the two transcription factors (TFs) PDX1 and NKX6.1 are recognized as the indispensable precursors of functional pancreatic β cells. Here, we aimed to establish an efficient protocol for maximizing generation of PDX1+/NKX6.1+ PPs from human pluripotent stem cells (hPSCs). Methods In order to enhance the PDX1+/NKX6.1+ population, we manipulated in vitro culture conditions during differentiation by dissociating densely formed endodermal cells and re-plating them at different densities. These dissociated cells were subjected to an augmented duration of retinoid and fibroblast growth factor (FGF)10 signaling to induce higher PDX1 and NKX6.1 expression. Results Our optimized protocol dramatically increased the expression of NKX6.1, leading to an increase in the proportion of PDX1+/NKX6.1+ progenitors (~90%) in monolayer, higher than the previously published protocols, as well as upregulated key TFs controlling pancreatic development. The improved efficiency of pancreatic differentiation was complemented by an inhibited hepatic specification and an increased proliferation of NKX6.1+ cells. Interestingly, we were able to enrich a novel PDX1–/NKX6.1+ population by manipulating the re-plating density; these oriented themselves in three-dimensional clusters. Further differentiation validated the ability of our PDX1+/NKX6.1+ progenitors to generate NGN3+ endocrine progenitors. Conclusions We provide a novel technique that facilitates appropriate cellular rearrangement in monolayer culture to yield a high proportion of PDX1+/NKX6.1+ PPs with an elevated self-replicating capacity, thereby aiding scalable production of functional β cells from hPSCs in vitro. Our innovative method also enriches a novel NKX6.1+/PDX1– population, with characteristics of proposed endocrine precursors, allowing further studies on deciphering routes to β-cell development

Scalable Generation of Mesenchymal Stem Cells and Adipocytes from Human Pluripotent Stem Cells

Human pluripotent stem cells (hPSCs) can provide unlimited supply for mesenchymal stem cells (MSCs) and adipocytes that can be used for therapeutic applications. Here we developed a simple and highly efficient all-trans-retinoic acid (RA)-based method for generating an off-the-shelf and scalable number of human pluripotent stem cell (hPSC)-derived MSCs with enhanced adipogenic potential. We showed that short exposure of multiple hPSC lines (hESCs/hiPSCs) to 10 μM RA dramatically enhances embryoid body (EB) formation through regulation of genes activating signaling pathways associated with cell proliferation, survival and adhesion, among others. Disruption of cell adhesion induced the subsequent differentiation of the highly expanded RA-derived EB-forming cells into a pure population of multipotent MSCs (up to 1542-fold increase in comparison to RA-untreated counterparts). Interestingly, the RA-derived MSCs displayed enhanced differentiation potential into adipocytes. Thus, these findings present a novel RA-based approach for providing an unlimited source of MSCs and adipocytes that can be used for regenerative medicine, drug screening and disease modeling applications

Additional file 1: Figure S1. of Enhanced differentiation of human pluripotent stem cells into pancreatic progenitors co-expressing PDX1 and NKX6.1

Expression of E-cadherin in pancreatic progenitors generated from different protocols. Double immunofluorescence staining for PDX1 and E-cadherin in pancreatic progenitors generated using different protocols. Note the highest induction of E-cadherin, an epithelial marker, in PDX1+ progenitors derived using P2-D. Scale bars = 100 μm. (JPG 3473 kb