Developmental and pathological lymphangiogenesis: from models to human disease

The lymphatic vascular system, the body's second vascular system present in vertebrates, has emerged in recent years as a crucial player in normal and pathological processes. It participates in the maintenance of normal tissue fluid balance, the immune functions of cellular and antigen trafficking and absorption of fatty acids and lipid-soluble vitamins in the gut. Recent scientific discoveries have highlighted the role of lymphatic system in a number of pathologic conditions, including lymphedema, inflammatory diseases, and tumor metastasis. Development of genetically modified animal models, identification of lymphatic endothelial specific markers and regulators coupled with technological advances such as high-resolution imaging and genome-wide approaches have been instrumental in understanding the major steps controling growth and remodeling of lymphatic vessels. This review highlights the recent insights and developments in the field of lymphatic vascular biolog

Developmental and pathological lymphangiogenesis: from models to human disease.

The lymphatic vascular system, the body's second vascular system present in vertebrates, has emerged in recent years as a crucial player in normal and pathological processes. It participates in the maintenance of normal tissue fluid balance, the immune functions of cellular and antigen trafficking and absorption of fatty acids and lipid-soluble vitamins in the gut. Recent scientific discoveries have highlighted the role of lymphatic system in a number of pathologic conditions, including lymphedema, inflammatory diseases, and tumor metastasis. Development of genetically modified animal models, identification of lymphatic endothelial specific markers and regulators coupled with technological advances such as high-resolution imaging and genome-wide approaches have been instrumental in understanding the major steps controlling growth and remodeling of lymphatic vessels. This review highlights the recent insights and developments in the field of lymphatic vascular biology

Microenvironnement et lymphomes B du centre germinatif (importance de la niche mésenchymateuse)

Le lymphome folliculaire (FL) est une pathologie tumorale se développant au dépens de lymphocytes B des centres germinatifs des ganglions. Il est caractérisé par une forte dépendance à un environnement ganglionnaire cellulaire et cytokinique complexe. La moelle osseuse fournit également une niche propice au développement du FL, puisqu une infiltration tumorale est observée dans plus de 70% des cas au diagnostic, avec l'apparition ectopique d'un environnement de type ganglionnaire. L originalité et le but de notre projet ont été d étudier in vitro les cellules de FL dans le contexte de leur environnement de soutien, en nous intéressant plus particulièrement à deux compartiments mésenchymateux potentiellement impliqués dans la lymphomagenèse B: les cellules fibroblastiques réticulaires (FRC) et leur précurseur putatif, les cellules souches mésenchymateuses (CSM) présentes au niveau médullaire et ganglionnaire. Nous avons démontré que les CSM pouvaient acquérir l'ensemble des caractéristiques des FRC après stimulation par le tumor necrosis factor-a et la lymphotoxine-a1b2 ou après contact direct avec des cellules de FL, et devenaient ainsi capables de soutenir la migration, l'adhérence et la croissance des cellules de FL. Cependant, l effet de soutien des CSM et FRC était inhibé suite à leur exposition à un environnement comportant de l interféron-g. En effet, ces cellules mésenchymateuses dans ce contexte développaient une activité indoléamine 2,3 dioxygénase, responsable d effets antiprolifératif et pro-apoptotique sur les cellules tumorales. Ces résultats montrent l importance et la complexité de l environnement cellulaire et cytokinique au cours du FL.Follicular lymphoma (FL) results from the malignant transformation of germinal center-derived B cells that accumulate within lymph nodes. This disease is characterized by an important crosstalk between non malignant cells and the tumoral compartment. Bone marrow also provides a preferential niche for FL malignant cells, since tumoral infiltration is found in up to 70% of FL cases at diagnosis, in association with the emergence of ectopic lymph node-like environment. The originality and the goal of our project were to study in vitro FL cells in respect of their supportive microenvironment. We focused our studies on mesenchymal cell compartments. Two cell populations seemed to be of great interest in B-cell lymphomagenesis: fibroblastic reticular cells (FRCs), and their postulated progenitors mesenchymal stem cells (MSCs). Indeed, cells with phenotypic and functional features of MSCs could be found not only in the medullar but also in the lymphoid compartments. We demonstrated that MSCs could acquire a complete phenotype of FRCs after stimulation with tumor necrosis factor-a and lymphotoxin-a1b2 or after a direct contact with FL cells, and were able to support migration, adhesion and growth of lymphoma B cells. However, the B cell-supportive properties of MSCs and FRCs were overruled following their pretreatment with interferon-g. Indeed, IFN-g-conditioned mesenchymal cells developed functional indoleamine 2, 3 dioxygenase activity, which was reponsible of both antiproliferative and proapoptotic effects on tumoral B cells. Our results underline the key role and the complexity of cellular and molecular environment in FL.RENNES1-BU Sciences Philo (352382102) / SudocSudocFranceF

Human mesenchymal stem cells isolated from bone marrow and lymphoid organs support tumor B-cell growth: role of stromal cells in follicular lymphoma pathogenesis.

International audienceAccumulating evidence indicates that the cellular microenvironment plays a key role in follicular lymphoma (FL) pathogenesis, both within tumor lymph nodes (LNs) and in infiltrated bone marrow where ectopic LN-like reticular cells are integrated within malignant B-cell nodular aggregates. In normal secondary lymphoid organs, specific stromal cell subsets provide a highly specialized microenvironment that supports immune response. In particular, fibroblastic reticular cells (FRCs) mediate immune cell migration, adhesion, and reciprocal interactions. The role of FRCs and their postulated progenitors, that is, bone marrow mesenchymal stem cells (MSCs), in FL remains unexplored. In this study, we investigated the relationships between FRCs and MSCs and their capacity to sustain malignant B-cell growth. Our findings strongly suggest that secondary lymphoid organs contain MSCs able to give rise to adipocytes, chondrocytes, osteoblasts, as well as fully functional B-cell supportive FRCs. In vitro, bone marrow-derived MSCs acquire a complete FRC phenotype in response to a combination of tumor necrosis factor-alpha and lymphotoxin-alpha1beta2. Moreover, MSCs recruit primary FL cells that, in turn, trigger their differentiation into FRCs, making them able to support malignant B-cell survival. Altogether, these new insights into the cross talk between lymphoma cells and their microenvironment could offer original therapeutic strategies

Functional alteration of the lymphoma stromal cell niche by the cytokine context: role of indoleamine-2,3 dioxygenase.

International audienceHuman mesenchymal stem cells (MSC) strongly repress activated T-cell proliferation through the production of a complex set of soluble factors, including the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO), which is induced by IFN-gamma. Conversely, MSCs support survival of follicular lymphoma (FL) B cells, in particular after exposure to tumor necrosis factor-alpha (TNF) and lymphotoxin-alpha1beta2 (LT). The role of MSCs on normal and malignant B-cell growth in steady-state and inflammatory conditions remains to be fully explored. We show here that resting MSCs sustain activated normal B-cell proliferation and survival, whereas IFN-gamma-conditioned MSCs mediate IDO-dependent B-cell growth arrest and apoptosis. IFN-gamma, TNF, and LT are significantly overexpressed by the microenvironment of invaded FL-lymph nodes, but their relative expression patterns are highly heterogeneous between samples. In vitro, IFN-gamma abrogates the B-cell supportive phenotype induced by TNF and LT on MSCs. Moreover, IFN-gamma overrules the growth promoting effect of MSCs on primary purified FL B cells. Altogether, these results underline the crucial role of the cytokine context in the local crosstalk between malignant cells and their microenvironment and provide new insights into our knowledge of the FL cell niche that emerges as a new promising target for innovative therapeutic strategies

Nuclear Imaging Study of the Pharmacodynamic Effects of Debio 1143, an Antagonist of Multiple Inhibitor of Apoptosis Proteins (IAPs), in a Triple-Negative Breast Cancer Model

International audienceBackground . Debio 1143, a potent orally available SMAC mimetic, targets inhibitors of apoptosis proteins (IAPs) members and is currently in clinical trials. In this study, nuclear imaging evaluated the effects of Debio 1143 on tumor cell death and metabolism in a triple-negative breast cancer (TNBC) cell line (MDA-MB-231)-based animal model. Methods . Apoptosis induced by Debio 1143 was assessed by FACS (caspase-3, annexin 5 (A5)), binding of 99m Tc-HYNIC-Annexin V, and a cell proliferation assay. 99m Tc-HYNIC-Annexin V SPECT and [ 18 F]-FDG PET were also performed in mice xenografted with MDA-MB-231 cells. Results . Debio 1143 induced early apoptosis both in vitro and in vivo 6 h after treatment. Debio 1143 inhibited tumor growth, which was associated with a decreased tumor [ 18 F]-FDG uptake when measured during treatment. Conclusions . This imaging study combining SPECT and PET showed the early proapoptotic effects of Debio 1143 resulting in a robust antitumor activity in a preclinical TNBC model. These imaging biomarkers represent valuable noninvasive tools for translational and clinical research in TNBC