ABSTRACT
Lymphangiogenesis is induced by local pro-lymphatic growth factors and bone marrow (BM)-derived myeloid-lymphatic endothelial cell progenitors (M-LECP). We previously showed that M-LECP play a significant role in lymphangiogenesis and lymph node metastasis in clinical breast cancer (BC) and experimental BC models. We also showed that differentiation of mouse and human M-LECP can be induced through sequential activation of colony stimulating factor-1 (CSF-1) and Toll-like receptor-4 (TLR4) pathways. This treatment activates the autocrine interleukin-10 (IL-10) pathway that, in turn, induces myeloid immunosuppressive M2 phenotype along with lymphatic-specific proteins. Because IL-10 is implicated in differentiation of numerous lineages, we sought to determine whether this pathway specifically promotes the lymphatic phenotype or multipotent progenitors that can give rise to M-LECP among other lineages. Analyses of BM cells activated either by CSF-1/TLR4 ligands in vitro or orthotopic breast tumors in vivo showed expansion of stem/progenitor population and coincident upregulation of markers for at least four lineages including M2-macrophage, lymphatic endothelial, erythroid, and T-cells. Induction of cell plasticity and multipotency was IL-10 dependent as indicated by significant reduction of stem cell markers and those for multiple lineages in differentiated cells treated with anti-IL-10 receptor (IL-10R) antibody or derived from IL-10R knockout mice. However, multipotent CD11b+/Lyve-1+/Ter-119+/CD3e+ progenitors detected in BM appeared to split into a predominant myeloid-lymphatic fraction and minor subsets expressing erythroid and T-cell markers upon establishing tumor residence. Each sub-population was detected at a distinct intratumoral site. This study provides direct evidence for differences in maturation status between the BM progenitors and those reaching tumor destination. The study results suggest preferential tumor bias towards expansion of myeloid-lymphatic cells while underscoring the role of IL-10 in early BM production of multipotent progenitors that give rise to both hematopoietic and endothelial lineages.
Subject(s)
Interleukin-10 , Neoplasms , Neoplastic Stem Cells , Tumor Microenvironment , Animals , Humans , Mice , Bone Marrow Cells/pathology , Cell Differentiation , Cells, Cultured , Interleukin-10/metabolism , Macrophage Colony-Stimulating Factor , Neoplasms/pathology , Phenotype , Toll-Like Receptor 4 , Multipotent Stem Cells/metabolism , Lymphangiogenesis , Myeloid Cells/metabolism , Myeloid Cells/pathology , Neoplastic Stem Cells/metabolismABSTRACT
RESUMEN Introducción: Ecuador no cubre las recomendaciones de mantener la lactancia materna hasta los seis meses de edad del recién nacido. Objetivo: Analizar los factores relacionados con la duración de la lactancia materna exclusiva en madres trabajadoras de una institución universitaria ecuatoriana. La población de estudio. Métodos: Estudio cuantitativo, descriptivo, transversal, con carácter retrospectivo mediante un cuestionario diseñado ad hoc que se invitó a cumplimentar a todas las madres trabajadoras que lo habían sido en los últimos 10 años de la institución. El período de ejecución del estudio fue de septiembre 2018 a junio de 2019. Resultados: Participaron 316 madres, 62,8 % recibió información sobre lactancia materna y proveniente del médico 55,6 %. La primera hora de vida amamantaron 63,9 %. Más de la mitad de las participantes amamantaron durante un periodo de 6 meses (56,9 %), con lactancia materna exclusiva una media de 4,56 meses. El principal motivo para el abandono fue hipogalactia (26,9 %); incorporación al trabajo (19,2 %); enfermedad materna (5,1 %). La media de lactancia materna exclusiva fue mayor en las madres docentes e investigadoras 4,79 (DE ± 1,8) que en las administrativas y de servicios 4,2 (DE ± 2,05), p= 0,012. Conclusiones: Entre los factores que favorecen la lactancia materna están la información durante el embarazo, así como instaurarla en la primera hora de vida. La situación laboral de la mujer influye en el mantenimiento de dicha lactancia por más tiempo y es una causa de abandono, aunque la más frecuente son los problemas de salud de la madre o del recién nacido.
ABSTRACT Introduction: Ecuador does not cover the recommendations to maintain breastfeeding until six months of age of the newborn. Objective: Analyze the factors related to the duration of exclusive breastfeeding in working mothers of an Ecuadorian university institution. The study population. Methods: Quantitative, descriptive, cross-sectional study, with retrospective character using a questionnaire designed ad hoc; all working mothers who had been in the last 10 years in the institution were invited to fill it. The study was carried out from September 2018 to June 2019. Results: 316 mothers participated, 62.8% received information on breastfeeding and 55.6% from the doctor. The first hour of life, 63.9% mothers breastfed. More than half of the participants breastfed for a period of 6 months (56.9%), and with exclusive breastfeeding during an average of 4.56 months. The main reason for not breastfeeding was hypogalactia (26.9%); work placement (19.2%); maternal disease (5.1%). The mean of exclusive breastfeeding was higher in mother who are teachers and researchers (4.79) (SD ± 1.8) than in mothers with administrative and service positions 4.2 (SD ± 2.05), p = 0.012. Conclusions: Among the factors that favor breastfeeding are information during pregnancy, as well as establishing it in the first hour of life. The employment situation of women influences the maintenance of breastfeeding for longer and is a cause of dropout, although the most frequent are the health problems of the mother or the newborn.
ABSTRACT
Myeloid-lymphatic endothelial cell progenitors (M-LECP) are a subset of bone marrow (BM)-derived cells characterized by expression of M2-type macrophage markers. We previously showed significant contribution of M-LECP to tumor lymphatic formation and metastasis in human clinical breast tumors and corresponding mouse models. Since M2 type is induced in macrophages by immunosuppressive Th2 cytokines IL-4, IL-13, and IL-10, we hypothesized that these factors might promote pro-lymphatic specification of M-LECP during their differentiation from BM myeloid precursors. To test this hypothesis, we analyzed expression of Th2 cytokines and their receptors in mouse BM cells under conditions leading to M-LECP differentiation, namely, CSF-1 treatment followed by activation of TLR4. We found that under these conditions, all three Th2 receptors were strongly upregulated in >95% of the cells that also secrete endogenous IL-10, but not IL-4 or IL-13 ligands. However, addition of any of the Th2 factors to CSF-1 primed cells significantly increased generation of myeloid-lymphatic progenitors as indicated by co-induction of lymphatic-specific (eg, Lyve-1, integrin-a9, collectin-12, and stabilin-1) and M2-type markers (eg, CD163, CD204, CD206, and PD-L1). Antibody-mediated blockade of either IL-10 receptor (IL-10R) or IL-10 ligand significantly reduced both immunosuppressive and lymphatic phenotypes. Moreover, tumor-recruited Lyve-1+ lymphatic progenitors in vivo expressed all Th2 receptors as well as corresponding ligands, including IL-4 and IL-13, which were absent in BM cells. This study presents original evidence for the significant role of Th2 cytokines in co-development of immunosuppressive and lymphatic phenotypes in tumor-recruited M2-type myeloid cells. Progenitor-mediated increase in lymphatic vessels can enhance immunosuppression by physical removal of stimulatory immune cells. Thus, targeting Th2 pathways might simultaneously relieve immunosuppression and inhibit differentiation of pro-lymphatic progenitors that ultimately promote tumor spread.
