Runx3, Brn3a and Isl1 interplay orchestrates the transcriptional program in the early stages of proprioceptive neuron development.

Background: The development and diversification of sensory proprioceptive neurons, which reside in the dorsal root ganglia (DRG) and express the tropomyosin receptor kinase C (TrkC), depend on the transcription factor (TF) Runx3. Runx3-deficient mice develop severe limb ataxia due to TrkC neuron cell death. Two additional TFs Pou4f1 (also called Brn3a) and Isl1 also play an important role in sensory neuron development.

The expression of heparanase in term and preterm human placentas.

Purpose: Heparanase is an endo--glucuronidase that cleaves side chains of heparan-sulfate proteoglycans, an integral constituent of the extra cellular matrix. The abundance of heparanase in placental trophoblast cells implies its role in the processes of placentation and trophoblast invasion. This study aims to explore the involvement of heparanase in parturition and preterm deliveries (PTD).

Runx3 prevents spontaneous colitis by directing the differentiation of anti-inflammatory mononuclear phagocytes.

Mice deficient in the transcription factor Runx3 develop a multitude of immune system defects, including early onset colitis. This paper demonstrates that Runx3 is expressed in colonic mononuclear phagocytes (MNP), including resident macrophages (RM) and dendritic cell subsets (cDC2). Runx3 deletion in MNP causes early onset colitis due to their impaired maturation.

IGF1R Axis Inhibition Restores Dendritic Cell Antitumor Response in Ovarian Cancer.

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy. The insulin-like growth factor (IGF) system plays a key role in regulating growth and invasiveness in several malignancies, including ovarian cancer. IGF1R targeting showed antiproliferative activity of EOC cells.

Lipid droplets in granulosa cells are correlated with reduced pregnancy rates.

Background: Lipids are an important source for energy production during oocyte maturation. The accumulation of intracellular lipids binds to proteins to form lipid droplets. This may lead to cellular lipotoxicity.

The transcriptional profile of circulating myeloid derived suppressor cells correlates with tumor development and progression in mouse.

Myeloid derived suppressor cells (MDSCs) play key roles in cancer development. Accumulation of peripheral-blood MDSCs (PB-MDSCs) corresponds to the progression of various cancers, but provides only a crude indicator. We aimed toward identifying changes in the transcriptional profile of PB-MDSCs in response to tumor growth.

[THE PROLIFERATIVE EFFECT OF DENDRITIC CELLS IN OVARIAN CANCER AND THE RELATIONSHIP WITH THE IGF SIGNALING PATHWAY].

Introduction: Epithelial ovarian cancer (EOC) is the principal cause of death from gynecologic cancer in developed countries. While surgery and chemotherapy can improve survival, the mortality and morbidity rates remain significantly high. The insulin-like growth factor (IGF) axis has been shown to play an important part in carcinogenesis of several human malignancies.

Progesterone treatment enhances the expansion of placental immature myeloid cells in a mouse model of premature labor.

Introduction: immature-myeloid cells (IMCs) are proangiogenic bone marrow (BM)-derived cells that normally differentiate into inflammatory cells such as neutrophils, monocytes and dendritic cells (DCs). We characterized placental IMCs comparing their gene expression and subpopulations to tumor IMCs, and tested our hypothesis that progesterone that inhibits preterm labor, may affect their abundance and differentiation.

Methods: differences between IMC-subpopulations in subcutaneous tumors versus placentas in C57BL/6 or ICR (CD-1) mice were analyzed by flow cytometry and gene expression was detected by microarrays.

The Role of the Insulin-Like Growth Factor 1 Pathway in Immune Tumor Microenvironment and Its Clinical Ramifications in Gynecologic Malignancies.

Treatment of patients with gynecologic malignancies diagnosed at advanced stages remains a therapeutic challenge. Survival rates of these patients remain significantly low, despite surgery and chemotherapy. Advances in understanding the role of the immune system in the pathogenesis of cancer have led to the rapid evolution of immunotherapeutic approaches.

Runx3 in Immunity, Inflammation and Cancer.

In this chapter we summarize the pros and cons of the notion that Runx3 is a major tumor suppressor gene (TSG). Inactivation of TSGs in normal cells provides a viability/growth advantage that contributes cell-autonomously to cancer. More than a decade ago it was suggested that RUNX3 is involved in gastric cancer development, a postulate extended later to other epithelial cancers portraying RUNX3 as a major TSG.

Runx3 at the interface of immunity, inflammation and cancer.

Inactivation of tumor suppressor genes (TSG) in normal cells provides a viability/growth advantage that contributes cell-autonomously to cancer. More than a decade ago claims arose that the RUNX3 member of the RUNX transcription factor family is a major TSG inactivated in gastric cancer, a postulate extended later to other cancers. However, evidence that Runx3 is not expressed in normal gastric and other epithelia has challenged the RUNX3-TSG paradigm.

Loss of osteoblast Runx3 produces severe congenital osteopenia.

Congenital osteopenia is a bone demineralization condition that is associated with elevated fracture risk in human infants. Here we show that Runx3, like Runx2, is expressed in precommitted embryonic osteoblasts and that Runx3-deficient mice develop severe congenital osteopenia. Runx3-deficient osteoblast-specific (Runx3(fl/fl)/Col1α1-cre), but not chondrocyte-specific (Runx3(fl/fl)/Col1α2-cre), mice are osteopenic.

Carcinogen-induced skin tumor development requires leukocytic expression of the transcription factor Runx3.

Carcinogen-induced skin tumorigenesis depends heavily on proinflammatory tumor-promoting processes. Here, we show that leukocytic Runx3 expression is central to the two-stage DMBA/TPA-induced skin tumorigenesis. Runx3-null mice were highly resistant to this process and concomitant ablation of Runx3 in dendritic and T cells fully recapitulated this resistance.

The development of endometriosis in a murine model is dependent on the presence of dendritic cells.

Endometriosis is a common condition associated with pelvic pain and infertility. This study group has previously shown that supplementation of dendritic cells led to enhancement of endometriosis lesion growth and angiogenesis. This study determined whether endometriosis is dependent on the presence of endogenous dendritic cells.

Transcriptional reprogramming of CD11b+Esam(hi) dendritic cell identity and function by loss of Runx3.

Classical dendritic cells (cDC) are specialized antigen-presenting cells mediating immunity and tolerance. cDC cell-lineage decisions are largely controlled by transcriptional factor regulatory cascades. Using an in vivo cell-specific targeting of Runx3 at various stages of DC lineage development we show that Runx3 is required for cell-identity, homeostasis and function of splenic Esam(hi) DC.

Myeloid cell alterations in the mouse placenta precede the onset of labor and delivery.

Objective: Immature myeloid cells (IMCs) are bone marrow-derived cells that normally differentiate into granulocytes, macrophages, and dendritic cells (DCs) but expand in pathological conditions such as malignancy. DCs are antigen-presenting cells that regulate the immune response. Both IMCs and DCs were shown to take part in angiogenesis; however, little is known of their function in the placenta.

Immature myeloid cells derived from mouse placentas and malignant tumors demonstrate similar proangiogenic transcriptional signatures.

Objective: To determine whether CD11b(+)Gr1(+) immature myeloid cells (IMCs), initially identified to infiltrate tumors and support angiogenesis and recently identified also in mouse and human placentas, are similar in that they share common gene expression.

Design: Animal experiment.

Setting: Reproductive immunology laboratory.

Proangiogenic immature myeloid cells populate the human placenta and their presence correlates with placental and birthweight.

Objective: To determine whether proangiogenic immature myeloid cells are present in human placentas.

Study Design: Biopsies were obtained from 61 placentas of term pregnancies. Percentage of CD45(+)CD33(+)LIN2(-)HLADR(-) immature myeloid cells of total CD45(+) hematopoietic cells was determined by flow cytometry.

CD11c+HLADR+ dendritic cells are present in human ovarian follicular fluid, and their maturity correlates with serum estradiol levels in response to gonadotropins.

Objective: To determine whether dendritic cells (DCs), innate immune cells that specialize in initiation and modulation of immune responses, are present in ovarian follicular fluid (FF) and whether their abundance and maturation state correlate with ovarian response to gonadotropins.

Design: Observational study.

Setting: IVF unit and laboratory for reproductive immunology.

Maturation of human ovarian follicles is accompanied by a decrease in the CD56+CD16+ natural killer cell population.

Objective: To investigate whether "proangiogenic" CD56+CD16- natural killer (NK) cells, which accumulate in follicular fluid (FF) of patients with a good response to ovarian stimulation, are also present in earlier stages of follicular development.

Design: Observational study.

Setting: Academic in vitro fertilization (IVF) unit.

Immature myeloid cells accumulate in mouse placenta and promote angiogenesis.

Objective: We sought to determine whether CD11b(+)Gr1(+) immature myeloid cells (IMCs), which have been shown to promote tumor angiogenesis, accumulate in the placenta and similarly contribute to blood vessel formation.

Study Design: Experiments were performed on 6- to 8-week-old C57Bl/6J female mice. Placentas from pregnant mice or B16F10 tumors that were subcutaneously implanted were analyzed by flow cytometry and confocal microscopy.

Accelerated chemokine receptor 7-mediated dendritic cell migration in Runx3 knockout mice and the spontaneous development of asthma-like disease.

The Runx3 transcription factor is a key regulator of lineage-specific gene expression in several developmental pathways and could also be involved in autoimmunity. We report that, in dendritic cells (DC), Runx3 regulates TGFbeta-mediated transcriptional attenuation of the chemokine receptor CCR7. When Runx3 is lost, i.

Dual-specificity phosphatase Pyst2-L is constitutively highly expressed in myeloid leukemia and other malignant cells.

Northern blotting confirmed previous results indicating that the mitogen-activated protein kinase (MAPK) phosphatase Pyst2-L was highly expressed in leukocytes obtained from acute myeloid leukemia (AML) patients. High levels of Pyst2-L mRNA were expressed in bone marrow (BM) and peripheral leukocytes from nine AML and acute lymphoblastic leukemia (ALL) patients. BM from healthy individuals expressed very low levels of Pyst2-L.