Highlights d G-CSF is required, but not sufficient, to mobilize immature low-density neutrophils d Immature low-density neutrophils are defined by a C/EBPε transcriptional signature d Immature low-density neutrophils promote the formation of liver metastases d Immature low-density neutrophils have a higher global bioenergetic capacity
Preexisting diabetes is a risk factor for the development of multiple types of cancer. Additionally, diabetic patients face a poorer prognosis when diagnosed with cancer. To gain insight into the effects of hyperglycemia, a hallmark of diabetes, on tumor growth and metastatic progression, we combined mouse models of cancer and hyperglycemia. We show that while hyperglycemia attenuates primary tumor growth, it concomitantly increases metastatic seeding in a distant organ. We further show that the increase in metastatic seeding is due to impaired secretion of granulocyte colony-stimulating factor (G-CSF) and impaired neutrophil mobilization. Normalizing blood glucose levels using insulin rescues neutrophil recruitment and tumor growth and concomitantly reduces metastatic seeding. These results provide links among hyperglycemia-induced changes in neutrophil mobilization, primary tumor growth, and metastatic progression. Furthermore, our observations highlight the importance of normalizing blood glucose levels in hyperglycemic cancer patients.
Neutrophils are the most abundant population of white blood cells in the human circulation playing a critical role in inflammation and in host defense against microbial infections. In recent years there has been growing interest in understanding the role the tumor microenvironment plays in tumor growth and progression. In this context, the role neutrophils play has been a matter of debate as neutrophils were shown to possess both tumor promoting and tumor limiting properties. These conflicting observations stem from differences in how neutrophils respond to environmental cues as well as from the existence of distinct tumor-promoting and tumor-limiting neutrophil populations. Here, we review general aspects of neutrophil biology and the favorable functions of neutrophils in the primary tumor and the pre-metastatic microenvironment. We further discuss the mechanisms neutrophils employ to limit tumor progression and highlight the aspects of neutrophil biology that may be targeted in future neutrophil-based cancer immunotherapies.
Adult neural stem cells with the ability to generate neurons and glia cells are active throughout life in both the dentate gyrus (DG) and the subventricular zone (SVZ). Differentiation of adult neural stem cells is induced by cell fate determinants like the transcription factor Prox1. Evidence has been provided for a function of Prox1 as an inducer of neuronal differentiation within the DG. We now show that within the SVZ Prox1 induces differentiation into oligodendrocytes. Moreover, we find that loss of Prox1 expression in vivo reduces cell migration into the corpus callosum, where the few Prox1 deficient SVZ-derived remaining cells fail to differentiate into oligodendrocytes. Thus, our work uncovers a novel function of Prox1 as a fate determinant for oligodendrocytes in the adult mammalian brain. These data indicate that the neurogenic and oligodendrogliogenic lineages in the two adult neurogenic niches exhibit a distinct requirement for Prox1, being important for neurogenesis in the DG but being indispensable for oligodendrogliogenesis in the SVZ. STEM CELLS 2016;34:2115-2129 SIGNIFICANCE STATEMENTIn the submitted study, we address the function of the homeobox transcription factor Prox1 for the specification of oligodendrocyte cell fate in adult neural stem cells. A function of Prox1 for neurogenesis is well described in Drosophila. Additionally, recently its implication in neuronal differentiation in neural stem cells has been shown. Therefore, the function seemed to be totally conserved from Drosophila to mammals. However, we here show that the function of Prox1 depends on the regional identity of the investigated neural stem cells. In neural stem cells of the hippocampus, Prox1 induces neuronal differentiation. However, in neural stem cell from the subventricular zone Prox1 induces differentiation in oligodendrocytes.
Neutrophils play critical roles in a broad spectrum of clinical conditions. Accordingly, manipulation of neutrophil function may provide a powerful immunotherapeutic approach. However, due to neutrophils characteristic short half-life and their large population number, this possibility was considered impractical. Here we describe the identification of peptides which specifically bind either murine or human neutrophils. Although the murine and human neutrophil-specific peptides are not cross-reactive, we identified CD177 as the neutrophil-expressed binding partner in both species. Decorating nanoparticles with a neutrophil-specific peptide confers neutrophil specificity and these neutrophil-specific nanoparticles accumulate in sites of inflammation. Significantly, we demonstrate that encapsulating neutrophil modifying small molecules within these nanoparticles yields specific modulation of neutrophil function (ROS production, degranulation, polarization), intracellular signaling and longevity both in vitro and in vivo. Collectively, our findings demonstrate that neutrophil specific targeting may serve as a novel mode of immunotherapy in disease.
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