A Local Action of Neurotrophin-3 Prevents the Death of Proliferating Sensory Neuron Precursor Cells

AbstractThe role of neurotrophin-3 (NT-3) in early development of the dorsal root ganglion was investigated. Excessive cell death in the dorsal root ganglion of mice that carry a deleted NT-3 gene (NT-3−/− mice) preceded the period of programmed cell death, detected by the TUNEL method, and caused a reduction in the number of proliferating precursors without altering the proportion of proliferating cells to total number of neurons. Furthermore, the majority of proliferating cells detected by bromodeoxyuridine incorporation also stained with the TUNEL method. NT-3 mRNA was expressed locally in the embryonic, but not the postnatal dorsal root ganglion. Most cultured early embryonic NT-3−/− neurons died in the absence of exogenous NT-3 as did the wild-type neurons when cultured with NT-3 neutralizing antibodies, suggesting that NT-3 acts locally to prevent the death of proliferating sensory precursor cells during neurogenesis. Thus, NT-3 may inflict constraints on the number of proliferating precursor cells and thereby affect the number of neurons generated during development of the peripheral nervous system

Aggressiveness Niche: Can It Be the Foster Ground for Cancer Metastasis Precursors?

The relationship between tumor initiation and tumor progression can follow a linear projection in which all tumor cells are equally endowed with the ability to progress into metastasis. Alternatively, not all tumor cells are equal genetically and/or epigenetically, and only few cells are induced to become metastatic tumor cells. The location of these cells within the tumor can also impact the fate of these cells. The most inner core of a tumor where an elevated pressure of adverse conditions forms, such as necrosis-induced inflammation and hypoxia-induced immunosuppressive environment, seems to be the most fertile ground to generate such tumor cells with metastatic potential. Here we will call this necrotic/hypoxic core the “aggressiveness niche” and will present data to support its involvement in generating these metastatic precursors. Within this niche, interaction of hypoxia-surviving cells with the inflammatory microenvironment influenced by newly recruited mesenchymal stromal cells (MSCs), tumor-associated macrophages (TAMs), and other types of cells and the establishment of bidirectional interactions between them elevate the aggressiveness of these tumor cells. Additionally, immune evasion properties induced in these cells most likely contribute in the formation and maintenance of such aggressiveness niche

BRCA1-IRIS Overexpression Promotes Formation of Aggressive Breast Cancers

Introduction: Women with HER2 + or triple negative/basal-like (TN/BL) breast cancers succumb to their cancer rapidly due, in part to acquired Herceptin resistance and lack of TN/BL-targeted therapies. BRCA1-IRIS is a recently discovered, 1399 residue, BRCA1 locus alternative product, which while sharing 1365 residues with the full-length product of this tumor suppressor gene, BRCA1/p220, it has oncoprotein-like properties. Here, we examine whether BRCA1-IRIS is a valuable treatment target for HER2 + and/or TN/BL tumors

Development requirements of neurotrophins in the mammalian nervous system

The survival of the mammalian peripheral nervous system neurons has long been known to depend on neurotrophic factor support during the period of programmed cell death. In fact this was the original hypothesis, put forward after the discovery of the prototype, nerve growth factor (NGF). This hypothesis postulated the existence of lin-iited amounts of neurotrophic factors in target areas of peripheral sensory neurons, which are originally generated in excess. Following differentiation and establishment of target contact the neurons acquire dependency for neurotrophic factors for their survival. Only the neurons that successfully compete survive, the remainder die. In addition to NGF, there are several other neurotrophic factors: brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT- 4). They share about 50% amino acid homology, and bind to a family of related tyrosine kinase receptors. NGF activates trkA, BDNF and NT-4, trkB, while NT-3 activates trkC. 1 have studied the importance of all these factors and their receptors during development in neurotrophin mutant mice. I began this study to increase our knowledge on the role of neurotrophins for neuronal survival in vivo. I have studied the developmental requirements of dorsal root, nodoselpetrosal and trigeminal ganglia neurons for neurotrophins during intervals of embryonic mouse development through early postnatal ages in single or compound null mutant mice. Together the results point out that NT-3 is affecting the precursors of these sensory neurons prior to target innervation and programmed cell death. 1 further showed that this effect is mediated, at least in the dorsal root ganglion, by a local production of NT-3. Moreover and most importantly NT-3 seems crucial for the sensory precursors to exit the cell cycle in order to differentiate, and if denied NT-3, the precursors remain in the cell cycle and die. As for BDNF and NT-4, we have confirmed and extended the earlier observations by identifying their roles for sensory neurons survival in vivo. The data describe the cooperative effect of these neurotrophic factors and defines an order of action in vivo. Finally, we established an animal model for an-dnoglycoside hearing iinpainnent and showed the protective effect of NT-3 against hearing impairment