Angpt2/Tie2 autostimulatory loop controls tumorigenesis.

Invasive nonfunctioning (NF) pituitary neuroendocrine tumors (PitNETs) are non-resectable neoplasms associated with frequent relapses and significant comorbidities. As the current therapies of NF-PitNETs often fail, new therapeutic targets are needed. The observation that circulating angiopoietin-2 (ANGPT2) is elevated in patients with NF-PitNET and correlates with tumor aggressiveness prompted us to investigate the ANGPT2/TIE2 axis in NF-PitNETs in the GH3 PitNET cell line, primary human NF-PitNET cells, xenografts in zebrafish and mice, and in MENX rats, the only autochthonous NF-PitNET model. We show that PitNET cells express a functional TIE2 receptor and secrete bioactive ANGPT2, which promotes, besides angiogenesis, tumor cell growth in an autocrine and paracrine fashion. ANGPT2 stimulation of TIE2 in tumor cells activates downstream cell proliferation signals, as previously demonstrated in endothelial cells (ECs). Tie2 gene deletion blunts PitNETs growth in xenograft models, and pharmacological inhibition of Angpt2/Tie2 signaling antagonizes PitNETs in primary cell cultures, tumor xenografts in mice, and in MENX rats. Thus, the ANGPT2/TIE2 axis provides an exploitable therapeutic target in NF-PitNETs and possibly in other tumors expressing ANGPT2/TIE2. The ability of tumor cells to coopt angiogenic signals classically viewed as EC-specific expands our view on the microenvironmental cues that are essential for tumor progression.

Neuronal Development-Related miRNAs as Biomarkers for Alzheimer's Disease, Depression, Schizophrenia and Ionizing Radiation Exposure.

Radiation exposure may induce Alzheimer's disease (AD), depression or schizophrenia. A number of experimental and clinical studies suggest the involvement of miRNA in the development of these diseases, and also in the neuropathological changes after brain radiation exposure. The current literature review indicated the involvement of 65 miRNAs in neuronal development in the brain. In the brain tissue, blood, or cerebral spinal fluid (CSF), 11, 55, or 28 miRNAs are involved in the development of AD respectively, 89, 50, 19 miRNAs in depression, and 102, 35, 8 miRNAs in schizophrenia. We compared miRNAs regulating neuronal development to those involved in the genesis of AD, depression and schizophrenia and also those driving radiation-induced brain neuropathological changes by reviewing the available data. We found that 3, 11, or 8 neuronal developmentrelated miRNAs from the brain tissue, 13, 16 or 14 miRNAs from the blood of patient with AD, depression and schizophrenia respectively were also involved in radiation-induced brain pathological changes, suggesting a possibly specific involvement of these miRNAs in radiation-induced development of AD, depression and schizophrenia respectively. On the other hand, we noted that radiationinduced changes of two miRNAs, i.e., miR-132, miR-29 in the brain tissue, three miRNAs, i.e., miR- 29c-5p, miR-106b-5p, miR-34a-5p in the blood were also involved in the development of AD, depression and schizophrenia, thereby suggesting that these miRNAs may be involved in the common brain neuropathological changes, such as impairment of neurogenesis and reduced learning memory ability observed in these three diseases and also after radiation exposure.