BackgroundCharacterization of the niches for stem-like tumor cells is important to understand and control the behavior of glioblastomas. Cell-cycle quiescence might be a common mechanism underlying the long-term maintenance of stem-cell function in normal and neoplastic stem cells, and our previous study demonstrated that quiescence induced by hypoxia-inducible factor (HIF)-1α is associated with a high long-term repopulation capacity of hematopoietic stem cells. Based on this, we examined human astrocytoma tissues for HIF-1α-regulated quiescent stem-like tumor cells as a candidate for long-term tumorigenic cells and characterized their niche histologically.MethodsMulti-color immunohistochemistry was used to visualize HIF-1α-expressing (HIF-1α+) quiescent stem-like tumor cells and their niche in astrocytoma (WHO grade II–IV) tissues. This niche was modeled using spheroids of cultured glioblastoma cells and its contribution to tumorigenicity was evaluated by sphere formation assay.ResultsA small subpopulation of HIF-1α+ quiescent stem-like tumor cells was found in glioblastomas but not in lower-grade astrocytomas. These cells were concentrated in the zone between large ischemic necroses and blood vessels and were closer to the necrotic tissues than to the blood vessels, which suggested that a moderately hypoxic microenvironment is their niche. We successfully modeled this niche containing cells of HIF-1α+ quiescent stem-like phenotype by incubating glioblastoma cell spheroids under an appropriately hypoxic condition, and the emergence of HIF-1α+ quiescent stem-like cells was shown to be associated with an enhanced sphere-forming activity.ConclusionsThese data suggest that the “peri-necrotic niche” harboring HIF-1α+ quiescent stem-like cells confers a higher tumorigenic potential on glioblastoma cells and therefore may be a therapeutic target to control the behavior of glioblastomas.
Glioblastomas are the most aggressive brain tumors. Glioblastoma stem cells (GSCs) are thought to be responsible for the recurrence, chemoresistance, and poor prognosis of glioblastoma. Fatty acid binding protein 7 (FABP7), which is a cellular chaperone for a variety of omega-3 fatty acids, is a known marker for neural stem cells. In this study, using a newly developed anti-FABP7 antibody and patient-derived GSC lines, we evaluated the expression of FABP7 in GSCs. Using immunocytochemistry, Western blotting, and qPCR analyses, FABP7 was found to be highly enriched in GSCs and its localization was found in cytosol and nuclei. FABP7 expression was significantly downregulated in differentiated GSCs induced by the addition of serum. In the glioma surgical specimens, FABP7 was highly expressed in the majority of glioblastoma. Double immunostaining for FABP7 and Sox2 showed that FABP7 + Sox2 + tumor cells were significantly increased in glioblastoma (grade IV) compared with diffuse astrocytoma (grade II) and anaplastic astrocytoma (grade III). Our data introduces FABP7 as a marker for GSCs and further highlights its possible significance for glioma diagnosis and treatment.
Abstract. The objectives of this research were to characterize plasma profiles of growth hormone (GH), prolactin (PRL) and insulin-like growth factor-I (IGF-I) during gestation and the lactation period in goats, as well as in their suckling growing kids. There were no obvious changes in the GH or PRL profiles during gestation, but secretion of both GH and PRL increased acutely after parturition. The elevated GH concentrations were maintained until 3 months after parturition, whereas the PRL concentrations decreased gradually after parturition. The elevated hormone concentrations are thought to be caused mainly by an increase in the secretory pulse amplitudes. In contrast to the GH and PRL profiles, the plasma IGF-I concentrations during late gestation were significantly higher than the post-parturition concentrations, and the IGF-I concentrations in late gestation decreased gradually until the day of parturition. The plasma GH, PRL and IGF-I concentrations in kids 1 week after birth were high, and concentrations of each hormone decreased thereafter. These results show that the increased secretory potencies of pituitary GH and PRL after parturition are caused mainly by an increase in the secretory pulse amplitudes and that plasma GH is inversely related to plasma IGF-I compared over gestation and the lactation period in goats. Key words: GH, PRL, IGF-I, Gestation, Lactation.(J. Reprod. Dev. 45: [273][274][275][276][277][278][279][280][281] 1999) G estation is a composite of integrated processes, resulting in the successful development of fetuses and the birth of offspring. The energy and nutrient requirements in pregnant animals are increased during gestation [1]. The survival of newborn animals is dependent on an adequate supply of milk secreted from the mammary glands of the mother after parturition [2]. Since growth hormone (GH) regulates many aspects of metabolic activity [3], it is meaningful to examine the GH profiles throughout gestation and during the lactation period in animals. Plasma or serum concentrations of GH and prolactin (PRL) in ruminants have been observed to elevate acutely during the periparturient period [4][5][6][7][8][9]. In these published observations, however, blood samples were usually collected for only a few weeks around parturition, and plasma profiles of GH and PRL have never been examined throughout gestation. Moreover, the blood samples were collected only about once a day, although GH and PRL are known to be secreted in transient pulses [3,[10][11][12][13][14]. PRL is required for the initiation of lactation [15,16]; therefore, it is of interest to determine how the pulsatile secretory patterns of both GH and PRL change throughout gestation and during the lactation period in animals. The anabolic action of GH is
Epithelioid glioblastoma (GBM) and rhabdoid GBM are rare variants that are morphologically similar, but there is no consensus on the characteristics of each disease. These tumors have aggressive features of early recurrence and leptomeningeal dissemination and tend to develop in younger patients compared to typical GBM. The prognosis is normally worse than typical GBM, even with intensive chemoradiotherapy after surgical resection. Thus, accurate diagnosis and effective therapy for epithelioid/rhabdoid GBM are required. Four consecutive patients aged 16-48 years were diagnosed with epithelioid/rhabdoid GBM by pathological and immunohistochemical analysis at Yamaguchi University Hospital from 2006 to 2012. Two of these patients had relatively long-term survival (19 and 23 months after diagnosis). Two cases had a BRAF V600E mutation, whereas no ATRX mutation was present in any cases. All patients suffered leptomeningeal and/or spinal dissemination that worsened their prognosis. These results illustrate the need for a new therapeutic approach, such as molecular targeted drug therapy like BRAF inhibition, in addition to standard chemoradiotherapy for typical GBM.
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