Growth hormone receptor immunoreactivity is increased in the subventricular zone of juvenile rat brain after focal ischemia: A potential role for growth hormone in injury-induced neurogenesis

Christophidis, Larissa Joy; Gorba, Thorsten; Gustavsson, Malin; Williams, Chris; Werther, George A.; Russo, Vincenzo; Scheepens, Arjan

doi:10.1016/j.ghir.2009.05.001

Cited by 48 publications

(32 citation statements)

References 61 publications

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“…These physiological processes are accentuated near sites of traumatic brain injury, and ischemia, suggesting a role for NPCs and their differentiated descendants in pathological responses. [25, 46]. Thus, although migratory NPCs are known to exist in the post-natal mammalian brain, little is known about any molecular cues mediating their activation, migration, and differentiation in during brain metastasis [47].…”

Section: Discussionmentioning

confidence: 99%

Co-evolution of breast-to-brain metastasis and neural progenitor cells

Neman

Choy

Kowolik

et al. 2013

Clin Exp Metastasis

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Brain colonization by metastatic tumor cells offers a unique opportunity to investigate microenvironmental influences on the neoplastic process. The bi-directional interplay of breast cancer cells (mesodermal origin) and brain cells (neuroectodermal origin) is poorly understood and rarely investigated. In our patients undergoing neurosurgical resection of breast-to-brain metastases, specimens from the tumor/brain interface exhibited increased active gliosis as previously described. In addition, our histological characterization revealed infiltration of neural progenitor cells (NPCs) both outside and inside the tumor margin, leading us to investigate the cellular and molecular interactions between NPCs and metastases. Since signaling by the TGF-β superfamily is involved in both developmental neurobiology and breast cancer pathogenesis, we examined the role of these proteins in the context of brain metastases. The brain-metastatic breast cancer cell line MDA-MB-231Br (231Br) expressed BMP-2 at significantly higher levels compared to its matched primary breast cancer cell line MDA-MB-231 (231). Co-culturing was used to examine bi-directional cellular effects and the relevance of BMP-2 overexpression. When co-cultured with NPCs, 231 (primary) tumor cells failed to proliferate over 15 days. However, 231Br (brain meta-static) tumor cells co-cultured with NPCs escaped growth inhibition after day 5 and proliferated, occurring in parallel with NPC differentiation into astrocytes. Using shRNA and gene knock-in, we then demonstrated BMP-2 secreted by 231Br cells mediated NPC differentiation into astrocytes and concomitant tumor cell proliferation in vitro. In xenografts, overexpression of BMP-2 in primary breast cancer cells significantly enhanced their ability to engraft and colonize the brain, thereby creating a metastatic phenotype. Conversely, BMP-2 knockdown in metastatic breast cancer cells significantly diminished engraftment and colonization. The results suggest metastatic tumor cells create a permissive neural niche by steering NPC differentiation toward astrocytes through paracrine BMP-2 signaling.

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Section: Discussionmentioning

confidence: 99%

Co-evolution of breast-to-brain metastasis and neural progenitor cells

Neman

Choy

Kowolik

et al. 2013

Clin Exp Metastasis

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“…In response to a hypoxia/ischemic injury, the brain initiates a serial endogenous neuroprotective strategies aimed at reducing neuronal cell death (Johansson et al, 1999;Slevin et al, 2005). Several studies suggested that GH may play a complex role in the pathophysiology of brain injury related to ischemia/hypoxia, similar to other neurotrophins in the brain (Shin et al, 2004;Scheepens et al, 2000;Christophidis et al, 2009). …”

Section: Discussionmentioning

confidence: 99%

“…However, the exact source and distribution of GH under the hypoxia condition is largely unknown. Increased GH and GHR expression or GHR immunoreactivity have been reported after hypoxic-ischemic brain injury (Scheepens et al, 1999;Christophidis et al, 2009). Furthermore, even though it is still controversial whether exogenous GH will cross the blood brain barrier (BBB), we now report on the exogenous GH-mediated effects on the expression of selected genes as well as the mitigation of the functional consequences of IH.…”

Section: Discussionmentioning

confidence: 99%

Exogenous growth hormone attenuates cognitive deficits induced by intermittent hypoxia in rats

Li¹,

Guo²,

Raccurt³

et al. 2011

Neuroscience

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Sleep disordered breathing (SDB), which is characterized by intermittent hypoxia (IH) during sleep, causes substantial cardiovascular and neurocognitive complications and has become a growing public health problem. SDB is associated with suppression of growth hormone (GH) secretion, the latter being integrally involved in the growth, development and function of the central nervous system (CNS). Since GH treatment is able to attenuate neurocognitive deficits in a hypoxic-ischemic stroke model, GH, GH receptor (GHR) mRNA expression and GH protein expression were assessed in rat hippocampus after exposures to chronic sustained hypoxia (CH, 10% O2) or intermittent hypoxia (IH, 10% O2 alternating with 21% O2 every 90 sec). In addition, the effect of GH treatment (50 µg/kg, daily s.c. injection) on EPO, VEGF, HO-1 and GLUT-1 mRNA expression and neurobehavioral function was assessed. CH significantly increased GH mRNA and protein expression, as well as IGF-1. In contrast, IH only induced a moderate increase in GH mRNA and a slight elevation in GH protein at day 1, but no increases in IGF-1. CH, but not IH, up-regulated GHR mRNA in the hippocampus. IH induced marked neurocognitive deficits compared to CH or room air (RA). Furthermore, exogenous GH administration increased hippocampal mRNA expression of IGF-1, EPO and VEGF, and not only reduced IH-induced hippocampal injury, but also attenuated IH-induced cognitive deficits. Thus, exogenous GH may provide a viable therapeutic intervention to protect IH-vulnerable brain regions from SDB-associated neuronal loss and associated neurocognitive dysfunction.

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“…Specifically, neurons of the hippocampus, astrocytes close to the ventricles, and neurons and astrocytes of the cerebral cortex express GHRs in rats [18]. In addition, GHRs appear to be expressed in ventricular astrocytes in the SVZ [19]. Therefore, it was somewhat surprising to find that GH did not increase proliferation in this brain region, especially considering that these cells have a high proliferative rate.…”

Section: Magnitude Of Cell Proliferation Induced By Bghmentioning

confidence: 99%