TGF-beta in neural stem cells and in tumors of the central nervous system

Abstract

Mechanisms that regulate neural stem cell activity in the adult brain are tightly coordinated. They provide new neurons and glia in regions associated with high cellular and functional plasticity, after injury, or during neurodegeneration. Because of the proliferative and plastic potential of neural stem cells, they are currently thought to escape their physiological control mechanisms and transform to cancer stem cells. Signals provided by proteins of the transforming growth factor (TGF)-beta family might represent a system by which neural stem cells are controlled under physiological conditions but released from this control after transformation to cancer stem cells. TGF-beta is a multifunctional cytokine involved in various physiological and patho-physiological processes of the brain. It is induced in the adult brain after injury or hypoxia and during neurodegeneration when it modulates and dampens inflammatory responses. After injury, although TGF-beta is neuroprotective, it may limit the self-repair of the brain by inhibiting neural stem cell proliferation. Similar to its effect on neural stem cells, TGF-beta reveals anti-proliferative control on most cell types; however, paradoxically, many brain tumors escape from TGF-beta control. Moreover, brain tumors develop mechanisms that change the anti-proliferative influence of TGF-beta into oncogenic cues, mainly by orchestrating a multitude of TGF-beta-mediated effects upon matrix, migration and invasion, angiogenesis, and, most importantly, immune escape mechanisms. Thus, TGF-beta is involved in tumor progression. This review focuses on TGF-beta and its role in the regulation and control of neural and of brain-cancer stem cells.

Human Stem/Progenitor Cells from Bone Marrow Enhance Glial Differentiation of Rat Neural Stem Cells: A Role for Transforming Growth Factor β and Notch Signaling

“…A role for TGFb1 in glial differentiation is consistent with its being a member of a superfamily of growth factors known to produce a diverse range of biological effects in the developing CNS, including NSC expansion and fate determination [38][39][40]. Its role is also consistent with the observation that conditioned medium from hMSCs increased oligodendrogenesis by rNSCs incubated in medium containing 10% FBS [41,42].…”

Transforming Growth Factor Beta in the Central Nervous System

“…Subsequent in vitro experiments using quail neural crest cell demonstrated that TGF-β inhibits proliferation of neural crest cells while neurogenesis increased significantly in the presence of TGF-β (Zhang et al, 1997). Subsequent experiments using brains supported an inhibitory role of TGF-βs on neuronal stem cell proliferation (Aigner & Bogdahn, 2008). TGF-β had an antimitotic effect on progenitors and increased expression of neuronal markers in hippocampal and cortical primary cell cultures of developing mouse (Vogel et al, 2010).…”

“…In fact, they develop mechanisms that change the anti-proliferative influence of TGF-β into oncogenic cues. Thus, TGF-β is involved in tumor progression (Aigner & Bogdahn, 2008). The dominant hypothesis of TGF-β's pathogenetic association with malignant transformation has been predicated upon acquisition of resistance to its growth inhibitory effects.…”

Aberrant signaling pathways in medulloblastomas: a stem cell connection

“…The TGFβ superfamily consists of more than 100 different proteins, such as activins and inhibins, bone morphogenetic proteins (BMP), veg-1, the Drosophila decapentaplegic complex, and Mullerian-inhibiting substance. Thus far, more than 40 members of this superfamily have been described in mammals 38,39 as being involved in various physiological and pathophysiological processes of the brain. All three isoforms TGFβ1, TGFβ2 and TGFβ3 are expressed in neurons and glial cells 36 .…”

“…A similar effect on neurogenesis occurs during normal mammalian CNS development, when TGFβ has been reported to inhibit neural stem cell proliferation. In cancer, however, this TGFβ mediated cell growth control seems to be bypassed 39 . Resistance to growth inhibition can be detected in malignant glioma cells with functionally active TGFβ receptors 53 .…”