Subventricular zone

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Subventricular zone
Identifiers
NeuroLex ID nlx_144262
Anatomical terms of neuroanatomy
Human subventricular zone. From a paper by Oscar Arias-Carrion, 2008 Human subventricular zone.jpg
Human subventricular zone. From a paper by Oscar Arias-Carrión, 2008
In an embryonic rat brain, GAD67-binding marker tends to concentrate in subventricular zone. An image from Popp et al., 2009. Autoradiography of a brain slice from an embryonal rat - PMID19190758 PLoS 0004371.png
In an embryonic rat brain, GAD67-binding marker tends to concentrate in subventricular zone. An image from Popp et al., 2009.

The subventricular zone (SVZ) is a region situated on the outside wall of each lateral ventricle of the vertebrate brain. [2] It is present in both the embryonic and adult brain. In embryonic life, the SVZ refers to a secondary proliferative zone containing neural progenitor cells, which divide to produce neurons in the process of neurogenesis. [3] The primary neural stem cells of the brain and spinal cord, termed radial glial cells, instead reside in the ventricular zone (VZ) (so-called because the VZ lines the inside of the developing ventricles). [4]

Contents

In the developing cerebral cortex, which resides in the dorsal telencephalon, the SVZ and VZ are transient tissues that do not exist in the adult. [4] However, the SVZ of the ventral telencephalon persists throughout life. The adult SVZ is composed of four distinct layers [5] of variable thickness and cell density as well as cellular composition. Along with the dentate gyrus of the hippocampus, the SVZ is one of two places where neurogenesis has been found to occur in the adult mammalian brain. [6] Adult SVZ neurogenesis takes the form of neuroblast precursors of interneurons that migrate to the olfactory bulb through the rostral migratory stream. The SVZ also appears to be involved in the generation of astrocytes following a brain injury. [7]

Structure

Layer I

The innermost layer (Layer I) contains a single layer (monolayer) of ependymal cells lining the ventricular cavity; these cells possess apical cilia and several basal expansions that may stand in either parallel or perpendicular to the ventricular surface. These expansions may interact intimately with the astrocytic processes that are interconnected with the hypocellular layer (Layer II). [5]

Layer II

The secondary layer (Layer II) provides for a hypocellular gap abutting the former and has been shown to contain a network of functionally correlated Glial Fibrillary Acid Protein (GFAP)-positive astrocytic processes that are linked to junctional complexes, yet lack cell bodies except for the rare neuronal somata. While the function of this layer is yet unknown in humans, it has been hypothesized that the astrocytic and ependymal interconnections of Layer I and II may act to regulate neuronal functions, establish metabolic homeostasis, and/or control neuronal stem cell proliferation and differentiation during development. Potentially, such characteristics of the layer may act as a remainder of early developmental life or pathway for cellular migration given similarity to a homologous layer in bovine SVZ shown to have migratory cells common only to higher order mammals. [5]

Layer III

The third layer (Layer III) forms a ribbon of astrocyte cell bodies that are believed to maintain a subpopulation of astrocytes able to proliferate in vivo and form multipotent neurospheres with self-renewal abilities in vitro. While some oligodendrocytes and ependymal cells have been found within the ribbon, they not only serve an unknown function, they are uncommon by comparison to the population of astrocytes that reside in the layer. The astrocytes present in Layer III can be divided into three populations through electron microscopy, with no unique functions yet recognizable; the first type is a small astrocyte of long, horizontal, tangential projections mostly found in Layer II; the second type is found between Layers II and III as well as within the astrocyte ribbon, characterized by its large size and many organelles; the third type is typically found in the lateral ventricles just above the hippocampus and is similar in size to the second type but contains few organelles. [5]

Layer IV

The fourth and final layer (Layer IV) serves as a transition zone between Layer III with its ribbon of astrocytes and the brain parenchyma. It is identified by a high presence of myelin in the region. [5]

Cell types

Four cell types are described in the SVZ: [8]

1. Ciliated Ependymal Cells (Type E): are positioned facing the lumen of the ventricle, and function to circulate the cerebrospinal fluid.

2. Proliferating Neuroblasts (Type A): express PSA-NCAM (NCAM1), Tuj1 (TUBB3), and Hu, and migrate in line order to the olfactory bulb

3. Slow Proliferating Cells (Type B): express Nestin and GFAP, and function to ensheathe migrating Type A Neuroblasts [9]

4. Actively Proliferating Cells or Transit Amplifying Progenitors (Type C): express Nestin, and form clusters interspaced among chains throughout region [10]

Function

The SVZ is a known site of neurogenesis and self-renewing neurons in the adult brain, [11] serving as such due to the interacting cell types, extracellular molecules, and localized epigenetic regulation promoting such cellular proliferation. Along with the subgranular zone of the dentate gyrus, the subventricular zone serves as a source of neural stem cells (NSCs) in the process of adult neurogenesis. It harbors the largest population of proliferating cells in the adult brain of rodents, monkeys and humans. [12] In 2010, it was shown that the balance between neural stem cells and neural progenitor cells (NPCs) is maintained by an interaction between the epidermal growth factor receptor signaling pathway and the Notch signaling pathway. [13]

While it has yet to have been studied in-depth in the human brain, the SVZ function in the rodent brain has been, to a certain extent, examined and defined for its abilities. With such research, it has been found that the dual-functioning astrocyte is the dominant cell in the rodent SVZ; this astrocyte acts as not only a neuronal stem cell, but also as a supporting cell that promotes neurogenesis through interaction with other cells. [8] This function is also induced by microglia and endothelial cells that interact cooperatively with neuronal stem cells to promote neurogenesis in vitro, as well as extracellular matrix components such as tenascin-C (helps define boundaries for interaction) and Lewis X (binds growth and signaling factors to neural precursors). [14] The human SVZ is different, however, from the rodent SVZ in two distinct ways; the first is that the astrocytes of humans are not in close juxtaposition to the ependymal layer, rather separated by a layer lacking cell bodies; the second is that the human SVZ lacks chains of migrating neuroblasts seen in rodent SVZ, in turn providing for a lesser number of neuronal cells in the human than the rodent. [2] For this reason, while rodent SVZ proves as a valuable source of information regarding the SVZ and its structure-to-function relationship, the human model will prove significantly different.

Epigenetic DNA modifications have a central role in regulating gene expression during differentiation of neural stem cells. The conversion of cytosine to 5-methylcytosine (5mC) in DNA by DNA methyltransferase DNMT3A appears to be an important type of epigenetic modification occurring in the SVZ. [15]

In addition, some current theories propose that the SVZ may also serve as a site of proliferation for brain tumor stem cells (BTSCs), [16] which are similar to neural stem cells in their structure and ability to differentiate into neurons, astrocytes, and oligodendrocytes. Studies have confirmed that a small population of BTSCs can not only produce tumors, but they can also maintain it through innate self-renewal and multipotent abilities. While this does not allow for inference that BTSCs arise from neural stem cells, it does raise an interesting question as to the relationship that exists from our own cells to those that can cause so much damage.[ citation needed ]

Current research

There are currently many different aspects of the SVZ being researched by individuals in the public and private sectors. Such research interests range from the role of the SVZ in neurogenesis, directed neuronal migration, to the previously mentioned tumorigenesis, as well as many others. Below there are summaries of the work of three different lab groups focusing primarily on one aspect of the SVZ; these include the role of SVZ in cell replacement after brain injury, simulation of NSC proliferation, and role in various tumorigenic cancers.

Role in cell replacement after brain injury

In their review, Romanko et al. characterized the impact of acute brain injury on the SVZ. Overall, the authors determined that moderate insults to the SVZ allowed for recovery while more severe injuries caused permanent damage to the region. Additionally, the neural stem cell population within the SVZ is likely responsible for this injury response. [17]

The effects of irradiation on the SVZ provided for a recognition of the amount or dose of radiation that can be given is determined mostly by the tolerance of the normal cells near the tumor. As described, the increasing dose of radiation and age led to decrease in three cell types of the SVZ, yet repair capacity of the SVZ was observed despite the lack of white matter necrosis; this occurred likely because the SVZ was able to gradually replace the neuroglia of the brain. Chemotherapeutics were also tested for their effects on the SVZ, as they are currently used for many diseases yet lead to complications within the central nervous system. To do so, methotrexate (MTX) was used alone and in combination with radiation to find that roughly 70% of the total nuclear density of the SVZ had been depleted, yet given loss of neuroblast cells (progenitor cells), it was remarkable to find that SVZ NSCs would still generate neurospheres similar to subjects that did not receive such treatment. In relation to interruption of blood supply to the brain, cerebral hypoxia/ischemia (H/I) was found to also decrease the cell count of the SVZ by 20%, with 50% of neurons in the striatum and neocortex being destroyed, but the cell types of the SVZ killed were as non-uniform as the region itself. Upon subsequent testing, it was found that a different portion of each cell was eliminated, yet the medial SVZ cell population remained mostly alive. This may provide for a certain resiliency of such cells, with the uncommitted progenitor cells acting as the proliferating population following ischemia. Mechanical brain injury also induces cell migration and proliferation, as was observed in rodents, and it may also increase cell number, negating the previously held notion that no new neuronal cells can be generated.[ citation needed ]

In conclusion, this group was able to determine that cells in the SVZ are able to produce new neurons and glia throughout life, given it does not suffer damage as it is sensitive to any deleterious effects. Therefore, the SVZ can recover itself following mild injury, and potentially provide for replacement cell therapy to other affected regions of the brain.[ citation needed ]

Role of neuropeptide Y in neurogenesis

In an attempt to characterize and analyze the mechanism concerning the proliferation of neuronal cells within the subventricular zone, Decressac et al. observed the proliferation of neural precursors in the mouse subventricular zone through injection of the neuropeptide Y (NPY). [18] NPY is a commonly expressed protein of the central nervous system that has previously been shown to stimulate proliferation of neuronal cells in the olfactory epithelium and hippocampus. The peptide’s effects were observed through BrdU labeling and cell phenotyping that provided evidence for the migration of neuroblasts through the rostral migratory stream to the olfactory bulb (confirming previous experiments) and to the striatum. Such data supports the author's hypothesis in that neurogenesis would be stimulated through introduction of such a peptide.[ citation needed ]

As NPY is a 36 amino acid peptide associated with many physiological and pathological conditions, it has multiple receptors that are broadly expressed in the developing and mature rodent brain. However, given in vivo studies performed by this group, the Y1 receptor displayed specifically mediated neuroproliferative effects through the induction of NPY with increased expression in the subventricular zone. Identification of the Y1 receptor also sheds light on the fact that the phenotype of expressed cells from such mitotic events are actually cells that are DCX+ (neuroblasts that migrate directly to the striatum) type. Along with the effects of NPY injection on striatal dopamine, GABA and glutamate parameters to regulate neurogenesis in the subventricular zone (previous study), this finding is still under consideration as it could be a secondary modulator of the aforementioned neurotransmitters.[ citation needed ]

As is necessary for all research, this group conducted its experiments with a broad perspective on the application of their findings, which they claimed could potentially benefit potential candidates for endogenous brain repair through stimulation of the subventricular zone neural stem cell proliferation. This natural molecular regulation of adult neurogenesis would be adjunct with therapies of appropriate molecules such as the tested NPY and Y1 receptor, in addition to pharmacological derivatives, in providing for manageable forms of neurodegenerative disorders of the striatal area.[ citation needed ]

As a potential source of brain tumors

In an attempt to characterize the role of the subventricular zone in potential tumorigenesis, Quinones-Hinojosa et al. found that brain tumor stem cells (BTSCs) are stem cells that can be isolated from brain tumors by similar assays used for neuronal stem cells. [5] In forming clonal spheres similar to neurospheres of neuronal stem cells, these BTSCs were able to differentiate into neurons, astrocytes and oligodendrocytes in vitro , yet more importantly capable of initiating tumors at low cell concentrations, providing a self-renewal capacity. It was therefore proposed that a small population of BTSCs with such self-renewal capabilities were maintaining tumors in diseases such as leukemia and breast cancer.[ citation needed ]

Several characterizing factors lead to the proposed idea of neuronal stem cells (NSCs) being the origin for BTSCs, as they share several features. These features are shown in the figure.

This group provides evidence of the SVZ's apparent role in tumorigenesis as demonstrated by the possession of mitogenic receptors and their response to mitogenic stimulation, specifically type C cells that express the epidermal growth factor receptor (EGFR), making them highly proliferative and invasive. Additionally, the existence of microglia and endothelial cells within the SVZ was found to enhance neurogenesis, as well as providing for some directional migration of neuroblasts from the SVZ.[ citation needed ]

Recently, the human SVZ has been characterized in brain tumor patients at phenotypic and genetic level. These data reveal that in half of the patients the SVZ is an exact site of tumorigenesis whereas in the remaining patients it represents an infiltrated region. [19] Thus, it is distinctly possible that in humans a relationship exists between the NSC generation of the region and the consistently self-renewing cells of primary tumors that give way to secondary tumors once removed or irradiated.[ citation needed ]

While it remains to be definitely proven whether the SVZ stem cells are the cell of origin for brain tumors such as gliomas, there is strong evidence that suggests increased tumor aggressiveness and mortality in those patients whose high-grade gliomas infiltrate or contact the SVZ. [20] [21]

In prostate cancer, tumor-induced neurogenesis is characterized by the recruitment of neural progenitor cells (NPC) from SVZ. NPCs infiltrate the tumor where they differentiate into autonomic neurons (adrenergic neurons mainly) that stimulate tumor growth. [22]

See also

Related Research Articles

<span class="mw-page-title-main">Adult neurogenesis</span> Generating of neurons from neural stem cells in adults

Adult neurogenesis is the process in which neurons are generated from neural stem cells in the adult. This process differs from prenatal neurogenesis.

In vertebrates, a neuroblast or primitive nerve cell is a postmitotic cell that does not divide further, and which will develop into a neuron after a migration phase. In invertebrates such as Drosophila, neuroblasts are neural progenitor cells which divide asymmetrically to produce a neuroblast, and a daughter cell of varying potency depending on the type of neuroblast. Vertebrate neuroblasts differentiate from radial glial cells and are committed to becoming neurons. Neural stem cells, which only divide symmetrically to produce more neural stem cells, transition gradually into radial glial cells. Radial glial cells, also called radial glial progenitor cells, divide asymmetrically to produce a neuroblast and another radial glial cell that will re-enter the cell cycle.

Oligodendrocyte progenitor cells (OPCs), also known as oligodendrocyte precursor cells, NG2-glia, O2A cells, or polydendrocytes, are a subtype of glia in the central nervous system named for their essential role as precursors to oligodendrocytes. They are typically identified in the human by co-expression of PDGFRA and CSPG4.

<span class="mw-page-title-main">Rostral migratory stream</span> One path neural stem cells take to reach the olfactory bulb


The rostral migratory stream (RMS) is a specialized migratory route found in the brain of some animals along which neuronal precursors that originated in the subventricular zone (SVZ) of the brain migrate to reach the main olfactory bulb (OB). The importance of the RMS lies in its ability to refine and even change an animal's sensitivity to smells, which explains its importance and larger size in the rodent brain as compared to the human brain, as our olfactory sense is not as developed. This pathway has been studied in the rodent, rabbit, and both the squirrel monkey and rhesus monkey. When the neurons reach the OB they differentiate into GABAergic interneurons as they are integrated into either the granule cell layer or periglomerular layer.

Neuroepithelial cells, or neuroectodermal cells, form the wall of the closed neural tube in early embryonic development. The neuroepithelial cells span the thickness of the tube's wall, connecting with the pial surface and with the ventricular or lumenal surface. They are joined at the lumen of the tube by junctional complexes, where they form a pseudostratified layer of epithelium called neuroepithelium.

Neural stem cells (NSCs) are self-renewing, multipotent cells that firstly generate the radial glial progenitor cells that generate the neurons and glia of the nervous system of all animals during embryonic development. Some neural progenitor stem cells persist in highly restricted regions in the adult vertebrate brain and continue to produce neurons throughout life. Differences in the size of the central nervous system are among the most important distinctions between the species and thus mutations in the genes that regulate the size of the neural stem cell compartment are among the most important drivers of vertebrate evolution.

<span class="mw-page-title-main">Radial glial cell</span> Bipolar-shaped progenitor cells of all neurons in the cerebral cortex and some glia

Radial glial cells, or radial glial progenitor cells (RGPs), are bipolar-shaped progenitor cells that are responsible for producing all of the neurons in the cerebral cortex. RGPs also produce certain lineages of glia, including astrocytes and oligodendrocytes. Their cell bodies (somata) reside in the embryonic ventricular zone, which lies next to the developing ventricular system.

Neuropoiesis is the process by which neural stem cells differentiate to form mature neurons, astrocytes, and oligodendrocytes in the adult mammal. This process is also referred to as adult neurogenesis.

Michael S. Kaplan is an American biology researcher, medical professor, and clinical physician. A pioneer of neurogenesis research, his work refuted the classic idea that no new nerve cells are born in the adult mammalian brain. His research using light and electron microscopy suggested that neurogenesis occurs in the brain of adult mammals, but his findings were rejected by the scientific community at the time in a field that continues to be contentious. Doctor Kaplan has recently begun a YouTube channel which offers patient interviews and insights to brain plasticity; kaplan brain health, YouTube.

<span class="mw-page-title-main">Subgranular zone</span>

The subgranular zone (SGZ) is a brain region in the hippocampus where adult neurogenesis occurs. The other major site of adult neurogenesis is the subventricular zone (SVZ) in the brain.

<span class="mw-page-title-main">BTG2</span> Protein-coding gene in the species Homo sapiens

Protein BTG2 also known as BTG family member 2 or NGF-inducible anti-proliferative protein PC3 or NGF-inducible protein TIS21, is a protein that in humans is encoded by the BTG2 gene and in other mammals by the homologous Btg2 gene. This protein controls cell cycle progression and proneural genes expression by acting as a transcription coregulator that enhances or inhibits the activity of transcription factors.

<span class="mw-page-title-main">Ganglion mother cell</span>

Ganglion mother cells (GMCs) are cells involved in neurogenesis, in non-mammals, that divide only once to give rise to two neurons, or one neuron and one glial cell or two glial cells, and are present only in the central nervous system. They are also responsible for transcription factor expression. While each ganglion mother cell necessarily gives rise to two neurons, a neuroblast can asymmetrically divide multiple times. GMCs are the progeny of type I neuroblasts. Neuroblasts asymmetrically divide during embryogenesis to create GMCs. GMCs are only present in certain species and only during the embryonic and larval stages of life. Recent research has shown that there is an intermediate stage between a GMC and two neurons. The GMC forms two ganglion cells which then develop into neurons or glial cells. Embryonic neurogenesis has been extensively studied in Drosophila melanogaster embryos and larvae.

Gliogenesis is the generation of non-neuronal glia populations derived from multipotent neural stem cells.

<span class="mw-page-title-main">Eomesodermin</span> Protein-coding gene in the species Homo sapiens

Eomesodermin also known as T-box brain protein 2 (Tbr2) is a protein that in humans is encoded by the EOMES gene.

Endogenous regeneration in the brain is the ability of cells to engage in the repair and regeneration process. While the brain has a limited capacity for regeneration, endogenous neural stem cells, as well as numerous pro-regenerative molecules, can participate in replacing and repairing damaged or diseased neurons and glial cells. Another benefit that can be achieved by using endogenous regeneration could be avoiding an immune response from the host.

The development of the cerebral cortex, known as corticogenesis is the process during which the cerebral cortex of the brain is formed as part of the development of the nervous system of mammals including its development in humans. The cortex is the outer layer of the brain and is composed of up to six layers. Neurons formed in the ventricular zone migrate to their final locations in one of the six layers of the cortex. The process occurs from embryonic day 10 to 17 in mice and between gestational weeks seven to 18 in humans.

Epigenetic regulation of neurogenesis is the role that epigenetics plays in the regulation of neurogenesis.

<span class="mw-page-title-main">Neuronal lineage marker</span> Endogenous tag expressed in different cells along neurogenesis and differentiated cells

A neuronal lineage marker is an endogenous tag that is expressed in different cells along neurogenesis and differentiated cells such as neurons. It allows detection and identification of cells by using different techniques. A neuronal lineage marker can be either DNA, mRNA or RNA expressed in a cell of interest. It can also be a protein tag, as a partial protein, a protein or an epitope that discriminates between different cell types or different states of a common cell. An ideal marker is specific to a given cell type in normal conditions and/or during injury. Cell markers are very valuable tools for examining the function of cells in normal conditions as well as during disease. The discovery of various proteins specific to certain cells led to the production of cell-type-specific antibodies that have been used to identify cells.

<span class="mw-page-title-main">Ventricular zone</span> Transient embryonic layer of tissue containing neural stem cells

In vertebrates, the ventricular zone (VZ) is a transient embryonic layer of tissue containing neural stem cells, principally radial glial cells, of the central nervous system (CNS). The VZ is so named because it lines the ventricular system, which contains cerebrospinal fluid (CSF). The embryonic ventricular system contains growth factors and other nutrients needed for the proper function of neural stem cells. Neurogenesis, or the generation of neurons, occurs in the VZ during embryonic and fetal development as a function of the Notch pathway, and the newborn neurons must migrate substantial distances to their final destination in the developing brain or spinal cord where they will establish neural circuits. A secondary proliferative zone, the subventricular zone (SVZ), lies adjacent to the VZ. In the embryonic cerebral cortex, the SVZ contains intermediate neuronal progenitors that continue to divide into post-mitotic neurons. Through the process of neurogenesis, the parent neural stem cell pool is depleted and the VZ disappears. The balance between the rates of stem cell proliferation and neurogenesis changes during development, and species from mouse to human show large differences in the number of cell cycles, cell cycle length, and other parameters, which is thought to give rise to the large diversity in brain size and structure.

Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). In short, it is brain growth in relation to its organization. This occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells (NECs), radial glial cells (RGCs), basal progenitors (BPs), intermediate neuronal precursors (INPs), subventricular zone astrocytes, and subgranular zone radial astrocytes, among others.

References

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  15. ↑ Wang Z, Tang B, He Y, Jin P. DNA methylation dynamics in neurogenesis. Epigenomics. 2016 Mar;8(3):401-14. doi: 10.2217/epi.15.119. Epub 2016 Mar 7. Review. PMID   26950681
  16. ↑ Parent JM, von dem Bussche N, Lowenstein DH (2006). "Prolonged seizures recruit caudal subventricular zone glial progenitors into the injured hippocampus" (PDF). Hippocampus. 16 (3): 321–8. doi:10.1002/hipo.20166. hdl: 2027.42/49285 . PMID   16435310. S2CID   17643839.
  17. ↑ Romanko, MJ; Rola, R; Fike, JR; Szele, FG; Dizon, ML; Felling, RJ; Brazel, CY; Levison, SW (Oct 2004). "Roles of the mammalian subventricular zone in cell replacement after brain injury". Progress in Neurobiology. 74 (2): 77–99. doi:10.1016/j.pneurobio.2004.07.001. PMID   15518954. S2CID   44399750.
  18. ↑ Decressac, M; Prestoz, L; Veran, J; Cantereau, A; Jaber, M; Gaillard, A (Jun 2009). "Neuropeptide Y stimulates proliferation, migration and differentiation of neural precursors from the subventricular zone in adult mice". Neurobiology of Disease. 34 (3): 441–9. doi:10.1016/j.nbd.2009.02.017. PMID   19285132. S2CID   24661524.
  19. ↑ Piccirillo, Sara G. M.; Spiteri, Inmaculada; Sottoriva, Andrea; Touloumis, Anestis; Ber, Suzan; Price, Stephen J.; Heywood, Richard; Francis, Nicola-Jane; Howarth, Karen D. (2015-01-01). "Contributions to Drug Resistance in Glioblastoma Derived from Malignant Cells in the Sub-Ependymal Zone". Cancer Research. 75 (1): 194–202. doi:10.1158/0008-5472.CAN-13-3131. ISSN   0008-5472. PMC   4286248 . PMID   25406193.
  20. ↑ Mistry, A.; et al. (2016). "Influence of glioblastoma contact with the lateral ventricle on survival: a meta-analysis". Journal of Neuro-Oncology. 131 (1): 125–133. doi:10.1007/s11060-016-2278-7. PMC   5262526 . PMID   27644688.
  21. ↑ Mistry, A.; et al. (2017). "Decreased survival in glioblastomas is specific to contact with the ventricular-subventricular zone, not subgranular zone or corpus callosum". Journal of Neuro-Oncology. 132 (2): 341–349. doi:10.1007/s11060-017-2374-3. PMC   5771712 . PMID   28074322.
  22. ↑ Cervantes-Villagrana RD, Albores-García D, Cervantes-Villagrana AR, García-Acevez SJ (18 June 2020). "Tumor-induced Neurogenesis and Immune Evasion as Targets of Innovative Anti-Cancer Therapies". Signal Transduct Target Ther. 5 (1): 99. doi:10.1038/s41392-020-0205-z. PMC   7303203 . PMID   32555170.
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