A Postnatal Pax7+ Progenitor Gives Rise to Pituitary Adenomas

Hosoyama, Tohru; Nishijo, Koichi; Garcia, Melinda; Schaffer, Beverly S.; Ohshima-Hosoyama, Sachiko; Prajapati, Suresh I.; Davis, M. Duff; Grant, Wilmon F.; Scheithauer, Bernd W.; Marks, Daniel L.; Rubin, Brian P.; Keller, Charles

doi:10.1177/1947601910370979

Cited by 52 publications

(53 citation statements)

References 63 publications

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“…Several groups have described the presence within the pituitary tumor of a side population containing cells with high efflux capacity and enriched with potentially tumor stem cells (Gleiberman et al 2008, Florio 2011, Mertens et al 2015. In line with that, enhanced selfrenewal as a mechanism of tumor initiation has been reported in pituitary adenomas (Hosoyama et al 2010, Gaston-Massuet et al 2011, Andoniadou et al 2013, Donangelo et al 2014. It has been proposed that the initial mutation that drives tumorigenesis occurs in a cell type (adult pituitary stem cells, SCs) that does not contribute cell autonomously to the tumor.…”

Section: Autocrine Il-6 Mediates Pituitary Tumor Senescencementioning

confidence: 89%

Programmed cell senescence: role of IL-6 in the pituitary

Sapochnik

Fuertes

Arzt

2017

Journal of Molecular Endocrinology

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IL-6 is a pleiotropic cytokine with multiple pathophysiological functions. As a key factor of the senescence secretome, it can not only promote tumorigenesis and cell proliferation but also exert tumor suppressive functions, depending on the cellular context. IL-6, as do other cytokines, plays important roles in the function, growth and neuroendocrine responses of the anterior pituitary gland. The multiple actions of IL-6 on normal and adenomatous pituitary function, cell proliferation, angiogenesis and extracellular matrix remodeling indicate its importance in the regulation of the anterior pituitary. Pituitary tumors are mostly benign adenomas with low mitotic index and rarely became malignant. Premature senescence occurs in slow-growing benign tumors, like pituitary adenomas. The dual role of IL-6 in senescence and tumorigenesis is well represented in pituitary tumor development, as it has been demonstrated that effects of paracrine IL-6 may allow initial pituitary cell growth, whereas autocrine IL-6 in the same tumor triggers senescence and restrains aggressive growth and malignant transformation. IL-6 is instrumental in promotion and maintenance of the senescence program in pituitary adenomas.

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Section: Autocrine Il-6 Mediates Pituitary Tumor Senescencementioning

confidence: 89%

Programmed cell senescence: role of IL-6 in the pituitary

Sapochnik

Fuertes

Arzt

2017

Journal of Molecular Endocrinology

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“…+ and Myf6 + ) induces tumor formation, although the latency was much shorter when the Rb gene was inactivated in early (Pax7 + ) versus late (Myf6 + ) progenitors (Hosoyama et al 2010).…”

Section: Neural Stem/progenitor Cellsmentioning

confidence: 99%

The retinoblastoma tumor suppressor and stem cell biology

Sage¹

2012

Genes Dev.

107

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Stem cells play a critical role during embryonic development and in the maintenance of homeostasis in adult individuals. A better understanding of stem cell biology, including embryonic and adult stem cells, will allow the scientific community to better comprehend a number of pathologies and possibly design novel approaches to treat patients with a variety of diseases. The retinoblastoma tumor suppressor RB controls the proliferation, differentiation, and survival of cells, and accumulating evidence points to a central role for RB activity in the biology of stem and progenitor cells. In some contexts, loss of RB function in stem or progenitor cells is a key event in the initiation of cancer and determines the subtype of cancer arising from these pluripotent cells by altering their fate. In other cases, RB inactivation is often not sufficient to initiate cancer but may still lead to some stem cell expansion, raising the possibility that strategies aimed at transiently inactivating RB might provide a novel way to expand functional stem cell populations. Future experiments dedicated to better understanding how RB and the RB pathway control a stem cell's decisions to divide, self-renew, or give rise to differentiated progeny may eventually increase our capacity to control these decisions to enhance regeneration or help prevent cancer development. Basic functions of the RB pathwayThe human retinoblastoma gene RB1 was initially cloned from children with a rare form of eye cancer of the same name. Since this seminal discovery, RB has been found to be inactivated in a wide range of pediatric and adult human cancers. The mechanisms of tumor suppression by the RB protein are thought to largely involve its ability to restrict cell cycle progression at the G1/S transition of the cell cycle by inhibition of E2F transcription factors. Phosphorylation of RB by Cyclin/Cdk (cyclin-dependent kinase) complexes can inhibit the ability of RB to bind to E2F. Cyclin/Cdk complexes are themselves under the control of small cell cycle inhibitors of the INK4 and CIP/KIP families, to which p16Ink4a and p21 Cip1 , respectively, belong. The module comprising INK4-CIP/KIP cell cycle inhibitors; Cyclin/Cdk complexes; RB and its two family members, p107 and p130; and E2F transcription factors constitutes the RB pathway in cells.

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“…LUSEAPm/WT Cre/LoxP reporter mice that express luciferase following Cre expression have been described previously (18,22,23). Mice were euthanized by CO 2 asphyxiation at 2 weeks after tamoxifen injection (for Pax7…”

Section: Rosa26mentioning

confidence: 99%

Rb1 Gene Inactivation Expands Satellite Cell and Postnatal Myoblast Pools

Hosoyama¹,

Nishijo²,

Prajapati³

et al. 2011

Journal of Biological Chemistry

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Satellite cells are well known as a postnatal skeletal muscle stem cell reservoir that under injury conditions participate in repair. However, mechanisms controlling satellite cell quiescence and activation are the topic of ongoing inquiry by many laboratories. In this study, we investigated whether loss of the cell cycle regulatory factor, pRb, is associated with the re-entry of quiescent satellite cells into replication and subsequent stem cell expansion. By ablation of Rb1 using a Pax7CreER,Rb1 conditional mouse line, satellite cell number was increased 5-fold over 6 months. Furthermore, myoblasts originating from satellite cells lacking Rb1 were also increased 3-fold over 6 months, while terminal differentiation was greatly diminished. Similarly, Pax7CreER,Rb1 mice exhibited muscle fiber hypotrophy in vivo under steady state conditions as well as a delay of muscle regeneration following cardiotoxin-mediated injury. These results suggest that cell cycle re-entry of quiescent satellite cells is accelerated by lack of Rb1, resulting in the expansion of both satellite cells and their progeny in adolescent muscle. Conversely, that sustained Rb1 loss in the satellite cell lineage causes a deficit of muscle fiber formation. However, we also show that pharmacological inhibition of protein phosphatase 1 activity, which will result in pRb inactivation accelerates satellite cell activation and/or expansion in a transient manner. Together, our results raise the possibility that reversible pRb inactivation in satellite cells and inhibition of protein phosphorylation may provide a new therapeutic tool for muscle atrophy by short term expansion of the muscle stem cells and myoblast pool.Skeletal muscle is a highly regenerative tissue because of the presence of muscle stem cells intertwined with individual muscle fibers. Muscle stem cells are also referred to as satellite cells because of their location of the cells under the basement membrane of muscle fibers (1). Satellite cells are maintained in quiescence in the adult steady state, while stimuli such as injury activate these myogenic (lineage-restricted) stem cells and induce differentiation into myoblasts then myofibers via the process of muscle regeneration (2, 3). Activated satellite cells divide symmetrically or asymmetrically to either replenish the reservoir of quiescent stem cells and/or to create myogenic cell progeny destined for differentiation (4,5,6). Although the regulatory mechanisms modulating the satellite cell quiescence/ activation cycle are not yet well understood, it is widely known that the HGF/c-Met signaling axis is one such mechanism regulating the cell cycle re-entry of quiescent satellite cells (3, 7). A related recent study suggested that high concentration of HGF inhibits satellite cell activation by the negative feedback mechanism through enhanced satellite cell expression of Myostatin (GDF8) (8), a potent regulator of quiescence/activation (10). In more broad-reaching studies, Fukada et al. (2007) recently performed a gene expression analys...

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A Postnatal Pax7+ Progenitor Gives Rise to Pituitary Adenomas

Cited by 52 publications

References 63 publications

Programmed cell senescence: role of IL-6 in the pituitary

Programmed cell senescence: role of IL-6 in the pituitary

The retinoblastoma tumor suppressor and stem cell biology

Rb1 Gene Inactivation Expands Satellite Cell and Postnatal Myoblast Pools

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