Nestin-Positive Stem Cells in Neurofibromas From Patients With Neurofibromatosis Type 1-Tumorigenic or Incidental?

Pongpudpunth, Marinya; Bhawan, Jag; Al-Natour, Sahar H.; Mahalingam, Meera

doi:10.1097/dad.0b013e3181cc8c7c

Cited by 5 publications

(4 citation statements)

References 17 publications

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“…Thus, it would be interesting to investigate Pax chromatin modifications in kidney tubules and Schwann cells during responses that involve dedifferentiation of injured cells and redifferentiation of their progeny. An understanding of this Pax epigenetic switching during homeostatic tissue repair may shed light on the aberrant processes of repair that may occur in chronic kidney disease and neurofibromatosis (Pongpudpunth et al, 2010). In addition, such an understanding could be applied to the therapeutic control of PAX gain of function in ARMS and other cancers.…”

Section: Aberrant Pax Gene Expression: Implications For Regeneration mentioning

confidence: 99%

Pax genes: regulators of lineage specification and progenitor cell maintenance

2014

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Pax genes encode a family of transcription factors that orchestrate complex processes of lineage determination in the developing embryo. Their key role is to specify and maintain progenitor cells through use of complex molecular mechanisms such as alternate RNA splice forms and gene activation or inhibition in conjunction with protein co-factors. The significance of Pax genes in development is highlighted by abnormalities that arise from the expression of mutant Pax genes. Here, we review the molecular functions of Pax genes during development and detail the regulatory mechanisms by which they specify and maintain progenitor cells across various tissue lineages. We also discuss mechanistic insights into the roles of Pax genes in regeneration and in adult diseases, including cancer. KEY WORDS: Pax genes, Embryogenesis, Lineage determination IntroductionPaired box (Pax) genes encode transcription factors that contain a highly conserved DNA-binding domain called the paired domain (PD, Fig. 1A) and can be considered to be a principle regulator of gene expression. Nine Pax genes (Pax1-Pax9) have been characterised in mammals and the evolutionary conserved paired domain has been identified across phylogenies from insects, to amphibians and birds. In higher vertebrates, PAX proteins are subclassified into groups according to inclusion of an additional DNA-binding homeodomain and/or an octapeptide region, which serves as a binding motif for protein co-factors for potent inhibition of downstream gene transcription (Eberhard et al., 2000) (Fig. 1B); all PAX proteins include a transactivation domain located within the C-terminal amino acids (Underhill, 2012). It is also known that all Pax genes, with the exception of Pax4 and Pax9, produce alternative RNA transcripts (see Table 1). The functional diversity of Pax proteins in vivo is thus linked to the ability to produce alternatively spliced gene products that differ in structure and, consequently, in the binding activity of their paired and homeodomain DNA-binding regions (Underhill, 2012).Three decades ago, the characterisation and roles of Pax genes in embryonic development began to unfold. Early studies discovered that regulatory gene families such as the Pax family are involved in the sequential compartmentalisation and body patterning of developing organisms; thereafter, studies highlighted a role for Pax genes in the early specification of cell fate and the subsequent morphogenesis of various tissues and organs. Following this, mutational studies of Pax genes confirmed the importance of these regulatory roles in the PRIMER School of Medical Sciences, Edith Cowan University, Joondalup, WA 6027, Australia.*Author for correspondence (j.blake@ecu.edu.au) This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.initiation and progression of ...

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Section: Aberrant Pax Gene Expression: Implications For Regeneration mentioning

confidence: 99%

Pax genes: regulators of lineage specification and progenitor cell maintenance

2014

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“…Some nerve tumors of soft tissue are thought to be derived from stem cells. [9,10] These findings suggest that the present perineuroma were derived from neural stem cells.…”

Section: Discussionmentioning

confidence: 67%

“…In central neural tumors and some peripheral nerve tumors, in particular neurofibromatosis, are derived from neural stem cells. [9,10] However, there have been no cases of perineuroma, neurothekeoma, and nerve sheath myxoma with stem cell features.…”

Section: Introductionmentioning

confidence: 99%

Perineuroma of the skin negative for S100 protein but positive for stem cell antigens: A possible stem cell tumor

Terada

2016

CRCP

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Perineuroma is a rare tumor originating from perineurium of the peripheral nerve. In contrast to neurofibroma and schwannoma, both of which arise from endoneurium and are immunohistochemically positive for S100 protein, perineuroma is negative for S100 protein; the fact makes the pathologic diagnosis difficult. As is well known, stem cells are highly associated with neuronal and organ developments in human embryos, and some neuronal cells are suspected to be derived from neuronal stem cells. Herein reported a very rare case of subcutaneous perineuroma negative for S100 protein but positive for a number of stem cell antigens; the case suggested that some perineuromas could arise from neuronal stem cells. A 68-year-old woman presented with a skin tumor of 10 mm in diameter in the foot. Physical examination revealed a small movable subcutaneous tumor, and resection was performed. Histologically, the tumor was a well-defined round tumor measuring 0.9 cm × 0.9 cm × 0.9 cm located in the subcutaneous tissue. No capsule was seen. The tumor was composed of hypocellular myxoid, neuroid tissues containing small areas of high cellularity where tumor cells resembled neuronal stem cells. Immunohistochemically, the tumor was negative for S100 protein, HMB-45, various cytokeratin (CK), EMA, α-SMA, desmin, p53, and many other antigens. The neuronal stem cell-like cells were positive for various stem cell antigens including NSE, KIT, bcl-2, chromogranin, synaptophysin, PDGFRA, MET, ErbB2, and CD34, as well as for vimentin and Ki-67 antigen (labeling index = 1.5%). Because the tumor was negative for S100 protein but positive for neuroendocrine molecules and neuronal stem cell antigens, the author diagnosed the tumor as perineuroma with stem cell features. Such a perineuroma has not been reported to date. The outcome of the patient was excellent.

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“…Neurofibromas consist primarily of NMSCs [75]–[77] where malignant transformation is linked to NMSC hyperproliferation and detrimental effects on adjacent cells [78]. Importantly, in neurofibroma, it has been found that tumours have a significant population of stem cells [79] and although the origin of the stem cells remains unknown, Pongpudpunth et al [79] proposed that “formation of neurofibromas may be linked to alterations in the self-renewal program of peripheral nerve progenitor cells”.…”

Section: Discussionmentioning

confidence: 99%

The Characterisation of Pax3 Expressant Cells in Adult Peripheral Nerve

Blake

Ziman

2013

PLoS ONE

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Pax3 has numerous integral functions in embryonic tissue morphogenesis and knowledge of its complex function in cells of adult tissue continues to unfold. Across a variety of adult tissue lineages, the role of Pax3 is principally linked to maintenance of the tissue’s resident stem/progenitor cell population. In adult peripheral nerves, Pax3 is reported to be expressed in nonmyelinating Schwann cells, however, little is known about the purpose of this expression. Based on the evidence of the role of Pax3 in other adult tissue stem and progenitor cells, it was hypothesised that the cells in adult peripheral nerve that express Pax3 may be peripheral glioblasts. Here, methods have been developed for identification and visualisation of Pax3 expressant cells in normal 60 day old mouse peripheral nerve that allowed morphological and phenotypic distinctions to be made between Pax3 expressing cells and other nonmyelinating Schwann cells. The distinctions described provide compelling support for a resident glioblast population in adult mouse peripheral nerve.

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Nestin-Positive Stem Cells in Neurofibromas From Patients With Neurofibromatosis Type 1-Tumorigenic or Incidental?

Cited by 5 publications

References 17 publications

Pax genes: regulators of lineage specification and progenitor cell maintenance

Pax genes: regulators of lineage specification and progenitor cell maintenance

Perineuroma of the skin negative for S100 protein but positive for stem cell antigens: A possible stem cell tumor

The Characterisation of Pax3 Expressant Cells in Adult Peripheral Nerve

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