Tumor-Like Stem Cells Derived from Human Keloid Are Governed by the Inflammatory Niche Driven by IL-17/IL-6 Axis

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Departmental Papers (Dental)
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MeSH: Adult
Animals
Cell Proliferation
Cell Separation
Cytokines
Fibroblasts
Humans
Inflammation
Interleukin-17
Interleukin-6
Keloid
Mesenchymal Stem Cells
Mice
Mice
Inbred C57BL
Middle Aged Species Index: Mus EMTREE drug terms: interleukin 17
interleukin 6
telomerase
cytokine
interleukin 17
interleukin 6 EMTREE medical terms: animal cell
animal experiment
animal model
article
autocrine effect
cell differentiation
cell function
cell population
cell renewal
cell surface
clonogenesis
controlled study
embryonic stem cell
enzyme activity
enzyme linked immunosorbent assay
flow cytometry
keloid
mesenchymal stem cell
mouse
nonhuman
paracrine signaling
protein expression
stem cell
target cell
Western blotting
adult
animal
C57BL mouse
cell proliferation
cell separation
cytology
fibroblast
human
inflammation
keloid
metabolism
middle aged
Dentistry
Oral and Maxillofacial Surgery
Oral Biology and Oral Pathology
Periodontics and Periodontology
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Zhang, Qunzhou
Yamaza, Takayoshi
Kelly, Paul A
Shi, Shihong
Wang, Songling
Brown, Jimmy James
Wang, Lina
French, Samuel William
Shi, Songtao
Le, Anh D
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Abstract

Background: Alterations in the stem cell niche are likely to contribute to tumorigenesis; however, the concept of niche promoted benign tumor growth remains to be explored. Here we use keloid, an exuberant fibroproliferative dermal growth unique to human skin, as a model to characterize benign tumor-like stem cells and delineate the role of their "pathological" niche in the development of the benign tumor. Methods and Findings: Subclonal assay, flow cytometric and multipotent differentiation analyses demonstrate that keloid contains a new population of stem cells, named keloid derived precursor cells (KPCs), which exhibit clonogenicity, self-renewal, distinct embryonic and mesenchymal stem cell surface markers, and multipotent differentiation. KPCs display elevated telomerase activity and an inherently upregulated proliferation capability as compared to their peripheral normal skin counterparts. A robust elevation of IL-6 and IL-17 expression in keloid is confirmed by cytokine array, western blot and ELISA analyses. The altered biological functions are tightly regulated by the inflammatory niche mediated by an autocrine/paracrine cytokine IL-17/IL-6 axis. Utilizing KPCs transplanted subcutaneously in immunocompromised mice we generate for the first time a human keloid-like tumor model that is driven by the in vivo inflammatory niche and allows testing of the anti-tumor therapeutic effect of antibodies targeting distinct niche components, specifically IL-6 and IL-17. Conclusions/Significance: These findings support our hypothesis that the altered niche in keloids, predominantly inflammatory, contributes to the acquirement of a benign tumor-like stem cell phenotype of KPCs characterized by the uncontrolled self-renewal and increased proliferation, supporting the rationale for in vivo modification of the "pathological" stem cell niche as a novel therapy for keloid and other mesenchymal benign tumors. © 2009 Zhang et al.

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2009-11-11
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PLoS ONE
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At the time of publication, author Qunzhou Zheng was affiliated with the University of Southern California, School of Dentistry. Currently, (s)he is a faculty member at the School of Dental Medicine at the University of Pennsylvania. At the time of publication, author Shihong Shi was affiliated with the University of Southern California, School of Dentistry. Currently, (s)he is a faculty member at the School of Dental Medicine at the University of Pennsylvania. At the time of publication, author Songtao Shi was affiliated with the University of Southern California, School of Dentistry. Currently, (s)he is a faculty member at the School of Dental Medicine at the University of Pennsylvania. At the time of publication, author Anh D. Le was affiliated with the University of Southern California, School of Dentistry. Currently, (s)he is a faculty member at the School of Dental Medicine at the University of Pennsylvania.
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