Departmental Papers (Dental)

Document Type

Journal Article

Date of this Version

11-11-2009

Publication Source

PLoS ONE

Volume

4

Issue

11

Start Page

Article number e7798

DOI

10.1371/journal.pone.0007798

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.

Comments

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.

Keywords

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

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Date Posted: 09 February 2023

This document has been peer reviewed.