Tumor-like stem cells derived from human keloid are governed by the inflammatory niche driven by IL-17/IL-6 axis

Qunzhou Zhang, Takayoshi Yamaza, A. Paul Kelly, Shihong Shi, Songlin Wang, Jimmy Brown, Lina Wang, Samuel W. French, Songtao Shi, Anh D. Le

研究成果: ジャーナルへの寄稿記事

50 引用 (Scopus)

抄録

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.

元の言語英語
記事番号e7798
ジャーナルPloS one
4
発行部数11
DOI
出版物ステータス出版済み - 11 11 2009

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Keloid
Neoplastic Stem Cells
Interleukin-17
Stem cells
interleukin-6
stem cells
Tumors
Interleukin-6
niches
neoplasms
Stem Cell Niche
skin (animal)
Skin
Neoplasms
cytokines
Cytokines
cells
Telomerase
Differentiation Antigens
telomerase

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

これを引用

Tumor-like stem cells derived from human keloid are governed by the inflammatory niche driven by IL-17/IL-6 axis. / Zhang, Qunzhou; Yamaza, Takayoshi; Kelly, A. Paul; Shi, Shihong; Wang, Songlin; Brown, Jimmy; Wang, Lina; French, Samuel W.; Shi, Songtao; Le, Anh D.

:: PloS one, 巻 4, 番号 11, e7798, 11.11.2009.

研究成果: ジャーナルへの寄稿記事

Zhang, Q, Yamaza, T, Kelly, AP, Shi, S, Wang, S, Brown, J, Wang, L, French, SW, Shi, S & Le, AD 2009, 'Tumor-like stem cells derived from human keloid are governed by the inflammatory niche driven by IL-17/IL-6 axis', PloS one, 巻. 4, 番号 11, e7798. https://doi.org/10.1371/journal.pone.0007798
Zhang, Qunzhou ; Yamaza, Takayoshi ; Kelly, A. Paul ; Shi, Shihong ; Wang, Songlin ; Brown, Jimmy ; Wang, Lina ; French, Samuel W. ; Shi, Songtao ; Le, Anh D. / Tumor-like stem cells derived from human keloid are governed by the inflammatory niche driven by IL-17/IL-6 axis. :: PloS one. 2009 ; 巻 4, 番号 11.
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title = "Tumor-like stem cells derived from human keloid are governed by the inflammatory niche driven by IL-17/IL-6 axis",
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.",
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AU - Wang, Songlin

AU - Brown, Jimmy

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AU - French, Samuel W.

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AB - 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.

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