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


RESULTS
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
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.
Zhang
Qunzhou
Q
Center for Craniofacial Molecular Biology, School of Dentistry, University of Southern California, Los Angeles, CA, USA.
Yamaza
Takayoshi
T
Kelly
A Paul
AP
Shi
Shihong
S
Wang
Songlin
S
Brown
Jimmy
J
Wang
Lina
L
French
Samuel W
SW
Shi
Songtao
S
Le
Anh D
AD
D000328:Adult; D000818:Animals; D049109:Cell Proliferation; D002469:Cell Separation; D016207:Cytokines / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D020381:Interleukin-17 / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D007627:Keloid / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged
D016207:Cytokines; D020381:Interleukin-17; D015850:Interleukin-6