BackgroundAlterations 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 FindingsSubclonal 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/SignificanceThese 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.

Hypoxia-inducible factor-1A (HIF-1A) is overexpressed in many human tumors and their metastases, and is closely associated with a more aggressive tumor phenotype. In this study, we investigated the effect of resveratrol, a natural product commonly found in grapes and various other fruits, on hypoxia-induced HIF-1A protein accumulation and vascular endothelial growth factor (VEGF) expression in human tongue squamous cell carcinomas and hepatoma cells. Our results showed that resveratrol significantly inhibited both basal level and hypoxia-

Purpose: Human papillomavirus (HPV)-16 oncoproteins, E6 and E7, are associated with enhanced tumor angiogenesis in human cervical cancers. The purpose of this study was (a) to investigate whether expression of HPV-16 E6 and E7 oncoproteins induces hypoxia-inducible factor 1a (HIF-1a) and vascular endothelial growth factor expression in cervical cancer cells; and (b) to assess the effect of resveratrol on 16 E6-and E7-induced HIF-1a and VEGF gene expression. Experimental Design: Human cervical cancer cell lines C-33A and HeLa were transiently cotransfected with pSG5-HPV-16 E6 or 16 E7 constructs along with HIF-1a small interfering RNA (siRNA) or nonspecific siRNA. The expression of HIF-1a/VEGF was measured using realtime PCR, Western blot analysis, or ELISA. The in vitro angiogenic activity induced by 16 E6-and E7-transfected cells was examined. The effect of resveratrol on oncoprotein-induced HIF-1a/VEGF expression and in vitro angiogenesis was investigated. Results: HPV-16 E6-and E7-transfected cervical cancer cells express increased HIF-1a protein andVEGF expression.These stimulatory effects were abrogated by cotransfection with either HIF1a siRNA or treatment with resveratrol. Blocking extracellular signal-regulated kinase 1/2 (ERK 1/ 2) and phosphoinositide-3-kinase by PD98059 and LY294002, respectively, abolished 16 E6-and E7-induced HIF-1aand VEGF expression. Functionally, we showed that HPV-16 E6-and E7-transfected cervical cancer cells stimulated in vitro capillary or tubule formation, and these angiogenic effects could be abolished either by cotransfection with HIF-1asiRNA or by treatment with resveratrol. Conclusion: HPV-16 oncoproteins contribute to enhanced angiogenesis in cervical cancer cells via HIF-1a^dependentVEGF expression. Resveratrol suppresses 16 E6-and E7-induced HIF-1am ediated angiogenic activity and, thus, is a promising chemotherapeutic agent for human cervical cancer.

Overexpression of hypoxia inducible factor-1␣ (HIF-1␣

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