RESUMEN

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.

Asunto(s)

RESUMEN

Keloids are scars, unique to humans, that grow beyond the boundaries of a cutaneous injury, inflammation, burn, or surgical incision. Although benign, keloids are often aesthetically malignant. The etiology of keloids is uncertain. However, we do know that they occur more often in African-American and Asian than Caucasian patients. There is no one therapeutic modality that either prevents the formation of keloids or treats active or inactive lesions. Consequently, there are many therapeutic options. In this review, an approach to medical and surgical management of keloids is provided, as well as a review of experimental therapeutic modalities.

Asunto(s)

RESUMEN

Keloid, a chronic fibro-proliferative disease, exhibits distinctive histological features characterized by an abundant extracellular matrix stroma, a local infiltration of inflammatory cells including mast cells (MCs), and a milieu of enriched cytokines. Previous studies have demonstrated that co-culture with MCs stimulate type I collagen synthesis in fibroblasts, but the signaling mechanisms remain largely unknown. In this study, we investigated the signaling pathways involved in MC-stimulated type I collagen synthesis and the effects of green tea extract (GTE) and its major catechin, (-)-epigallocatechin-3-gallate (EGCG), on collagen homeostasis in keloid fibroblasts. Our results showed that MCs significantly stimulated type I collagen expression in keloid fibroblasts, and the upregulation of type I collagen was significantly attenuated by blockade of phosphatidylinositol-3-kinase (PI-3K), mammalian target of rapamycin (mTOR), and p38 MAPK signaling pathways, but not by blockade of ERK1/2 pathway. Furthermore, GTE and EGCG dramatically inhibited type I collagen production possibly by interfering with the PI-3K/Akt/mTOR signaling pathway. Our findings suggest that interaction between MCs and keloid fibroblasts may contribute to excessive collagen accumulation in keloids and imply a therapeutic potential of green tea for the intervention and prevention of keloids and other fibrotic diseases.

Asunto(s)

RESUMEN

Melasma is a common hyperpigmentation disorder that is frequently recalcitrant to treatment. An 8-week, multicenter, open-label, community-based study evaluated a new therapeutic approach that combines tretinoin 0.05%, hydroquinone 4.0%, and fluocinolone acetonide 0.01% (RA+HQ+FA) in a hydrophilic cream formulation. The trial enrolled 1290 patients of diverse races/ethnicities with a full range of Fitzpatrick skin types (I through VI). The mean Melasma Area and Severity Index (MASI) decreased significantly at both weeks 4 and 8 compared with baseline in the overall study population and across all Fitzpatrick skin types and races/ethnicities (P<.0001). The mean MASI darkness and homogeneity scores likewise fell significantly at weeks 4 and 8 in all facial regions involved (forehead, right and left malar regions, and chin) and in all Fitzpatrick skin types (P<.0001). By week 8, investigators' global evaluations showed that 75% of patients had "moderate or marked improvement" or were "almost clear" or "clear." The study medication was found to be safe and well tolerated. The results of this study demonstrate that RA+HQ+FA produces significant rapid improvement of melasma across the range of patients seen in daily practice, including whites, Hispanics, blacks, Asians, American Indians, Alaskan natives, and Pacific Islanders.

Asunto(s)

RESUMEN

Keloids represent a prolonged inflammatory fibrotic state with areas that display distinctive histological features characterized by an abundant extracellular matrix stroma, a local infiltration of inflammatory cells including mast cells, and a milieu of enriched cytokines. Previous studies from our laboratory demonstrated an intrinsic higher level of HIF-1alpha and VEGF protein expression in keloid tissues compared with their adjacent unremarkable skins. To further investigate the mechanisms underlying the elevated expression of HIF-1alpha and VEGF in keloids, we exposed a co-culture of keloid fibroblasts and mast cells (HMC-1) to hypoxic conditions and studied the expression of HIF-1alpha and its target gene, VEGF. Our results showed that hypoxia-dependent HIF-1alpha protein accumulation and VEGF expression is augmented in keloid fibroblasts when co-cultured with HMC-1 cells under the condition where direct cell-cell contact is allowed. But such augmentation is not observed in the transwell co-culture system whereas fibroblasts and HMC-1 cells were separated by a porous membrane. Our results also indicated that the enhancement of hypoxia-mediated activation of ERK1/2 and Akt requires direct cell-cell interaction between mast cells and keloid fibroblasts, and activation of both ERK1/2 and Akt is involved in the hypoxia-dependent HIF-1alpha protein accumulation and VEGF expression in the co-culture system. These findings suggest that under hypoxic conditions mast cells may contribute, at least in part, to an elevated expression of HIF-1alpha and VEGF protein in keloids via direct cell-cell interaction with fibroblasts.

Asunto(s)

RESUMEN

The objective of this study was to examine the effects of polyphenolic compounds, present in noncommercially available green tea, on hair loss among rodentts. In an experimental study, we randomly assigned 60female Balb/black mice, which had developed spontaneous hair loss on the head, neck and dorsal areas into two equal groups; A (experimental) and B (control). Group A received 50% fraction of polyphenol extract from dehydrated green tea in their drinking water for six months. Group B received regular drinking water. Both groups were fed regular rodent diets (Purina Rodent Chow 5001) and housed individually in polycarbonate cages. The results showed that 33% of the mice in experimental Group A, who received polyphenol extract in their drinking water, had significant hair regrowth during six months of treatment (p = 0.014). No hair growth was observed among mice in the control group, which received regular water.

Asunto(s)

Asunto(s)

RESUMEN

Keloids are characterized as an "over-exuberant" healing response resulting in a disproportionate extracellular matrix (ECM) accumulation and tissue fibrosis. In view of the integral role of inflammation and cytokines in the healing response, it is logical to assume that they may play a part in orchestrating the pathology of this "abnormal" healing process. Tumor necrosis factor-alpha (TNF-alpha) is a potent proinflammatory cytokine involved in activation of signaling events and transcriptional programs, such as NFkappaB. This study attempts to determine the difference in NFkappaB and its related genes expression and DNA binding activity between keloid and normal skin fibroblasts. Three keloid and normal skin tissues (NSk) and their derived fibroblasts were used to determine NFkappaB signaling pathway expression using specific cDNA microarrays, Western blot analysis and immunohistochemistry. Electrophoretic mobility gel shift assay (EMSA) was used to assess NFkappaB-binding activity, all assays were performed in the presence and absence of TNF-alpha. TNF-alpha up-regulated 15% of NFkappaB signal pathway related genes in keloid fibroblast compared to normal skin. At the protein level, keloid fibroblasts and tissues showed higher basal levels of TNF- receptor-associated factors-TRAF1, TRAF2-TNF-alpha, inhibitor of apoptosis (c-IAP-1), and NFkappaB, compared with NSk. Keloid fibroblasts showed a constitutive increase in NFkappaB-binding activity in comparison to NSk both with and without TNF-alpha treatment. NFkappaB and its targeted genes, especially the antiapoptotic genes, could play a role in keloid pathogenesis; targeting NFkappaB could help in developing therapeutic interventions for the treatment of keloid scarring.

Asunto(s)

RESUMEN

Keloids are benign, but sometimes painful and/or pruritic, proliferative growths of dermal collagen, usually resulting from excessive tissue response to trauma. Although benign, the social and psychological impact on affected individuals must be considered. Keloids often arise secondary to ear piercing and operative procedures. No single treatment modality is always successful. The more common ones are discussed. Some of the medical therapies include corticosteroids, interferon, 5-fluorouracil, and imiquimod. Primary excision and cryosurgery are among the major surgical options. Radiation therapies and other physical modalities are also discussed.

Asunto(s)

RESUMEN

Excessive scar or keloid shares common features of a benign dermal growth. Yet, in contrast to malignant tumor, a keloid does not expand beyond the dermis. What triggers the continuing growth of a benign lesion? Deficient or overabundant levels of vascular endothelial growth factor have been reported to contribute to impaired or excessive wound healing. Although numerous studies have examined the pathophysiology of impaired wounds, little information has been provided on mechanisms of exuberant healing. The molecular basis of keloid formation is governed by the interplay of cellular signaling pathways, specific target gene activation, and the nature of the microenvironment. Recent works have demonstrated an accumulation of hypoxia-inducible factor-1alpha protein in freshly biopsied keloid tissues, thus providing first evidence that a local state of hypoxia exists in keloids. Our findings and the findings of others support at least two plausible mechanisms implicated in the development of fibrotic wounds, a state of ongoing fibroplasia or inflammation and an excessive accumulation of extracellular matrix. This article will review recent works examining the potential role of vascular endothelial growth factor in keloid pathogenesis with particular focus on its involvement in the two proposed pathological processes, a prolonged inflammation and an altered balance in extracellular matrix metabolism.

Asunto(s)

RESUMEN

Hair care in African American women is wrought with historical and cultural issues. Dermatologists need to improve their understanding of hair and scalp disorders in their African American patient population by being informed about the styling methods commonly used by and for these patients. The styling habits described in this article are intended to encompass the hairstyles adapted by a wide range of African American women with varying hair textures.

Asunto(s)

RESUMEN

There is therapeutic and help and hope for AKN patients using the excision and second-intention healing technique, plus some of the recently reported laser techniques.

Asunto(s)

RESUMEN

Keloids are an excessive accumulation of extracellular matrix. Although numerous studies have shown elevated plasminogen activator inhibitor-1 (PAI-1) levels in keloid fibroblasts compared with those of normal skin. Their specific mechanisms involved in the differential expression of PAI-1 in these cell types. In this study, the upregulation of PAI-1 expression is demonstrated in keloid tissues and their derived dermal fibroblasts, attesting to the persistence, if any, of fundamental differences between in vivo and in vitro paradigms. We further examined the mechanisms involved in hypoxia-induced regulation of PAI-1 gene in dermal fibroblast derived from keloid lesions and associated clinically normal peripheral skins from the same patient. Primary cultures were exposed to an environmental hypoxia or desferroxamine. We found that the hypoxia-induced elevation of PAI-1 gene appears to be regulated at both transcriptional and post-transcriptional levels in keloid fibroblasts. Furthermore, our results showed a consistent elevation of HIF-1alpha protein level in keloid tissues compared with their normal peripheral skin controls, implying a potential role as a biomarker for local skin hypoxia. Treatment with antisense oligonucleotides against hypoxia-inducible factor 1alpha (HIF-1alpha) led to the downregulation of steady-state levels of PAI-1 mRNA under both normoxic and hypoxic conditions. Conceivably, our results suggest that HIF-1alpha may be a novel therapeutic target to modulate the scar fibrosis process.

Asunto(s)

RESUMEN

The National Institute of Arthritis and Musculoskeletal and Skin Diseases hosted a diverse group of physicians and scientists to discuss health disparities in arthritis, musculoskeletal, and skin diseases. This article discusses the cutaneous disease portion of the conference. Speakers described a history of scarce information on cutaneous diseases in skin of color, problems with the data that do exist, and inappropriate use of dermatologic data. Basic descriptive data on the structure and function of skin in people of color is needed. For specific cutaneous diseases, information must be collected on their epidemiology, clinical presentation, natural history, complications, and therapeutics. Researchers are standardizing methods for studying keloidal scars, and are developing and validating measurement tools for cutaneous diseases in skin of color, such as atypical nevi, psoriasis, and hand dermatitis, but more is needed.

Asunto(s)