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. 2011 Jan 27;469(7331):548-53.
doi: 10.1038/nature09666. Epub 2011 Jan 19.

V体育平台登录 - Interferon-γ links ultraviolet radiation to melanomagenesis in mice

M Raza Zaidi  1 , Sean Davis, Frances P Noonan, Cari Graff-Cherry, Teresa S Hawley, Robert L Walker, Lionel Feigenbaum, Elaine Fuchs, Lyudmila Lyakh, Howard A Young, Thomas J Hornyak, Heinz Arnheiter, Giorgio Trinchieri, Paul S Meltzer, Edward C De Fabo, Glenn Merlino
Affiliations

"VSports" Interferon-γ links ultraviolet radiation to melanomagenesis in mice

M Raza Zaidi et al. Nature. .

Abstract

Cutaneous malignant melanoma is a highly aggressive and frequently chemoresistant cancer, the incidence of which continues to rise. Epidemiological studies show that the major aetiological melanoma risk factor is ultraviolet (UV) solar radiation, with the highest risk associated with intermittent burning doses, especially during childhood. We have experimentally validated these epidemiological findings using the hepatocyte growth factor/scatter factor transgenic mouse model, which develops lesions in stages highly reminiscent of human melanoma with respect to biological, genetic and aetiological criteria, but only when irradiated as neonatal pups with UVB, not UVA. However, the mechanisms underlying UVB-initiated, neonatal-specific melanomagenesis remain largely unknown. Here we introduce a mouse model permitting fluorescence-aided melanocyte imaging and isolation following in vivo UV irradiation. We use expression profiling to show that activated neonatal skin melanocytes isolated following a melanomagenic UVB dose bear a distinct, persistent interferon response signature, including genes associated with immunoevasion VSports手机版. UVB-induced melanocyte activation, characterized by aberrant growth and migration, was abolished by antibody-mediated systemic blockade of interferon-γ (IFN-γ), but not type-I interferons. IFN-γ was produced by macrophages recruited to neonatal skin by UVB-induced ligands to the chemokine receptor Ccr2. Admixed recruited skin macrophages enhanced transplanted melanoma growth by inhibiting apoptosis; notably, IFN-γ blockade abolished macrophage-enhanced melanoma growth and survival. IFN-γ-producing macrophages were also identified in 70% of human melanomas examined. Our data reveal an unanticipated role for IFN-γ in promoting melanocytic cell survival/immunoevasion, identifying a novel candidate therapeutic target for a subset of melanoma patients. .

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Conflict of interest statement (VSports在线直播)

Competing Interests V体育安卓版. Authors have no competing interests.

Figures

Figure 1
Figure 1. Melanocyte-specific GFP expression reveals UVB-induced activation
a, E11.5 iDct-GFP embryo showing GFP+ cells in neural crest (red arrow) and telencephalon (white arrow). b, In 7-day old pup skin GFP+ cells are located in the bulb (lower arrow) and bulge (upper arrow) regions of hair follicles. Blue = DAPI; E, epidermis; D, dermis. c, Immunohistochemistry with anti-Dct antibody shows co-localization with GFP in iDct-GFP skin. d, UVB-induced activation of melanocytes, characterized by proliferation and migration towards epidermis. Dorsal skins were examined at 1 day (at age P2) and 6 days (P7) post-irradiation. Scale bars = 40 μm. e, Schematic of the regime for isolating GFP+ melanocytes by FACS. Pups are irradiated at P1, and dorsal skins harvested at either P2 (24 h post-UV) or P7 (6 d post-UV). Doxycycline injections are always given after irradiation, 24 h prior to skin harvest.
Figure 2
Figure 2. UVB-induced melanocyte activation is mediated by interferon-γ
a, Unsupervised clustering of cDNA microarray analysis of gene expression in FACS-sorted melanocytes from 1 day (P2) or 6 days (P7) following UVB or UVA irradiation, and respective unirradiated controls. The expanded heatmap (right) shows the delayed induced gene subset, which includes multiple genes known to be induced by IFN-γ. Primary mouse keratinocytes (PrKC) were included as controls. All groups included biological triplicates. b, qRT-PCR validation of expression of 4 genes (n=3 samples each) from IFN signature (error bars = s.e.m.). c, Antibody-mediated blockade of interferons by treating pups with intraperitoneal injections of anti-IFN-αR1, anti-IFN-γ, or both in combination, 1 h prior to and 3 days after UVB irradiation at P1. The dorsal skins were harvested (n=3 each group) and analyzed for melanocyte activation. Representative images are shown. E, epidermis; D, dermis. Scale bars = 40 μm.
Figure 3
Figure 3. UVB induces chemoattraction of IFN-γ-producing macrophages into neonatal skin
a, IHC with anti-F4/80 and anti-Gr-1 antibodies in dorsal skins of UVB-irradiated and unirradiated neonatal (upper panel) and adult (lower panel) mice. Scale bars = 40 μm. b, qRT-PCR for IFN-α, IFN-β, and IFN-γ expression in F4/80+ and CD11b+ cells FACS isolated from P1-UVB-P7 neonatal dorsal skins, compared with non-activated RAW264.7 macrophages. c, Flow cytometric analysis of P1-UVB-P7 skin cell suspensions identified IFN-γ+ macrophages. d, Flow cytometric analysis of macrophage (F4/80+) infiltration into skin, 2 days post UVB irradiation in Ccr2-deficient pups (irradiated at P1), as compared to wildtype pups. **p<0.01; One-Way ANOVA test with post-hoc Tukey analysis. e, F5061 melanoma cells ectopically expressing Ccl8 chemoattract F4/80+ macrophages (red), but not Gr-1+ cells, to sites of subcutaneous inoculation in syngeneic FVB/N mice. One vector-transfected and two Ccl8-transfected clone cells were used. Blue = DAPI.
Figure 4
Figure 4. IFN-γ mediates pro-tumourigenic effects of UVB-recruited skin macrophages
a, Mean volumes (±s.e.m.) of F5061 melanomas admixed with skin macrophages isolated from P1-UVB-P7 pups (F5061+MΦ, n=10), vs. F5061 only controls (n=9), following subcutaneous transplantation in syngeneic FVB/N mice; **p<0.01. b, Percentages of TUNEL+ cells (±s.e.m.) in admixed and control tumours (n=6 each); ***p<0.001. c, Antibody-mediated blockade of IFN-γ significantly inhibits pro-tumourigenic effects of macrophages; *p<0.05; **p<0.01; ns = not significant. One-Way ANOVA test with post-hoc Tukey analysis. d, Dual IHC with anti-IFN-γ (red) and anti-CD68 (green) antibodies on a human melanoma tissue microarray (TMA) exhibits IFN-γ-expressing macrophages (yellow). Representative tumour is shown. e, Schematic representation of the UVB-induced inflammatory cascade leading to IFN-γ-mediated immunoevasion and survival of melanocytes during sunburn-associated remodeling. UV induces release of CCR2 ligands (1) that activate CCR2+ macrophages (2), which are recruited to neonatal skin (3). Macrophages secrete IFN-γ (4), which activates melanocytes, inducing expression of genes that include CCL8/MCP-2, fueling inflammation (5) and immunoevasion (6).
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References

    1. Garibyan L, Fisher DE. How sunlight causes melanoma. Curr Oncol Rep. 2010;12:319–326. - PubMed
    1. Whiteman DC, Whiteman CA, Green AC. Childhood sun exposure as a risk factor for melanoma: a systematic review of epidemiologic studies. Cancer Causes Control. 2001;12:69–82. - VSports在线直播 - PubMed
    1. Noonan FP, et al. Neonatal sunburn and melanoma in mice. Nature. 2001;413:271–272. - PubMed
    1. De Fabo EC, Noonan FP, Fears T, Merlino G. Ultraviolet B but not ultraviolet A radiation initiates melanoma. Cancer Res. 2004;64:6372–6376. - PubMed
    1. Nishimura EK, et al. Dominant role of the niche in melanocyte stem-cell fate determination. Nature. 2002;416:854–860. - PubMed

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