Impact of UVR Exposure Pattern on Squamous Cell Carcinoma-A Dose–Delivery and Dose–Response Study in Pigmented Hairless Mice

Lerche, Catharina M.; Togsverd‐Bo, Katrine; Philipsen, Peter Alshede; Wulf, Hans Christian

doi:10.3390/ijms18122738

Cited by 9 publications

(10 citation statements)

References 37 publications

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“…Our study employs a well-described autochthonous mouse model in which tumors develop in situ from healthy skin tissue exposed to UVR, which is the main risk factor for SCC in humans [25,29]. Other studies used xenografts, generated by the injection of immortalized human cell lines, as model systems to study laser-induced immune responses [13,14].…”

Section: Discussionmentioning

confidence: 99%

“…The UVR-dose was measured using a Solatell Sola-Hazard spectroradiometer (4D Controls, Ltd., Redruth, UK), and the UVR-exposure time was adjusted continuously to the corresponding three SEDs. This autochthonous SCC mouse model is well-established for investigating interventions that may influence the formation of UV-induced SCCs [25]. The histology of representative SCCs is shown in Figure 1.…”

Section: Uvr To Induce Sccsmentioning

confidence: 99%

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Tumor Clearance and Immune Cell Recruitment in UV‐Induced Murine Squamous Cell Carcinoma Exposed to Ablative Fractional Laser and Imiquimod Treatment

et al. 2021

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Background and Objectives: Keratinocyte carcinoma (KC) is the most common cancer worldwide, and squamous cell carcinoma (SCC) is the second most frequent subtype. Ablative fractional laser (AFL)-assisted drug delivery significantly enhances the uptake of topically applied drugs. The objective of this study was to assess tumor response and perform a descriptive characterization of the local recruitment of immune cells and systemic immune mediator levels in an ultraviolet radiation (UVR)-induced murine SCC model after AFL treatment alone and combined with topical imiquimod. Study Design/Materials and Methods: Immunocompetent hairless mice (C3•Cg/TifBomTac, n = 74) were irradiated with solar-simulated UVR until 3-mm SCCs developed. The mice were divided into four interventional groups: AFL alone, AFL + imiquimod, imiquimod alone, and untreated SCC controls. AFL was given as a single treatment, whereas imiquimod was applied daily until the mice were euthanized on Days 0, 2, 7, or 14. SCCs were photographed and measured (mm) to assess the therapeutic response. Skin samples were processed for histopathological and immunohistochemical analyses, as well as for flow cytometry. Cytokine expression changes in sera were analyzed using ELISpot cytokine arrays. Results: Treatment of mouse SCCs with AFL + imiquimod induced the most robust immune cell infiltration and the greatest proportion of tumor clearance compared to other interventions. Early innate immune cell infiltration was induced by AFL + imiquimod treatment as the number of neutrophils and macrophages had increased fourfold within 2 days of treatment initiation compared with untreated SCC control mice (P < 0.05). AFL treatment alone had a more limited effect, with a fourfold increase in neutrophils (P < 0.05) but no significant increase in the number of macrophages. Correspondingly, treatment with AFL + imiquimod had the greatest effects on the adaptive immune cell recruitment: CD4 + T-helper cells increased threefold at Day 7 compared with untreated SCCs (P = 0.0001) and, notably, cytotoxic CD8 + T cells increased 14-fold at Day 14 (P = 0.0112). In addition, FOXP3 + regulatory T cells (Tregs) increased 14-fold at Day 7 (P = 0.0026), suggesting the resolution of the inflammatory infiltration. AFL treatment alone induced a moderate immune cell infiltration (a twofold increase in CD4 + T-helper cells, P = 0.0200; a threefold increase in CD8 + T cells, P = 0.0100; and a 14-fold increase in FOXP3 + Tregs at Day 14, P = 0.0021), whereas imiquimod alone did not significantly increase cell counts. AFL + imiquimod treatment increased CXCL12 serum levels threefold at Day 14 (P = 0.0200). Conclusion: AFL treatment alone and in combination with imiquimod induces substantial tumor clearance associated with local recruitment of innate and adaptive immune cells in UVR-induced murine SCCs. These results may provide a basis for new immunotherapeutic approaches to KC treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Uvr To Induce Sccsmentioning

confidence: 99%

Tumor Clearance and Immune Cell Recruitment in UV‐Induced Murine Squamous Cell Carcinoma Exposed to Ablative Fractional Laser and Imiquimod Treatment

et al. 2021

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“…This indicates that MAL-PDT produces an intense PDT effect, as reported by previous studies [ 23 ]. The intense pigmentation may partly explain the delay in tumor development, although tumors do appear if UVR treatment is prolonged, despite the high levels of pigmentation [ 24 , 25 ].…”

Section: Discussionmentioning

confidence: 99%

A Skin Cancer Prophylaxis Study in Hairless Mice Using Methylene Blue, Riboflavin, and Methyl Aminolevulinate as Photosensitizing Agents in Photodynamic Therapy

et al. 2021

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The high incidence of sunlight-induced human skin cancers reveals a need for more effective photosensitizing agents. In this study, we compared the efficacy of prophylactic photodynamic therapy (PDT) when methylene blue (MB), riboflavin (RF), or methyl aminolevulinate (MAL) were used as photosensitizers. All mice in four groups of female C3.Cg/TifBomTac hairless immunocompetent mice (N = 100) were irradiated with three standard erythema doses of solar-simulated ultraviolet radiation (UVR) thrice weekly. Three groups received 2 × 2 prophylactic PDT treatments (days 45 + 52 and 90 + 97). The PDT treatments consisted of topical administration of 16% MAL, 20% MB, or 20% RF, and subsequent illumination that matched the photosensitizers’ absorption spectra. Control mice received no PDT. We recorded when the first, second, and third skin tumors developed. The pattern of tumor development after MB-PDT or RF-PDT was similar to that observed in irradiated control mice (p > 0.05). However, the median times until the first, second, and third skin tumors developed in mice given MAL-PDT were significantly delayed, compared with control mice (256, 265, and 272 vs. 215, 222, and 230 days, respectively; p < 0.001). Only MAL-PDT was an effective prophylactic treatment against UVR-induced skin tumors in hairless mice.

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“…Mice were examined for tumors weekly. The "time to the first tumor'' was the number of days it took for the first 1 mm-diameter tumor to appear that later grew to a size of 4 mm [27]. As secondary endpoints, we also recorded the time to the second and third tumors based on the same criteria.…”

Section: Methodsmentioning

confidence: 99%

Few X-ray and PUVA treatments accelerate photocarcinogenesis in hairless mice

Lerche

Al-Chaer

Glud

et al. 2021

Photochem Photobiol Sci

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PUVA is a treatment that combines oral methoxypsoralen (8-MOP) with ultraviolet radiation A (UVA). It is used for severe psoriasis and the early stages of T-cell lymphoma. X-rays are an effective treatment for skin cancers. Both treatments are in higher doses used to treat skin malignancies and simultaneously increase the risk of keratinocyte cancer. The main objective of this study was to test whether a few PUVA or X-ray treatments could delay the development of ultraviolet radiation (UVR)-induced skin tumors in a well-established hairless mouse model. Three groups of immunocompetent mice (total, N = 75) were included in the study. All groups were UVR-exposed during the study period. In addition, one group was treated with PUVA and another group was treated with X-rays at days 45, 52, 90 and 97. A control group was treated with UVR only. We recorded when the first, second and third skin tumors were induced in each mouse. Skin tumors developed significantly earlier in both the PUVA and X-ray groups (median, 188 days) than in the control mice (median, 215 days; p < 0.001). Therefore, a few X-ray and PUVA treatments both significantly accelerated the development of skin tumors in hairless mice, compared to UVR controls. Neither treatment showed a delay of UVR-induced skin tumors and caution should be exercised before applying these treatments to sun-damaged skin.

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Impact of UVR Exposure Pattern on Squamous Cell Carcinoma-A Dose–Delivery and Dose–Response Study in Pigmented Hairless Mice

Cited by 9 publications

References 37 publications

Tumor Clearance and Immune Cell Recruitment in UV‐Induced Murine Squamous Cell Carcinoma Exposed to Ablative Fractional Laser and Imiquimod Treatment

Tumor Clearance and Immune Cell Recruitment in UV‐Induced Murine Squamous Cell Carcinoma Exposed to Ablative Fractional Laser and Imiquimod Treatment

A Skin Cancer Prophylaxis Study in Hairless Mice Using Methylene Blue, Riboflavin, and Methyl Aminolevulinate as Photosensitizing Agents in Photodynamic Therapy

Few X-ray and PUVA treatments accelerate photocarcinogenesis in hairless mice

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