Non-ablative Fractional Thulium Laser Irradiation Suppresses Early Tumor Growth

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  • ABSTRACT

    In addition to its typical use for skin rejuvenation, fractional laser irradiation of early cancerous lesions may reduce the risk of tumor development as a byproduct of wound healing in the stroma after the controlled injury. While fractional ablative lasers are commonly used for cosmetic/aesthetic purposes (e.g., photorejuvenation, hair removal, and scar reduction), we propose a novel use of such laser treatments as a stromal treatment to delay tumorigenesis and suppress carcinogenesis. In this study, we found that non-ablative fractional laser (NAFL) irradiation may have a possible suppressive effect on early tumor growth in syngeneic mouse tumor models. We included two syngeneic mouse tumor models in irradiation groups and control groups. In the irradiation group, a thulium fiber based NAFL at 1927 nm was used to irradiate the skin area including the tumor injection region with 70 mJ/spot, while no laser irradiation was applied to the control group. Numerical simulation with the same experimental condition showed that thermal damage was confined only to the irradiation spots, sparing the adjacent tissue area. The irradiation groups of both tumor models showed smaller tumor volumes than the control group at an early tumor growth stage. We also detected elevated inflammatory cytokine levels a day after the NAFL irradiation. NAFL treatment of the stromal tissue could potentially be an alternative anticancer therapeutic modality for early tumorigenesis in a minimally invasive manner.


  • KEYWORD

    Non-ablative fractional laser , Tumor growth suppression , Early cancer therapy

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  • [FIG. 1.] Non-ablative fractional laser (NAFL) irradiation of the syngeneic mouse tumor model. (A) Schematic illustration of the experiment. Cancer cell-injected mice were divided into irradiation and control groups. NAFL (70 mJ/spot) was applied to the irradiation group, whereas no irradiation was delivered to the control group. The serial tumor volume was followed to measure the therapeutic efficacy of NAFL irradiation from day 7 to 21; (B) NAFL irradiated mouse. Left: NAFL irradiated SL4-DsRed tumor model mouse (red-dotted circle: cancer cell-injected site). Right upper: Magnified image of the flank lesion. Right lower: Array of NAFL irradiated spots on black paper; (C) Photo image shows no significant elevated lesion one day after cancer cell injection (red-dotted circle: cancer cell injection site); (D) Fluorescence image from an optical imaging system; (E) Excised flank skin from an SL4-DsRed injected mouse right after NAFL irradiation; (F) Magnified image of the excised tissue; (G) White light image of the excised tissue slice. (H) Fluorescence image of the excised tissue slice.
    Non-ablative fractional laser (NAFL) irradiation of the syngeneic mouse tumor model. (A) Schematic illustration of the experiment. Cancer cell-injected mice were divided into irradiation and control groups. NAFL (70 mJ/spot) was applied to the irradiation group, whereas no irradiation was delivered to the control group. The serial tumor volume was followed to measure the therapeutic efficacy of NAFL irradiation from day 7 to 21; (B) NAFL irradiated mouse. Left: NAFL irradiated SL4-DsRed tumor model mouse (red-dotted circle: cancer cell-injected site). Right upper: Magnified image of the flank lesion. Right lower: Array of NAFL irradiated spots on black paper; (C) Photo image shows no significant elevated lesion one day after cancer cell injection (red-dotted circle: cancer cell injection site); (D) Fluorescence image from an optical imaging system; (E) Excised flank skin from an SL4-DsRed injected mouse right after NAFL irradiation; (F) Magnified image of the excised tissue; (G) White light image of the excised tissue slice. (H) Fluorescence image of the excised tissue slice.
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  • [FIG. 2.] Numerical simulation of non-ablative fractional laser (NAFL) irradiation to skin tissue. (A) 3D image of the tissue model for numerical simulation; (B) Cross-cut image of the 3D tissue model with plane α?α’ in Figure 2A; (C) Three representative spots and three image planes for temporal and spatial analysis; (D) Temporal distribution of the temperature changes at points a, b, and c; (E, F) Spatial distribution of the temperature in the tissue model along Plane 1 (E) and Plane 2 (F); (G, H) Spatial distribution of the temperature during heating (G) and cooling (H) in the tissue model along plane 3.
    Numerical simulation of non-ablative fractional laser (NAFL) irradiation to skin tissue. (A) 3D image of the tissue model for numerical simulation; (B) Cross-cut image of the 3D tissue model with plane α?α’ in Figure 2A; (C) Three representative spots and three image planes for temporal and spatial analysis; (D) Temporal distribution of the temperature changes at points a, b, and c; (E, F) Spatial distribution of the temperature in the tissue model along Plane 1 (E) and Plane 2 (F); (G, H) Spatial distribution of the temperature during heating (G) and cooling (H) in the tissue model along plane 3.
  • [TABLE 1.] Thermal properties of the skin and blood
    Thermal properties of the skin and blood
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  • [FIG. 3.] Tumor volume changes in syngeneic mouse tumor models. (A) Representative images of serial tumor volume (TV) changes during the follow-up periods. The blue- and red-dotted lines show the contour of the tumor. A single dot means no significant tumor lesion at the site; (B) In the CT26 implanted tumor model, the irradiation group (blue-dotted line) had smaller mean TVs (MTVs) than the control group (black solid line). On day 10 and day 17 after CT26 injection there is a statistically significant difference in MTVs between the irradiation and control groups; (C) In the SL4-DsRed tumor model, the irradiation group (red-dotted line) had smaller MTVs than the control group (black solid line). This difference in TV between the irradiation and control groups was observed on day 10 but not on day 17. Noticeably, 2 of the 5 SL4-DsRed cancer cell-injected mice had shown no significant tumor growth until 90 days after cancer cell injection. An asterisk (*) indicates statistical significance < 0.05 while NS indicates no significance. All results are presented as mean ± SEM.
    Tumor volume changes in syngeneic mouse tumor models. (A) Representative images of serial tumor volume (TV) changes during the follow-up periods. The blue- and red-dotted lines show the contour of the tumor. A single dot means no significant tumor lesion at the site; (B) In the CT26 implanted tumor model, the irradiation group (blue-dotted line) had smaller mean TVs (MTVs) than the control group (black solid line). On day 10 and day 17 after CT26 injection there is a statistically significant difference in MTVs between the irradiation and control groups; (C) In the SL4-DsRed tumor model, the irradiation group (red-dotted line) had smaller MTVs than the control group (black solid line). This difference in TV between the irradiation and control groups was observed on day 10 but not on day 17. Noticeably, 2 of the 5 SL4-DsRed cancer cell-injected mice had shown no significant tumor growth until 90 days after cancer cell injection. An asterisk (*) indicates statistical significance < 0.05 while NS indicates no significance. All results are presented as mean ± SEM.
  • [FIG. 4.] Cytokine analysis of SL4-DsRed tumor models. Enzyme-linked immunosorbent assays (ELISA) were performed to analyze the levels of the cytokines (A) TNF-α, (B) IL-1β, (C) IFN-γ, and (D) TGF-β. TNF-α, IL-1β, and IFN-γ levels were elevated on day 1 after NAFL irradiation. TGF-β did not show any significance changes during the experimental period. All results are shown as mean ± SEM.
    Cytokine analysis of SL4-DsRed tumor models. Enzyme-linked immunosorbent assays (ELISA) were performed to analyze the levels of the cytokines (A) TNF-α, (B) IL-1β, (C) IFN-γ, and (D) TGF-β. TNF-α, IL-1β, and IFN-γ levels were elevated on day 1 after NAFL irradiation. TGF-β did not show any significance changes during the experimental period. All results are shown as mean ± SEM.
  • [FIG. 5.] Tumor volume changes of the tumor-bearing mouse model after injection of an increased number of cancer cells. Half a million cancer cells were injected into each mouse. (A) In the CT26 implanted tumor model, the irradiation group (blue-dotted line) had a smaller mean tumor volume (MTV) than the control group (black solid line). Day 7 and day 10 after CT26 injection there was a statistically significant difference in MTV between the irradiation and control group; (B) In the SL4-DsRed tumor model, the irradiation group (red-dotted line) had a smaller MTV than the control group (black solid line). This difference in MTV between the irradiation and control groups was observed on day 7 but not on day 10. Representative images of serial MTV change during the follow-up period. An asterisk (*) indicates statistical significance < 0.05 while NS means no significance. All results are presented as mean ± SEM.
    Tumor volume changes of the tumor-bearing mouse model after injection of an increased number of cancer cells. Half a million cancer cells were injected into each mouse. (A) In the CT26 implanted tumor model, the irradiation group (blue-dotted line) had a smaller mean tumor volume (MTV) than the control group (black solid line). Day 7 and day 10 after CT26 injection there was a statistically significant difference in MTV between the irradiation and control group; (B) In the SL4-DsRed tumor model, the irradiation group (red-dotted line) had a smaller MTV than the control group (black solid line). This difference in MTV between the irradiation and control groups was observed on day 7 but not on day 10. Representative images of serial MTV change during the follow-up period. An asterisk (*) indicates statistical significance < 0.05 while NS means no significance. All results are presented as mean ± SEM.