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Reversing the aging stromal phenotype prevents carcinoma initiation.

Lewis DA, Travers JB, Machado C, Somani AK, Spandau DF - Aging (Albany NY) (2011)

Bottom Line: We hypothesized that commonly used therapeutic stromal wounding therapies can reduce the percentage of senescent fibroblasts and consequently prevent the formation of keratinocytes proliferating with DNA mutations following acute genotoxic (UVB) stress.In geriatric skin, we found that dermabrasion wounding decreases the proportion of senescent fibroblasts found in geriatric dermis, increases the expression of IGF-1, and restores the appropriate UVB response to epidermal keratinocytes in geriatric skin.Therefore, dermal rejuvenation therapies may play a significant role in preventing the initiation of skin cancer in geriatric patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, Indiana University School of Medicine, Indianapolis, Indiana, USA.

ABSTRACT
The accumulation of senescent stromal cells in aging tissue changes the local microenvironment from normal to a state similar to chronic inflammation. This inflammatory microenvironment can stimulate the proliferation of epithelial cells containing DNA mutations which can ultimately lead to cancer. Using geriatric skin as a model, we demonstrated that senescent fibroblasts also alter how epithelial keratinocytes respond to genotoxic stress, due to the silencing of IGF-1 expression in geriatric fibroblasts. These data indicate that in addition to promoting epithelial tumor growth, senescent fibroblasts also can promote carcinogenic initiation. We hypothesized that commonly used therapeutic stromal wounding therapies can reduce the percentage of senescent fibroblasts and consequently prevent the formation of keratinocytes proliferating with DNA mutations following acute genotoxic (UVB) stress. Sun-protected skin on the lower back of geriatric human volunteers was wounded by dermabrasion and the skin was allowed to heal for three months. In geriatric skin, we found that dermabrasion wounding decreases the proportion of senescent fibroblasts found in geriatric dermis, increases the expression of IGF-1, and restores the appropriate UVB response to epidermal keratinocytes in geriatric skin. Therefore, dermal rejuvenation therapies may play a significant role in preventing the initiation of skin cancer in geriatric patients.

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Dermabrasion stimulates fibroblast replication and suppresses senescence in geriatric dermis(A) Skin biopsies described in Fig. 3B were stained with antibodies to 53BP1 and γH2AX. Senescent nuclei are indicated by white arrows, the basement membrane is designated by a dashed grey line, bar = 25 µm. (B) The density of fibroblasts in the papillary dermis was determined using the Nikon Elements Image Analysis software. Asterisk indicates statistical significance from control values (p = 0.0048), two-tailed t-test). (C) Sections of biopsies were stained with antibodies to Ki67. The percentage of Ki67(+) fibroblasts in the papillary dermis and the percentage of Ki67(+) keratinocytes in the basal layer of the epidermis were calculated using Nikon Elements image analysis software. Asterisks indicate statistical significance from control values (papillary dermis, p = 0.039; epidermis p = 0.058, two-tailed t-test).
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Figure 4: Dermabrasion stimulates fibroblast replication and suppresses senescence in geriatric dermis(A) Skin biopsies described in Fig. 3B were stained with antibodies to 53BP1 and γH2AX. Senescent nuclei are indicated by white arrows, the basement membrane is designated by a dashed grey line, bar = 25 µm. (B) The density of fibroblasts in the papillary dermis was determined using the Nikon Elements Image Analysis software. Asterisk indicates statistical significance from control values (p = 0.0048), two-tailed t-test). (C) Sections of biopsies were stained with antibodies to Ki67. The percentage of Ki67(+) fibroblasts in the papillary dermis and the percentage of Ki67(+) keratinocytes in the basal layer of the epidermis were calculated using Nikon Elements image analysis software. Asterisks indicate statistical significance from control values (papillary dermis, p = 0.039; epidermis p = 0.058, two-tailed t-test).

Mentions: Cosmetic dermal rejuvenation techniques have been widely used to stimulate the production of new collagen synthesis by inducing a ‘wounding response' in the skin [39-40]. As such, it was of interest to determine if these dermal rejuvenation techniques restored a more youthful phenotype and biology to geriatric skin, and specifically to determine if these techniques could restore the appropriate DNA-damage response found in young skin to UVB-irradiated geriatric skin. Small areas of sun-protected skin on geriatric volunteers were treated by dermabrasion. Biopsies of dermabraded and untreated skin were analyzed after the treated sites were allowed to heal for three months. Consistent with previous reports, dermabraded skin demonstrated increased synthesis of collagen [39-40; Supplemental Fig. 2] and a restoration of the dermal collagen structure similar to that found in young adults (Fig. 3A, panels i and iv). Dermabasion also reversed the aging-associated atrophy of the papillary dermis (Fig. 2D) by significantly increasing the area of the papillary dermis (Fig. 3B). The thickness of the epidermis was modestly increased by dermabrasion, although this result was not statistically significant (Fig. 3B). Increased thickness of the papillary dermis was accompanied by an increase in fibroblast density in the dermabraded geriatric skin (Fig. 4B; see Supplemental Fig. 3 for example of fibroblast verification) and statistically greater numbers of replicating keratinocytes and fibroblasts (Fig. 4C). The increased proliferative potential of fibroblasts in the dermis corresponded with a decrease in the proportion of dermal senescent fibroblasts (Fig. 3C). The round phenotype of the senescent fibroblast nuclei in control geriatric dermis was replaced with increasing percentages of replicating elliptical fibroblast nuclei (Fig. 3A, panels iii and vi). The loss of senescent cells in dermabraded skin can also be observed by assaying for DDR markers. In contrast to the abundant expression of DDR markers in senescent fibroblasts of control geriatric dermis, DDR-positive fibroblasts are not detected in dermabraded geriatric dermis (Fig. 4A).


Reversing the aging stromal phenotype prevents carcinoma initiation.

Lewis DA, Travers JB, Machado C, Somani AK, Spandau DF - Aging (Albany NY) (2011)

Dermabrasion stimulates fibroblast replication and suppresses senescence in geriatric dermis(A) Skin biopsies described in Fig. 3B were stained with antibodies to 53BP1 and γH2AX. Senescent nuclei are indicated by white arrows, the basement membrane is designated by a dashed grey line, bar = 25 µm. (B) The density of fibroblasts in the papillary dermis was determined using the Nikon Elements Image Analysis software. Asterisk indicates statistical significance from control values (p = 0.0048), two-tailed t-test). (C) Sections of biopsies were stained with antibodies to Ki67. The percentage of Ki67(+) fibroblasts in the papillary dermis and the percentage of Ki67(+) keratinocytes in the basal layer of the epidermis were calculated using Nikon Elements image analysis software. Asterisks indicate statistical significance from control values (papillary dermis, p = 0.039; epidermis p = 0.058, two-tailed t-test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3117456&req=5

Figure 4: Dermabrasion stimulates fibroblast replication and suppresses senescence in geriatric dermis(A) Skin biopsies described in Fig. 3B were stained with antibodies to 53BP1 and γH2AX. Senescent nuclei are indicated by white arrows, the basement membrane is designated by a dashed grey line, bar = 25 µm. (B) The density of fibroblasts in the papillary dermis was determined using the Nikon Elements Image Analysis software. Asterisk indicates statistical significance from control values (p = 0.0048), two-tailed t-test). (C) Sections of biopsies were stained with antibodies to Ki67. The percentage of Ki67(+) fibroblasts in the papillary dermis and the percentage of Ki67(+) keratinocytes in the basal layer of the epidermis were calculated using Nikon Elements image analysis software. Asterisks indicate statistical significance from control values (papillary dermis, p = 0.039; epidermis p = 0.058, two-tailed t-test).
Mentions: Cosmetic dermal rejuvenation techniques have been widely used to stimulate the production of new collagen synthesis by inducing a ‘wounding response' in the skin [39-40]. As such, it was of interest to determine if these dermal rejuvenation techniques restored a more youthful phenotype and biology to geriatric skin, and specifically to determine if these techniques could restore the appropriate DNA-damage response found in young skin to UVB-irradiated geriatric skin. Small areas of sun-protected skin on geriatric volunteers were treated by dermabrasion. Biopsies of dermabraded and untreated skin were analyzed after the treated sites were allowed to heal for three months. Consistent with previous reports, dermabraded skin demonstrated increased synthesis of collagen [39-40; Supplemental Fig. 2] and a restoration of the dermal collagen structure similar to that found in young adults (Fig. 3A, panels i and iv). Dermabasion also reversed the aging-associated atrophy of the papillary dermis (Fig. 2D) by significantly increasing the area of the papillary dermis (Fig. 3B). The thickness of the epidermis was modestly increased by dermabrasion, although this result was not statistically significant (Fig. 3B). Increased thickness of the papillary dermis was accompanied by an increase in fibroblast density in the dermabraded geriatric skin (Fig. 4B; see Supplemental Fig. 3 for example of fibroblast verification) and statistically greater numbers of replicating keratinocytes and fibroblasts (Fig. 4C). The increased proliferative potential of fibroblasts in the dermis corresponded with a decrease in the proportion of dermal senescent fibroblasts (Fig. 3C). The round phenotype of the senescent fibroblast nuclei in control geriatric dermis was replaced with increasing percentages of replicating elliptical fibroblast nuclei (Fig. 3A, panels iii and vi). The loss of senescent cells in dermabraded skin can also be observed by assaying for DDR markers. In contrast to the abundant expression of DDR markers in senescent fibroblasts of control geriatric dermis, DDR-positive fibroblasts are not detected in dermabraded geriatric dermis (Fig. 4A).

Bottom Line: We hypothesized that commonly used therapeutic stromal wounding therapies can reduce the percentage of senescent fibroblasts and consequently prevent the formation of keratinocytes proliferating with DNA mutations following acute genotoxic (UVB) stress.In geriatric skin, we found that dermabrasion wounding decreases the proportion of senescent fibroblasts found in geriatric dermis, increases the expression of IGF-1, and restores the appropriate UVB response to epidermal keratinocytes in geriatric skin.Therefore, dermal rejuvenation therapies may play a significant role in preventing the initiation of skin cancer in geriatric patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, Indiana University School of Medicine, Indianapolis, Indiana, USA.

ABSTRACT
The accumulation of senescent stromal cells in aging tissue changes the local microenvironment from normal to a state similar to chronic inflammation. This inflammatory microenvironment can stimulate the proliferation of epithelial cells containing DNA mutations which can ultimately lead to cancer. Using geriatric skin as a model, we demonstrated that senescent fibroblasts also alter how epithelial keratinocytes respond to genotoxic stress, due to the silencing of IGF-1 expression in geriatric fibroblasts. These data indicate that in addition to promoting epithelial tumor growth, senescent fibroblasts also can promote carcinogenic initiation. We hypothesized that commonly used therapeutic stromal wounding therapies can reduce the percentage of senescent fibroblasts and consequently prevent the formation of keratinocytes proliferating with DNA mutations following acute genotoxic (UVB) stress. Sun-protected skin on the lower back of geriatric human volunteers was wounded by dermabrasion and the skin was allowed to heal for three months. In geriatric skin, we found that dermabrasion wounding decreases the proportion of senescent fibroblasts found in geriatric dermis, increases the expression of IGF-1, and restores the appropriate UVB response to epidermal keratinocytes in geriatric skin. Therefore, dermal rejuvenation therapies may play a significant role in preventing the initiation of skin cancer in geriatric patients.

Show MeSH
Related in: MedlinePlus