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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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Senescent fibroblasts accumulate in geriatric dermis in vivoBiopsies of sun-protected skin were obtained from six young adult (20-28 years old) and six geriatric (>65 years old) volunteers. (A) Sections of skin were stained with antibodies to 53BP1 and γH2AX. Positive nuclei are indicated by white arrows; dashed line specifies the location of the basement membrane; bar = 25 µm. (B) Quantitative PCR analysis of mRNA isolated from skin biopsies, normalized to actin expression. Asterisk indicate statistical significance from young adult values (IGF-1 p = 0.005, COL1 p = 0.091; two-tailed t-test). (C) The number of senescent fibroblasts (based on circular or elliptical nuclear morphology as determined using Nikon Elements Image Analysis software) was counted in the papillary dermis. Asterisk indicates statistical significance from young adult values (p = 0.001; two-tailed t-test). (D) The area of the epidermis and papillary dermis were calculated from 3mm punch biopsies using Nikon Elements image analysis software. Asterisk indicates statistical significance from young adult values (Epidermis p = 0.0577, Papillary dermis p = 0.022; two-tailed t-test).
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Figure 2: Senescent fibroblasts accumulate in geriatric dermis in vivoBiopsies of sun-protected skin were obtained from six young adult (20-28 years old) and six geriatric (>65 years old) volunteers. (A) Sections of skin were stained with antibodies to 53BP1 and γH2AX. Positive nuclei are indicated by white arrows; dashed line specifies the location of the basement membrane; bar = 25 µm. (B) Quantitative PCR analysis of mRNA isolated from skin biopsies, normalized to actin expression. Asterisk indicate statistical significance from young adult values (IGF-1 p = 0.005, COL1 p = 0.091; two-tailed t-test). (C) The number of senescent fibroblasts (based on circular or elliptical nuclear morphology as determined using Nikon Elements Image Analysis software) was counted in the papillary dermis. Asterisk indicates statistical significance from young adult values (p = 0.001; two-tailed t-test). (D) The area of the epidermis and papillary dermis were calculated from 3mm punch biopsies using Nikon Elements image analysis software. Asterisk indicates statistical significance from young adult values (Epidermis p = 0.0577, Papillary dermis p = 0.022; two-tailed t-test).

Mentions: As we age, the skin becomes altered both phenotypically and biologically. The undulating structure of the dermal-epidermal junction in young skin becomes significantly flattened with age [33-34; Supplemental Fig. 1A]. Both the epidermis and the papillary dermis become atrophied in geriatric skin [33-37; Fig. 2D] and the transcriptome in the geriatric dermis becomes altered, including the relative silencing of the IGF-1 and collagen I genes [3; Fig. 2B]. Additionally, fibroblast morphology transforms from a spindle-shaped cell body and elliptical nucleus to a more rounded cell body and a rounded nucleus [37-38; Supplemental Fig. 1A, white circles]. These morphological changes in fibroblast shape are associated with increasing proportions of senescent fibroblasts in the papillary dermis (Fig. 2C). These senescent fibroblasts can be defined in vivo by increased expression of DDR markers (Fig. 2A). Previously, we and others have shown that senescent fibroblasts in vitro silence IGF-1 expression [3]. Similarly, intrinsic aging of skin in vivo can be characterized by a significantly increased proportion of senescent fibroblasts in the papillary dermis and a corresponding silencing of IGF-1 expression in geriatric dermis.


Reversing the aging stromal phenotype prevents carcinoma initiation.

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

Senescent fibroblasts accumulate in geriatric dermis in vivoBiopsies of sun-protected skin were obtained from six young adult (20-28 years old) and six geriatric (>65 years old) volunteers. (A) Sections of skin were stained with antibodies to 53BP1 and γH2AX. Positive nuclei are indicated by white arrows; dashed line specifies the location of the basement membrane; bar = 25 µm. (B) Quantitative PCR analysis of mRNA isolated from skin biopsies, normalized to actin expression. Asterisk indicate statistical significance from young adult values (IGF-1 p = 0.005, COL1 p = 0.091; two-tailed t-test). (C) The number of senescent fibroblasts (based on circular or elliptical nuclear morphology as determined using Nikon Elements Image Analysis software) was counted in the papillary dermis. Asterisk indicates statistical significance from young adult values (p = 0.001; two-tailed t-test). (D) The area of the epidermis and papillary dermis were calculated from 3mm punch biopsies using Nikon Elements image analysis software. Asterisk indicates statistical significance from young adult values (Epidermis p = 0.0577, Papillary dermis p = 0.022; two-tailed t-test).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Senescent fibroblasts accumulate in geriatric dermis in vivoBiopsies of sun-protected skin were obtained from six young adult (20-28 years old) and six geriatric (>65 years old) volunteers. (A) Sections of skin were stained with antibodies to 53BP1 and γH2AX. Positive nuclei are indicated by white arrows; dashed line specifies the location of the basement membrane; bar = 25 µm. (B) Quantitative PCR analysis of mRNA isolated from skin biopsies, normalized to actin expression. Asterisk indicate statistical significance from young adult values (IGF-1 p = 0.005, COL1 p = 0.091; two-tailed t-test). (C) The number of senescent fibroblasts (based on circular or elliptical nuclear morphology as determined using Nikon Elements Image Analysis software) was counted in the papillary dermis. Asterisk indicates statistical significance from young adult values (p = 0.001; two-tailed t-test). (D) The area of the epidermis and papillary dermis were calculated from 3mm punch biopsies using Nikon Elements image analysis software. Asterisk indicates statistical significance from young adult values (Epidermis p = 0.0577, Papillary dermis p = 0.022; two-tailed t-test).
Mentions: As we age, the skin becomes altered both phenotypically and biologically. The undulating structure of the dermal-epidermal junction in young skin becomes significantly flattened with age [33-34; Supplemental Fig. 1A]. Both the epidermis and the papillary dermis become atrophied in geriatric skin [33-37; Fig. 2D] and the transcriptome in the geriatric dermis becomes altered, including the relative silencing of the IGF-1 and collagen I genes [3; Fig. 2B]. Additionally, fibroblast morphology transforms from a spindle-shaped cell body and elliptical nucleus to a more rounded cell body and a rounded nucleus [37-38; Supplemental Fig. 1A, white circles]. These morphological changes in fibroblast shape are associated with increasing proportions of senescent fibroblasts in the papillary dermis (Fig. 2C). These senescent fibroblasts can be defined in vivo by increased expression of DDR markers (Fig. 2A). Previously, we and others have shown that senescent fibroblasts in vitro silence IGF-1 expression [3]. Similarly, intrinsic aging of skin in vivo can be characterized by a significantly increased proportion of senescent fibroblasts in the papillary dermis and a corresponding silencing of IGF-1 expression in geriatric dermis.

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