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The IGF-1/IGF-1R signaling axis in the skin: a new role for the dermis in aging-associated skin cancer.

Lewis DA, Travers JB, Somani AK, Spandau DF - Oncogene (2009)

Bottom Line: In human skin, epidermal keratinocytes do not express IGF-1, and hence the IGF-1 receptor on keratinocytes is activated by IGF-1 secreted from dermal fibroblasts.Finally, the appropriate UVB response is restored in geriatric skin in vivo through pretreatment with exogenous IGF-1.These studies provide further evidence for a role of the IGF-1 receptor (IGF-1R) in suppressing UVB-induced carcinogenesis, suggest that fibroblasts have a critical role in maintaining appropriate activation of the keratinocyte IGF-1R, and imply that reduced expression of IGF-1 in geriatric skin could be an important component in the development of aging-related non-melanoma skin cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

ABSTRACT
The appropriate response of human keratinocytes to ultraviolet-B (UVB) is dependent on the activation status of the insulin-like growth factor 1 (IGF-1) receptor. Keratinocytes grown in conditions in which the IGF-1 receptor is inactive inappropriately replicate in the presence of UVB-induced DNA damage. In human skin, epidermal keratinocytes do not express IGF-1, and hence the IGF-1 receptor on keratinocytes is activated by IGF-1 secreted from dermal fibroblasts. We now show that the IGF-1 produced by human fibroblasts is essential for the appropriate UVB response of keratinocytes. Furthermore, the expression of IGF-1 is silenced in senescent fibroblasts in vitro. Using quantitative reverse transcriptase-PCR and immunohistochemisty, we can show that IGF-1 expression is also silenced in geriatric dermis in vivo. The diminished IGF-1 expression in geriatric skin correlates with an inappropriate UVB response in geriatric volunteers. Finally, the appropriate UVB response is restored in geriatric skin in vivo through pretreatment with exogenous IGF-1. These studies provide further evidence for a role of the IGF-1 receptor (IGF-1R) in suppressing UVB-induced carcinogenesis, suggest that fibroblasts have a critical role in maintaining appropriate activation of the keratinocyte IGF-1R, and imply that reduced expression of IGF-1 in geriatric skin could be an important component in the development of aging-related non-melanoma skin cancer.

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The influence of aging on IGF-1 expression in the skin and its role in UVB-induced carcinogenesisKeratinocytes in aged epidermis exposed to UVB wavelengths in sunlight may respond inappropriately to the UVB exposure. The dermis of young adults produces sufficient levels of IGF-1 to activate the IGF-1R on epidermal keratinocytes. The appropriate activation of the IGF-1R on keratinocytes leads to the induction of stress-induced senescence following sufficient UVB exposure. In contrast, the expression of IGF-1 is silenced in aged dermis. The consequence of diminished IGF-1 expression is a lack of IGF-1R activation in epidermal keratinocytes. Instead of undergoing stress-induced senescence, the aged keratinocytes are able to proliferate in the presence of UVB-damaged DNA. We hypothesize this decrease in IGF-1 expression with advancing age is a contributor to the increase in non-melanoma skin cancer seen in geriatric patients.
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Figure 8: The influence of aging on IGF-1 expression in the skin and its role in UVB-induced carcinogenesisKeratinocytes in aged epidermis exposed to UVB wavelengths in sunlight may respond inappropriately to the UVB exposure. The dermis of young adults produces sufficient levels of IGF-1 to activate the IGF-1R on epidermal keratinocytes. The appropriate activation of the IGF-1R on keratinocytes leads to the induction of stress-induced senescence following sufficient UVB exposure. In contrast, the expression of IGF-1 is silenced in aged dermis. The consequence of diminished IGF-1 expression is a lack of IGF-1R activation in epidermal keratinocytes. Instead of undergoing stress-induced senescence, the aged keratinocytes are able to proliferate in the presence of UVB-damaged DNA. We hypothesize this decrease in IGF-1 expression with advancing age is a contributor to the increase in non-melanoma skin cancer seen in geriatric patients.

Mentions: Although skin cancer can occur at any age, there is a strong correlation between the development of skin cancer and increasing age [Kraemer, 1997]. Eighty percent of all skin cancers are found in people over the age of 60; therefore, age is a risk factor for the development of skin cancer. While the correlation between aged epidermis and skin is apparent, the mechanism responsible for this relationship remains obscure. The historical explanation for the correlation between skin cancer and aging argues that UVB damage inflicted on skin during adolescence initiates mutations in keratinocytes that are selectively enriched over many decades until enough genetic changes have accumulated in these keratinocytes that they become carcinogenic. Recent data from a variety of labs have proposed a modification of this theory based on changes in the stromal support cells of epithelial cells with advancing age [Shelton et al., 1999; Krtolica et al., 2001; Parrienllo et al., 2005]. This hypothesis states that the selection of mutated cells is accelerated in aged tissue due to inflammatory changes that have been observed in senescent fibroblasts supporting epithelial cell growth [Shelton et al., 1999; Krtolica et al., 2001; Parrienllo et al., 2005]. The integration of data from our lab on the role of the IGF-1R and normal UVB response of keratinocytes with data describing the declining production of IGF-1 by senescent fibroblasts have led to a third hypothesis correlating aging skin with the development of skin cancer (Figure 8). As noted previously, keratinocytes express the IGF-1R but they do not synthesize IGF-1 [Tavakkol et al., 1992]. Dermal fibroblasts support the proliferation of keratinocytes in the epidermis by secreting IGF-1. However, dermal fibroblasts in geriatric dermis produce far less IGF-1 than fibroblasts in young adult dermis, implying that keratinocytes in aged skin may be supplied with an insufficient concentration of IGF-1. We believe this decrease in IGF-1 expression with advancing age is a major component of the increase in non-melanoma skin cancer seen in geriatric patients. A corollary of this hypothesis would be that individuals with an increased activation of the IGF-1R might have some protection from UVB-induced skin cancer that could be detected by a decrease in skin cancer incidence. IGF-1 and insulin have very similar molecular structures and high concentrations of insulin will activate the IGF-1R. Patients with type II diabetes frequently have to take exogenous systemic insulin to overcome their insulin resistance. We hypothesized that the high systemic insulin levels in these patients would compensate for an aging-dependent decline in IGF-1 in the skin by inadvertently maintaining IGF-1R activation despite declining levels of IGF-1. If this were true, our control population would have an increasing incidence of skin cancer with advancing age, while the type 2 insulin-using diabetic patient cohort would not see a change in skin cancer incidence with age. In fact, the use of insulin was protective of the age-dependent increase in skin cancer incidence [Chuang et al., 2005].


The IGF-1/IGF-1R signaling axis in the skin: a new role for the dermis in aging-associated skin cancer.

Lewis DA, Travers JB, Somani AK, Spandau DF - Oncogene (2009)

The influence of aging on IGF-1 expression in the skin and its role in UVB-induced carcinogenesisKeratinocytes in aged epidermis exposed to UVB wavelengths in sunlight may respond inappropriately to the UVB exposure. The dermis of young adults produces sufficient levels of IGF-1 to activate the IGF-1R on epidermal keratinocytes. The appropriate activation of the IGF-1R on keratinocytes leads to the induction of stress-induced senescence following sufficient UVB exposure. In contrast, the expression of IGF-1 is silenced in aged dermis. The consequence of diminished IGF-1 expression is a lack of IGF-1R activation in epidermal keratinocytes. Instead of undergoing stress-induced senescence, the aged keratinocytes are able to proliferate in the presence of UVB-damaged DNA. We hypothesize this decrease in IGF-1 expression with advancing age is a contributor to the increase in non-melanoma skin cancer seen in geriatric patients.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2837099&req=5

Figure 8: The influence of aging on IGF-1 expression in the skin and its role in UVB-induced carcinogenesisKeratinocytes in aged epidermis exposed to UVB wavelengths in sunlight may respond inappropriately to the UVB exposure. The dermis of young adults produces sufficient levels of IGF-1 to activate the IGF-1R on epidermal keratinocytes. The appropriate activation of the IGF-1R on keratinocytes leads to the induction of stress-induced senescence following sufficient UVB exposure. In contrast, the expression of IGF-1 is silenced in aged dermis. The consequence of diminished IGF-1 expression is a lack of IGF-1R activation in epidermal keratinocytes. Instead of undergoing stress-induced senescence, the aged keratinocytes are able to proliferate in the presence of UVB-damaged DNA. We hypothesize this decrease in IGF-1 expression with advancing age is a contributor to the increase in non-melanoma skin cancer seen in geriatric patients.
Mentions: Although skin cancer can occur at any age, there is a strong correlation between the development of skin cancer and increasing age [Kraemer, 1997]. Eighty percent of all skin cancers are found in people over the age of 60; therefore, age is a risk factor for the development of skin cancer. While the correlation between aged epidermis and skin is apparent, the mechanism responsible for this relationship remains obscure. The historical explanation for the correlation between skin cancer and aging argues that UVB damage inflicted on skin during adolescence initiates mutations in keratinocytes that are selectively enriched over many decades until enough genetic changes have accumulated in these keratinocytes that they become carcinogenic. Recent data from a variety of labs have proposed a modification of this theory based on changes in the stromal support cells of epithelial cells with advancing age [Shelton et al., 1999; Krtolica et al., 2001; Parrienllo et al., 2005]. This hypothesis states that the selection of mutated cells is accelerated in aged tissue due to inflammatory changes that have been observed in senescent fibroblasts supporting epithelial cell growth [Shelton et al., 1999; Krtolica et al., 2001; Parrienllo et al., 2005]. The integration of data from our lab on the role of the IGF-1R and normal UVB response of keratinocytes with data describing the declining production of IGF-1 by senescent fibroblasts have led to a third hypothesis correlating aging skin with the development of skin cancer (Figure 8). As noted previously, keratinocytes express the IGF-1R but they do not synthesize IGF-1 [Tavakkol et al., 1992]. Dermal fibroblasts support the proliferation of keratinocytes in the epidermis by secreting IGF-1. However, dermal fibroblasts in geriatric dermis produce far less IGF-1 than fibroblasts in young adult dermis, implying that keratinocytes in aged skin may be supplied with an insufficient concentration of IGF-1. We believe this decrease in IGF-1 expression with advancing age is a major component of the increase in non-melanoma skin cancer seen in geriatric patients. A corollary of this hypothesis would be that individuals with an increased activation of the IGF-1R might have some protection from UVB-induced skin cancer that could be detected by a decrease in skin cancer incidence. IGF-1 and insulin have very similar molecular structures and high concentrations of insulin will activate the IGF-1R. Patients with type II diabetes frequently have to take exogenous systemic insulin to overcome their insulin resistance. We hypothesized that the high systemic insulin levels in these patients would compensate for an aging-dependent decline in IGF-1 in the skin by inadvertently maintaining IGF-1R activation despite declining levels of IGF-1. If this were true, our control population would have an increasing incidence of skin cancer with advancing age, while the type 2 insulin-using diabetic patient cohort would not see a change in skin cancer incidence with age. In fact, the use of insulin was protective of the age-dependent increase in skin cancer incidence [Chuang et al., 2005].

Bottom Line: In human skin, epidermal keratinocytes do not express IGF-1, and hence the IGF-1 receptor on keratinocytes is activated by IGF-1 secreted from dermal fibroblasts.Finally, the appropriate UVB response is restored in geriatric skin in vivo through pretreatment with exogenous IGF-1.These studies provide further evidence for a role of the IGF-1 receptor (IGF-1R) in suppressing UVB-induced carcinogenesis, suggest that fibroblasts have a critical role in maintaining appropriate activation of the keratinocyte IGF-1R, and imply that reduced expression of IGF-1 in geriatric skin could be an important component in the development of aging-related non-melanoma skin cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

ABSTRACT
The appropriate response of human keratinocytes to ultraviolet-B (UVB) is dependent on the activation status of the insulin-like growth factor 1 (IGF-1) receptor. Keratinocytes grown in conditions in which the IGF-1 receptor is inactive inappropriately replicate in the presence of UVB-induced DNA damage. In human skin, epidermal keratinocytes do not express IGF-1, and hence the IGF-1 receptor on keratinocytes is activated by IGF-1 secreted from dermal fibroblasts. We now show that the IGF-1 produced by human fibroblasts is essential for the appropriate UVB response of keratinocytes. Furthermore, the expression of IGF-1 is silenced in senescent fibroblasts in vitro. Using quantitative reverse transcriptase-PCR and immunohistochemisty, we can show that IGF-1 expression is also silenced in geriatric dermis in vivo. The diminished IGF-1 expression in geriatric skin correlates with an inappropriate UVB response in geriatric volunteers. Finally, the appropriate UVB response is restored in geriatric skin in vivo through pretreatment with exogenous IGF-1. These studies provide further evidence for a role of the IGF-1 receptor (IGF-1R) in suppressing UVB-induced carcinogenesis, suggest that fibroblasts have a critical role in maintaining appropriate activation of the keratinocyte IGF-1R, and imply that reduced expression of IGF-1 in geriatric skin could be an important component in the development of aging-related non-melanoma skin cancer.

Show MeSH
Related in: MedlinePlus