Reduced susceptibility to two-stage skin carcinogenesis in mice with low circulating insulin-like growth factor I levels

Tricia Moore, Steve Carbajal, Linda Beltran, Susan N. Perkins, Shoshana Yakar, Derek LeRoith, Stephen D. Hursting, John Digiovanni

Research output: Contribution to journalArticle

Abstract

Calorie restriction has been shown to inhibit epithelial carcinogenesis and this method of dietary restriction reduces many circulating proteins, including insulin-like growth factor I (IGF-I). Previously, we identified a relationship between elevated tissue IGF-I levels and enhanced susceptibility to chemically induced skin tumorigenesis. In this study, liver IGF-I-deficient (LID) mice, which have a 75% reduction in serum IGF-I, were subjected to the standard two-stage skin carcinogenesis protocol using 7,12-dimethylbenz(a)anthraacene as the initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as the promoter. We observed a significant reduction in epidermal thickness and labeling index in LID mice treated with either vehicle or TPA. A significant decrease in both tumor incidence and tumor multiplicity was observed in LID mice undergoing two-stage skin carcinogenesis relative to wild-type littermates. Western blot analyses of epidermal extracts revealed reduced activation of both the epidermal growth factor and IGF-I receptors in response to TPA treatment in LID mice. In addition, reduced activation of both Akt and the mammalian target of rapamycin (mTOR) was observed in LID mice following TPA treatment relative to wild-type controls. Signaling downstream of mTOR was also reduced. These data suggest a possible mechanism whereby reduced circulating IGF-I leads to attenuated activation of the Akt and mTOR signaling pathways, and thus, diminished epidermal response to tumor promotion, and ultimately, two-stage skin carcinogenesis. The current data also suggest that reduced circulating IGF-I levels which occur as a result of calorie restriction may lead to the inhibition of skin tumorigenesis, at least in part, by a similar mechanism.

Original languageEnglish (US)
Pages (from-to)3680-3688
Number of pages9
JournalCancer Research
Volume68
Issue number10
DOIs
StatePublished - May 15 2008

Fingerprint

Insulin-Like Growth Factor I
Carcinogenesis
Skin
Tetradecanoylphorbol Acetate
Sirolimus
Liver
Neoplasms
IGF Type 1 Receptor
Epidermal Growth Factor
Western Blotting
Incidence
Serum

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Reduced susceptibility to two-stage skin carcinogenesis in mice with low circulating insulin-like growth factor I levels. / Moore, Tricia; Carbajal, Steve; Beltran, Linda; Perkins, Susan N.; Yakar, Shoshana; LeRoith, Derek; Hursting, Stephen D.; Digiovanni, John.

In: Cancer Research, Vol. 68, No. 10, 15.05.2008, p. 3680-3688.

Research output: Contribution to journalArticle

Moore, T, Carbajal, S, Beltran, L, Perkins, SN, Yakar, S, LeRoith, D, Hursting, SD & Digiovanni, J 2008, 'Reduced susceptibility to two-stage skin carcinogenesis in mice with low circulating insulin-like growth factor I levels', Cancer Research, vol. 68, no. 10, pp. 3680-3688. https://doi.org/10.1158/0008-5472.CAN-07-6271
Moore, Tricia ; Carbajal, Steve ; Beltran, Linda ; Perkins, Susan N. ; Yakar, Shoshana ; LeRoith, Derek ; Hursting, Stephen D. ; Digiovanni, John. / Reduced susceptibility to two-stage skin carcinogenesis in mice with low circulating insulin-like growth factor I levels. In: Cancer Research. 2008 ; Vol. 68, No. 10. pp. 3680-3688.
@article{3df9fba33da146ce92e7f230f1e61372,
title = "Reduced susceptibility to two-stage skin carcinogenesis in mice with low circulating insulin-like growth factor I levels",
abstract = "Calorie restriction has been shown to inhibit epithelial carcinogenesis and this method of dietary restriction reduces many circulating proteins, including insulin-like growth factor I (IGF-I). Previously, we identified a relationship between elevated tissue IGF-I levels and enhanced susceptibility to chemically induced skin tumorigenesis. In this study, liver IGF-I-deficient (LID) mice, which have a 75{\%} reduction in serum IGF-I, were subjected to the standard two-stage skin carcinogenesis protocol using 7,12-dimethylbenz(a)anthraacene as the initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as the promoter. We observed a significant reduction in epidermal thickness and labeling index in LID mice treated with either vehicle or TPA. A significant decrease in both tumor incidence and tumor multiplicity was observed in LID mice undergoing two-stage skin carcinogenesis relative to wild-type littermates. Western blot analyses of epidermal extracts revealed reduced activation of both the epidermal growth factor and IGF-I receptors in response to TPA treatment in LID mice. In addition, reduced activation of both Akt and the mammalian target of rapamycin (mTOR) was observed in LID mice following TPA treatment relative to wild-type controls. Signaling downstream of mTOR was also reduced. These data suggest a possible mechanism whereby reduced circulating IGF-I leads to attenuated activation of the Akt and mTOR signaling pathways, and thus, diminished epidermal response to tumor promotion, and ultimately, two-stage skin carcinogenesis. The current data also suggest that reduced circulating IGF-I levels which occur as a result of calorie restriction may lead to the inhibition of skin tumorigenesis, at least in part, by a similar mechanism.",
author = "Tricia Moore and Steve Carbajal and Linda Beltran and Perkins, {Susan N.} and Shoshana Yakar and Derek LeRoith and Hursting, {Stephen D.} and John Digiovanni",
year = "2008",
month = "5",
day = "15",
doi = "10.1158/0008-5472.CAN-07-6271",
language = "English (US)",
volume = "68",
pages = "3680--3688",
journal = "Journal of Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "10",

}

TY - JOUR

T1 - Reduced susceptibility to two-stage skin carcinogenesis in mice with low circulating insulin-like growth factor I levels

AU - Moore, Tricia

AU - Carbajal, Steve

AU - Beltran, Linda

AU - Perkins, Susan N.

AU - Yakar, Shoshana

AU - LeRoith, Derek

AU - Hursting, Stephen D.

AU - Digiovanni, John

PY - 2008/5/15

Y1 - 2008/5/15

N2 - Calorie restriction has been shown to inhibit epithelial carcinogenesis and this method of dietary restriction reduces many circulating proteins, including insulin-like growth factor I (IGF-I). Previously, we identified a relationship between elevated tissue IGF-I levels and enhanced susceptibility to chemically induced skin tumorigenesis. In this study, liver IGF-I-deficient (LID) mice, which have a 75% reduction in serum IGF-I, were subjected to the standard two-stage skin carcinogenesis protocol using 7,12-dimethylbenz(a)anthraacene as the initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as the promoter. We observed a significant reduction in epidermal thickness and labeling index in LID mice treated with either vehicle or TPA. A significant decrease in both tumor incidence and tumor multiplicity was observed in LID mice undergoing two-stage skin carcinogenesis relative to wild-type littermates. Western blot analyses of epidermal extracts revealed reduced activation of both the epidermal growth factor and IGF-I receptors in response to TPA treatment in LID mice. In addition, reduced activation of both Akt and the mammalian target of rapamycin (mTOR) was observed in LID mice following TPA treatment relative to wild-type controls. Signaling downstream of mTOR was also reduced. These data suggest a possible mechanism whereby reduced circulating IGF-I leads to attenuated activation of the Akt and mTOR signaling pathways, and thus, diminished epidermal response to tumor promotion, and ultimately, two-stage skin carcinogenesis. The current data also suggest that reduced circulating IGF-I levels which occur as a result of calorie restriction may lead to the inhibition of skin tumorigenesis, at least in part, by a similar mechanism.

AB - Calorie restriction has been shown to inhibit epithelial carcinogenesis and this method of dietary restriction reduces many circulating proteins, including insulin-like growth factor I (IGF-I). Previously, we identified a relationship between elevated tissue IGF-I levels and enhanced susceptibility to chemically induced skin tumorigenesis. In this study, liver IGF-I-deficient (LID) mice, which have a 75% reduction in serum IGF-I, were subjected to the standard two-stage skin carcinogenesis protocol using 7,12-dimethylbenz(a)anthraacene as the initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as the promoter. We observed a significant reduction in epidermal thickness and labeling index in LID mice treated with either vehicle or TPA. A significant decrease in both tumor incidence and tumor multiplicity was observed in LID mice undergoing two-stage skin carcinogenesis relative to wild-type littermates. Western blot analyses of epidermal extracts revealed reduced activation of both the epidermal growth factor and IGF-I receptors in response to TPA treatment in LID mice. In addition, reduced activation of both Akt and the mammalian target of rapamycin (mTOR) was observed in LID mice following TPA treatment relative to wild-type controls. Signaling downstream of mTOR was also reduced. These data suggest a possible mechanism whereby reduced circulating IGF-I leads to attenuated activation of the Akt and mTOR signaling pathways, and thus, diminished epidermal response to tumor promotion, and ultimately, two-stage skin carcinogenesis. The current data also suggest that reduced circulating IGF-I levels which occur as a result of calorie restriction may lead to the inhibition of skin tumorigenesis, at least in part, by a similar mechanism.

UR - http://www.scopus.com/inward/record.url?scp=45549106969&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=45549106969&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-07-6271

DO - 10.1158/0008-5472.CAN-07-6271

M3 - Article

VL - 68

SP - 3680

EP - 3688

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0008-5472

IS - 10

ER -