Altered expression of epidermal growth factor receptor ligands in tumor promoter–treated mouse epidermis and in primary mouse skin tumors induced by an initiation-promotion protocol

Kiguchi, Kaoru; Beltrán, Linda; Rupp, Tim; DiGiovanni, John

doi:10.1002/(sici)1098-2744(199806)22:2<73::aid-mc2>3.0.co;2-l

Cited by 39 publications

(21 citation statements)

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“…Previous studies have shown that the EGFR is activated (20) and the levels of its ligands (both mRNA and protein; Refs. 18,19,21) are elevated in tumor promoter-treated mouse epidermis and in skin papillomas. Through a series of experiments whereby EGFR function was modulated, we demonstrated that Stat3 activity was regulated, at least in part, by EGFR signaling during skin tumor promotion.…”

Section: Discussionmentioning

confidence: 97%

“…Our laboratory has previously shown activation of the EGFR (18,20) concomitant with an elevated expression of its ligands (18,19,21) in mouse epidermis treated with TPA. In addition, these changes are constitutive in skin papillomas generated by the two-stage DMBA-TPA regimen (20,21). Therefore, we examined whether the EGFR pathway is involved in the activation of Stat3 during tumor promotion and multistage skin carcinogenesis.…”

Section: Activation Of Stats In Mousementioning

confidence: 97%

“…We have previously shown that skin tumor promoters up-regulate EGFR ligands (e.g., TGF-␣), leading to activation of the EGFR (18,19). In addition, skin tumors generated in this model system exhibit constitutively up-regulated EGFR ligands (20,21). Transgenic mice overexpressing TGF-␣ showed a hyperproliferative phenotype and were highly susceptible to skin tumor development induced by the two-stage regimen and also developed skin tumors after treatment with either DMBA or TPA alone (22)(23)(24)(25).…”

Section: Introductionmentioning

confidence: 93%

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Epidermal Growth Factor Receptor-Mediated Activation of Stat3 during Multistage Skin Carcinogenesis

et al. 2004

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In the present study, we have investigated the possible role of signal transducers and activators of transcription (STATs), particularly Stat3, in mouse skin tumor promotion and multistage carcinogenesis. Stat1, Stat3, and Stat5 were activated in mouse epidermis after treatment with different classes of tumor promoters, including 12-O-tetradecanoylphorbol-13-acetate (TPA), okadaic acid, and chrysarobin. In addition, Stat1, Stat3, and Stat5 were constitutively activated in skin tumors generated by the two-stage carcinogenesis regimen using 7,12-dimethylbenz(a)anthracene as initiator and TPA as promoter. Several approaches were used to examine the possible role of epidermal growth factor receptor (EGFR) in modulating Stat3 activity during tumor promotion. In primary cultures of mouse keratinocytes, addition of exogenous EGF led to activation of Stat3 as shown by an elevation in tyrosine phosphorylation and nuclear translocation. In epidermis of transgenic mice expressing transforming growth factor ␣ under control of the keratin 14 promoter, Stat3 was constitutively activated. Abrogation of EGFR function in mouse epidermis using an EGFR kinase inhibitor or by overexpressing a dominant negative form of EGFR led to a reduction in Stat3 activation in response to TPA treatment. Immunoprecipitation analyses using lysates from TPA-treated epidermis and skin papillomas showed enhanced interaction between the EGFR and Stat3. Finally, Stat3 deficiency in mouse epidermis significantly reduced the proliferative response after TPA treatment. Collectively, the current results suggest that Stat3 activation may be a critical event during mouse skin tumor promotion, possibly through regulation of keratinocyte proliferation. In addition, Stat3 activation in tumor promoter-treated epidermis and in skin papillomas may occur, at least in part, via interaction with and phosphorylation by the EGFR. Finally, constitutive activation of Stat3 in both papillomas and squamous cell carcinomas suggest a role in both the development of autonomous growth and the progression of epithelial tumors in mouse skin.

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Section: Discussionmentioning

confidence: 97%

Section: Activation Of Stats In Mousementioning

confidence: 97%

Section: Introductionmentioning

confidence: 93%

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Epidermal Growth Factor Receptor-Mediated Activation of Stat3 during Multistage Skin Carcinogenesis

et al. 2004

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“…Furthermore, invasion through Matrigel was also elevated in a similar manner (Supplementary Figure 2). Many growth factors (for example, EGF receptor ligands) are upregulated during tumor promotion in the mouse skin model (Rho et al, 1994;Kiguchi et al, 1998). Previous work using a human skin organ culture model demonstrated enhanced invasion of epidermal Stat3 in malignant progression of skin tumors KS Chan et al keratinocytes into the underlying dermal tissue following exposure to both EGF and HGF (Zeigler et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Forced expression of a constitutively active form of Stat3 in mouse epidermis enhances malignant progression of skin tumors induced by two-stage carcinogenesis

et al. 2007

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“…Several of these ligands are up-regulated during wound healing (Grotendorst et al, 1989;McCarthy et al, 1996;Stoll et al, 1997), in hyperproliferative skin conditions such as psoriasis (Elder et al, 1989;Cook et al, 1992;Downing et al, 1997; and retinoid-treated skin Varani et al, 2001), and during malignant transformation by chemical carcinogens (Kiguchi et al, 1998) or oncogenes (Dlugosz et al, 1995). Using the skin organ culture system, we have shown that the induction of HB-EGF and amphiregulin (AR) expression during wounding is strongly dependent on ErbB signaling (Stoll et al, 1997), and also on downstream signaling through the extracellular signal-regulated kinase (ERK) pathway .…”

Section: Introductionmentioning

confidence: 99%

Autocrine Extracellular Signal-regulated Kinase (ERK) Activation in Normal Human Keratinocytes: Metalloproteinase-mediated Release of Amphiregulin Triggers Signaling from ErbB1 to ERK

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Stoll

Johnson

et al. 2004

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ErbB signaling through extracellular signal-regulated kinase (ERK) has been implicated in regulating the expression of ErbB ligands in hyperproliferative skin disorders and wound healing. Here, we characterize the process of autocrine ERK activation in cultured normal human keratinocytes (NHKs) subjected to growth factor (GF) deprivation. Basal ERK phosphorylation was lower after 48 h than after 24 h of GF deprivation, and lowest at 30 -60 min after an additional medium change. ERK phosphorylation was markedly increased by low concentrations of epidermal growth factor (EGF) (0.2-1 ng/ml) that provoked only a limited increase in ErbB1 tyrosine phosphorylation and internalization. Basal ErbB tyrosine phosphorylation and ERK phosphorylation were inhibited by two different ErbB receptor tyrosine kinase inhibitors, by the ErbB1-specific neutralizing monoclonal antibody 225 IgG, by two different metalloproteinase inhibitors, and by neutralizing antibodies against amphiregulin (AR). In contrast, these responses were unaffected by neutralizing antibodies against other ErbB1 ligands or the ErbB2 inhibitors geldanamycin and AG825. The time course of autocrine ERK phosphorylation correlated with the appearance of soluble AR, and two different metalloproteinase inhibitors blocked AR release. These results define an amphiregulin-and ErbB1-dependent mechanism by which autocrine ERK activation is maintained in NHKs, even when ErbB1 autophosphorylation and internalization are limited. INTRODUCTIONThe mammalian c-ErbB family is comprised of four closely related receptor tyrosine kinases (RTKs) that interact hierarchically in response to multiple ErbB receptor ligands (Klapper et al., 2000;Olayioye et al., 2000). Ligand binding to the extracellular domain promotes receptor homo-and heterodimerization, resulting in phosphorylation of specific tyrosine residues on the cytoplasmic domain. These events lead to activation of multiple signal transduction pathways via Src homology 2 (SH2)-and phosphotyrosine binding (PTB)-domain containing cytoplasmic proteins, ultimately affecting many cellular functions, including cell migration, proliferation, and differentiation (Hubbard et al., 1998;Hackel et al., 1999). We and others have demonstrated that human skin expresses ErbB1, ErbB2, and ErbB3, but little or no ErbB4 (Press et al., 1990;Prigent et al., 1992;De Potter et al., 2001;Stoll et al., 2001).ErbB signaling plays a very important role in the reepithelialization of skin wounds, as evidenced by acceleration of burn or partial-thickness wound healing by epidermal growth factor (EGF) (Brown et al., 1989), transforming growth factor-␣ (TGF-␣) (Schultz et al., 1987), heparin-binding EGF-like growth factor (HB-EGF) (Cribbs et al., 1998), and epiregulin (Draper et al., 2003). Corneal wound healing also is markedly inhibited after treatment with ErbB receptor tyrosine kinase inhibitors (RTKIs) (Nakamura et al., 2001). Organ cultures of skin display many features of early wounds, including rapid keratinocyte cytoskeletal alterations, an early ...

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Altered expression of epidermal growth factor receptor ligands in tumor promoter–treated mouse epidermis and in primary mouse skin tumors induced by an initiation-promotion protocol

Cited by 39 publications

References 42 publications

Epidermal Growth Factor Receptor-Mediated Activation of Stat3 during Multistage Skin Carcinogenesis

Epidermal Growth Factor Receptor-Mediated Activation of Stat3 during Multistage Skin Carcinogenesis

Forced expression of a constitutively active form of Stat3 in mouse epidermis enhances malignant progression of skin tumors induced by two-stage carcinogenesis

Autocrine Extracellular Signal-regulated Kinase (ERK) Activation in Normal Human Keratinocytes: Metalloproteinase-mediated Release of Amphiregulin Triggers Signaling from ErbB1 to ERK

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