- Email: [email protected]
Seborrheic Keratoses: The Rodney Dangerfield of Skin lesions, and Why They Should Get Our Respect
COMMENTARY Strid J, Hourihane J, Kimber I, Callard R, Strobel S. Disruption of the stratum corneum allows potent epicutaneous immunization with protein antigens resulting in a dominant systemic Th2 response. Eur J Immunol 2004;34:2100e9. Strid J, Sobolev O, Zafirova B, Polic B, Hayday A. The intraepithelial T cell response to NKG2D-ligands links lymphoid stress surveillance to atopy. Science 2011;334:1293e7. Tabata Y, Khurana Hershey GK. IL-13 receptor isoforms: breaking through the complexity. Curr Allergy Asthma Rep 2007;7:338e45. Tazawa T, Sugiura H, Sugiura Y, Uehara M. Relative importance of IL-4 and IL-13 in lesional skin of atopic dermatitis. Arch Dermatol Res 2004;295:459e64. Thaci D, Simpson EL, Beck LA, Bieber T, Blauvelt A, Papp K, et al. Efficacy and safety of
dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebocontrolled, dose-ranging phase 2b trial [e-pub ahead of print]. Lancet 2015; http://dx.doi.org/ 10.1016/S0140-6736(15)00388-8. Tsuchisaka A, Furumura M, Hashimoto T. Cytokine regulation during epidermal differentiation and barrier formation. J Invest Dermatol 2014; 134:1194e6. Weidinger S, Novak N. Atopic dermatitis [e-pub ahead of print]. Lancet 2015; http://dx.doi.org/ 10.1016/S0140-6736(15)00149-X. Zheng T, Oh MH, Oh SY, Schroeder JT, Glick AB, Zhu Z. Transgenic expression of interleukin-13 in the skin induces a pruritic dermatitis and skin remodeling. J Invest Dermatol 2009;129: 742e51.
See related article on pg 696
Seborrheic Keratoses: The Rodney Dangerfield of Skin lesions, and Why They Should Get Our Respect Jack L. Arbiser1,2 and Michael Y. Bonner1 Neel et al. have demonstrated that seborrheic keratosis, the most common of all skin tumors, is dependent on acutely transforming retrovirus AKT8 in rodent T-cell lymphoma signaling. The authors found that these lesions are hypersensitive to Akt inhibitors which bind to the ATP binding site of Akt. Cutaneous squamous cell carcinoma is resistant to Akt inhibitors. The implications of this study are not limited to seborrheic keratosis. The presence of wild type p53 (seborrheic keratosis) or mutant p53 (cutaneous squamous cell carcinoma) appears to dictate whether a lesion is sensitive to Akt inhibition or not. Journal of Investigative Dermatology (2016) 136, 564e566. doi:10.1016/j.jid.2015.12.019
Seborrheic keratoses are the “Rodney Dangerfield” of skin lesions. They are common manifestations of aging, warty in appearance, and they have virtually no malignant potential. For the practicing dermatologist, they are a nuisance, treated usually with cryotherapy on request of patients for aesthetic reasons, and they are of concern only because they can mimic melanoma in clinical appearance. They receive little respect from both patients and physicians.
Why should we respect seborrheic keratosis? First, they are the most common benign tumors in humans. Second, they contain mutations in oncogenes that are present in aggressive malignancies such as ovarian carcinoma and multiple myeloma (Chesi et al., 1997; Shayesteh et al., 1999); yet, seborrheic keratoses rarely progress to malignancy. This raises two additional questions. First, what is the mutational stimulus that gives rise to these oncogenic mutations, as seborrheic keratoses
1
Department of Dermatology, Emory School of Medicine, and Winship Cancer Institute, Atlanta, Georgia, USA; and 2Dermatology Veterans Affairs Medical Center, Decatur, Georgia, USA
Correspondence: Jack L. Arbiser, Department of Dermatology, Emory University School of Medicine, WMB 5309, 1639 Pierce Drive, Atlanta, Georgia, USA. E-mail: [email protected]
564
Journal of Investigative Dermatology (2016), Volume 136
occur commonly in sun-protected areas? Second, what keeps the seborrheic keratosis from progressing to malignancy? These questions are of great importance because the same mutations are present in other malignancies, and if we understand the mechanism of preventing tumorigenesis in seborrheic keratoses, we may be able to develop better treatments for multiple myeloma, ovarian cancer, and other cancers.
The hypersensitivity to Akt inhibition appeared specific to seborrheic keratosis and not to squamous cell carcinoma or to other keratinocytes. The article “Akt activation is required to maintain cell viability in seborrheic keratosis, a benign epithelial tumor” by Neel et al. (2016) sheds light on the second question. We have demonstrated previously that tyrosine kinase profiling can be performed on benign tumors by establishing cell lines and examining their sensitivity to small molecule tyrosine kinase inhibitors (Arbiser et al., 2002). Neel et al. (2016) have extended this work by demonstrating the efficacy of tyrosine kinase inhibitors on seborrheic keratoses after exposing the cells directly to the compounds, without establishing cell lines. Surprisingly, they found hypersensitivity to ATP competitive Akt inhibitors, whereas other inhibitors, including allosteric Akt inhibitors, had little or no effect (Neel et al., 2016). The hypersensitivity to Akt inhibition appeared specific to seborrheic keratosis and not to squamous cell carcinoma or other keratinocytes. Second, they demonstrated a novel biomarker of the oncogenically activated but benign phenotype, FoxN1. Third, they established that Akt inhibition caused an increase in p53 protein expression, but not RNA expression, and that Aktmediated apoptosis was dependent on p53 and FoxO3, a target of Akt. What are the implications of this study for dermatology and oncology?
COMMENTARY
Figure 1. Divergent signaling pathways in cutaneous neoplasia. The presence of p53 mutations may dictate downstream pathways in common skin tumors. Ceramide dysfunction is proposed as a common initiating event.
First, the authors have demonstrated that a benign neoplasm, seborrheic keratosis, is dependent on Akt activation, regardless of mutational status. This argues for targeting a relevant signaling pathway rather than designing inhibitors to target specific mutations. Indeed, targeting mutant FGFR3 or PI3KA, so-called personalized medicine, had little effect on this system. Second, targeting Akt had little effect on squamous cell carcinoma, thus suggesting that direct Akt inhibitors might not be effective against squamous cell carcinoma. Third, in contrast to most cutaneous squamous cell carcinomas, mutations in p53 have not been observed in seborrheic keratosis (Mandinova et al., 2009) (Figure 1). The inhibition of Akt might lead to an increase in reactive oxygen specifically in seborrheic keratosis, which has wildtype p53, leading to superinduction of p53, and apoptosis. Of interest, in other studies, the combination of FGFR3 mutation and mutant p53 led to large mutant clones on sun-exposed blepharoplasty specimens that did not histologically resemble seborrheic keratosis, further supporting the hypothesis that p53 mutations may dictate the path of neoplasia, even with common driver
mutations (Martincorena et al., 2015). This phenomenon has been observed in the reactive oxygen-driven tumor, which uses low level reactive oxygen to inactivate wild-type p53 protein and activate Akt, but these tumors can be overwhelmed with reactive oxygen, leading to apoptosis (Bonner and Arbiser, 2012). What are the therapeutic implications of these findings? First, Akt inhibitors might be especially effective for malignancies that have mutations in FGFR3 and PI3KA. It would be of interest to determine whether Akt inhibition induces reactive oxygen, and if this is the case, one would not want to use antioxidants with these therapeutic compounds. Second, the finding that Akt inhibition does not kill squamous cell carcinomas should be examined in other cells, such as in actinic keratoses. It may be that either Akt is not involved in cells with mutant p53, consistent with the phenotype of the reactive oxygen-driven tumor, or squamous cell carcinoma cells may be inherently more resistant. Finally, there is a potential role of ceramides in both seborrheic keratoses and sun-induced squamous cell carcinomas, and the mutational status of p53 in these
different tumors may play roles in their distinct pathogenesis. Ceramides are endogenous lipids that can induce reactive oxygen, and we have shown that nonhydrolyzable analogs of ceramide can inhibit Akt and induce reactive oxygen (Karlsson et al., 2015). It may be that loss of ceramides could underlie both seborrheic keratosis, by allowing Akt activation, and actinic keratosis, by reducing endogenous levels of reactive oxygen and permitting growth of cells with mutant p53. Thus, seborrheic keratoses should no longer be regarded as the Rodney Dangerfield of cutaneous neoplasia, but a source of vital information on mechanisms and therapeutics. ACKNOWLEDGMENTS JLA was supported by the grant RO1 AR47901 and P30 AR42687 Emory Skin Disease Research Core Center Grant from the National Institutes of Health, a Veterans Administration Hospital Merit Award, as well as funds from the Margolis Foundation, David Roberts, MD, Rabinowitch-Davis Foundation for Melanoma Research, and the Betty Minsk Foundation for Melanoma Research.
REFERENCES Arbiser JL, Govindarajan B, Bai X, et al. Functional tyrosine kinase inhibitor profiling: a generally applicable method points to a novel role of platelet-derived growth factor receptor-beta in
www.jidonline.org
565
COMMENTARY tuberous sclerosis. Am J Pathol 2002;161: 781e6. Bonner MY, Arbiser JL. Targeting NADPH oxidases for the treatment of cancer and inflammation. Cell Mol Life Sci 2012;69:2435e42. Chesi M, Nardini E, Brents LA, et al. Frequent translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3. Nat Genet 1997;16:260e4.
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Karlsson I, Zhou X, Thomas R, et al. Solenopsin A and analogs exhibit ceramide-like biological activity. Vasc Cell 2015;7:5. Mandinova A, Kolev V, Neel V, et al. A positive FGFR3/FOXN1 feedback loop underlies benign skin keratosis versus squamous cell carcinoma formation in humans. J Clin Invest 2009;119: 3127e37. Martincorena I, Roshan A, Gerstung M, et al. Tumor evolution. High burden and pervasive
Journal of Investigative Dermatology (2016), Volume 136
positive selection of somatic mutations in normal human skin. Science 2015;348:880e6. Neel VA, Todorova K, Wang J, Kwon E, Kang M, Liu Q, et al. Sustained Akt activity is required to maintain cell viability in seborrheic keratosis, a benign epithelial tumor. J Invest Dermatol 2016;136:696e705. Shayesteh L, Lu Y, Kuo WL, et al. PIK3CA is implicated as an oncogene in ovarian cancer. Nat Genet 1999;21:99e102.
dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebocontrolled, dose-ranging phase 2b trial [e-pub ahead of print]. Lancet 2015; http://dx.doi.org/ 10.1016/S0140-6736(15)00388-8. Tsuchisaka A, Furumura M, Hashimoto T. Cytokine regulation during epidermal differentiation and barrier formation. J Invest Dermatol 2014; 134:1194e6. Weidinger S, Novak N. Atopic dermatitis [e-pub ahead of print]. Lancet 2015; http://dx.doi.org/ 10.1016/S0140-6736(15)00149-X. Zheng T, Oh MH, Oh SY, Schroeder JT, Glick AB, Zhu Z. Transgenic expression of interleukin-13 in the skin induces a pruritic dermatitis and skin remodeling. J Invest Dermatol 2009;129: 742e51.
See related article on pg 696
Seborrheic Keratoses: The Rodney Dangerfield of Skin lesions, and Why They Should Get Our Respect Jack L. Arbiser1,2 and Michael Y. Bonner1 Neel et al. have demonstrated that seborrheic keratosis, the most common of all skin tumors, is dependent on acutely transforming retrovirus AKT8 in rodent T-cell lymphoma signaling. The authors found that these lesions are hypersensitive to Akt inhibitors which bind to the ATP binding site of Akt. Cutaneous squamous cell carcinoma is resistant to Akt inhibitors. The implications of this study are not limited to seborrheic keratosis. The presence of wild type p53 (seborrheic keratosis) or mutant p53 (cutaneous squamous cell carcinoma) appears to dictate whether a lesion is sensitive to Akt inhibition or not. Journal of Investigative Dermatology (2016) 136, 564e566. doi:10.1016/j.jid.2015.12.019
Seborrheic keratoses are the “Rodney Dangerfield” of skin lesions. They are common manifestations of aging, warty in appearance, and they have virtually no malignant potential. For the practicing dermatologist, they are a nuisance, treated usually with cryotherapy on request of patients for aesthetic reasons, and they are of concern only because they can mimic melanoma in clinical appearance. They receive little respect from both patients and physicians.
Why should we respect seborrheic keratosis? First, they are the most common benign tumors in humans. Second, they contain mutations in oncogenes that are present in aggressive malignancies such as ovarian carcinoma and multiple myeloma (Chesi et al., 1997; Shayesteh et al., 1999); yet, seborrheic keratoses rarely progress to malignancy. This raises two additional questions. First, what is the mutational stimulus that gives rise to these oncogenic mutations, as seborrheic keratoses
1
Department of Dermatology, Emory School of Medicine, and Winship Cancer Institute, Atlanta, Georgia, USA; and 2Dermatology Veterans Affairs Medical Center, Decatur, Georgia, USA
Correspondence: Jack L. Arbiser, Department of Dermatology, Emory University School of Medicine, WMB 5309, 1639 Pierce Drive, Atlanta, Georgia, USA. E-mail: [email protected]
564
Journal of Investigative Dermatology (2016), Volume 136
occur commonly in sun-protected areas? Second, what keeps the seborrheic keratosis from progressing to malignancy? These questions are of great importance because the same mutations are present in other malignancies, and if we understand the mechanism of preventing tumorigenesis in seborrheic keratoses, we may be able to develop better treatments for multiple myeloma, ovarian cancer, and other cancers.
The hypersensitivity to Akt inhibition appeared specific to seborrheic keratosis and not to squamous cell carcinoma or to other keratinocytes. The article “Akt activation is required to maintain cell viability in seborrheic keratosis, a benign epithelial tumor” by Neel et al. (2016) sheds light on the second question. We have demonstrated previously that tyrosine kinase profiling can be performed on benign tumors by establishing cell lines and examining their sensitivity to small molecule tyrosine kinase inhibitors (Arbiser et al., 2002). Neel et al. (2016) have extended this work by demonstrating the efficacy of tyrosine kinase inhibitors on seborrheic keratoses after exposing the cells directly to the compounds, without establishing cell lines. Surprisingly, they found hypersensitivity to ATP competitive Akt inhibitors, whereas other inhibitors, including allosteric Akt inhibitors, had little or no effect (Neel et al., 2016). The hypersensitivity to Akt inhibition appeared specific to seborrheic keratosis and not to squamous cell carcinoma or other keratinocytes. Second, they demonstrated a novel biomarker of the oncogenically activated but benign phenotype, FoxN1. Third, they established that Akt inhibition caused an increase in p53 protein expression, but not RNA expression, and that Aktmediated apoptosis was dependent on p53 and FoxO3, a target of Akt. What are the implications of this study for dermatology and oncology?
COMMENTARY
Figure 1. Divergent signaling pathways in cutaneous neoplasia. The presence of p53 mutations may dictate downstream pathways in common skin tumors. Ceramide dysfunction is proposed as a common initiating event.
First, the authors have demonstrated that a benign neoplasm, seborrheic keratosis, is dependent on Akt activation, regardless of mutational status. This argues for targeting a relevant signaling pathway rather than designing inhibitors to target specific mutations. Indeed, targeting mutant FGFR3 or PI3KA, so-called personalized medicine, had little effect on this system. Second, targeting Akt had little effect on squamous cell carcinoma, thus suggesting that direct Akt inhibitors might not be effective against squamous cell carcinoma. Third, in contrast to most cutaneous squamous cell carcinomas, mutations in p53 have not been observed in seborrheic keratosis (Mandinova et al., 2009) (Figure 1). The inhibition of Akt might lead to an increase in reactive oxygen specifically in seborrheic keratosis, which has wildtype p53, leading to superinduction of p53, and apoptosis. Of interest, in other studies, the combination of FGFR3 mutation and mutant p53 led to large mutant clones on sun-exposed blepharoplasty specimens that did not histologically resemble seborrheic keratosis, further supporting the hypothesis that p53 mutations may dictate the path of neoplasia, even with common driver
mutations (Martincorena et al., 2015). This phenomenon has been observed in the reactive oxygen-driven tumor, which uses low level reactive oxygen to inactivate wild-type p53 protein and activate Akt, but these tumors can be overwhelmed with reactive oxygen, leading to apoptosis (Bonner and Arbiser, 2012). What are the therapeutic implications of these findings? First, Akt inhibitors might be especially effective for malignancies that have mutations in FGFR3 and PI3KA. It would be of interest to determine whether Akt inhibition induces reactive oxygen, and if this is the case, one would not want to use antioxidants with these therapeutic compounds. Second, the finding that Akt inhibition does not kill squamous cell carcinomas should be examined in other cells, such as in actinic keratoses. It may be that either Akt is not involved in cells with mutant p53, consistent with the phenotype of the reactive oxygen-driven tumor, or squamous cell carcinoma cells may be inherently more resistant. Finally, there is a potential role of ceramides in both seborrheic keratoses and sun-induced squamous cell carcinomas, and the mutational status of p53 in these
different tumors may play roles in their distinct pathogenesis. Ceramides are endogenous lipids that can induce reactive oxygen, and we have shown that nonhydrolyzable analogs of ceramide can inhibit Akt and induce reactive oxygen (Karlsson et al., 2015). It may be that loss of ceramides could underlie both seborrheic keratosis, by allowing Akt activation, and actinic keratosis, by reducing endogenous levels of reactive oxygen and permitting growth of cells with mutant p53. Thus, seborrheic keratoses should no longer be regarded as the Rodney Dangerfield of cutaneous neoplasia, but a source of vital information on mechanisms and therapeutics. ACKNOWLEDGMENTS JLA was supported by the grant RO1 AR47901 and P30 AR42687 Emory Skin Disease Research Core Center Grant from the National Institutes of Health, a Veterans Administration Hospital Merit Award, as well as funds from the Margolis Foundation, David Roberts, MD, Rabinowitch-Davis Foundation for Melanoma Research, and the Betty Minsk Foundation for Melanoma Research.
REFERENCES Arbiser JL, Govindarajan B, Bai X, et al. Functional tyrosine kinase inhibitor profiling: a generally applicable method points to a novel role of platelet-derived growth factor receptor-beta in
www.jidonline.org
565
COMMENTARY tuberous sclerosis. Am J Pathol 2002;161: 781e6. Bonner MY, Arbiser JL. Targeting NADPH oxidases for the treatment of cancer and inflammation. Cell Mol Life Sci 2012;69:2435e42. Chesi M, Nardini E, Brents LA, et al. Frequent translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3. Nat Genet 1997;16:260e4.
566
Karlsson I, Zhou X, Thomas R, et al. Solenopsin A and analogs exhibit ceramide-like biological activity. Vasc Cell 2015;7:5. Mandinova A, Kolev V, Neel V, et al. A positive FGFR3/FOXN1 feedback loop underlies benign skin keratosis versus squamous cell carcinoma formation in humans. J Clin Invest 2009;119: 3127e37. Martincorena I, Roshan A, Gerstung M, et al. Tumor evolution. High burden and pervasive
Journal of Investigative Dermatology (2016), Volume 136
positive selection of somatic mutations in normal human skin. Science 2015;348:880e6. Neel VA, Todorova K, Wang J, Kwon E, Kang M, Liu Q, et al. Sustained Akt activity is required to maintain cell viability in seborrheic keratosis, a benign epithelial tumor. J Invest Dermatol 2016;136:696e705. Shayesteh L, Lu Y, Kuo WL, et al. PIK3CA is implicated as an oncogene in ovarian cancer. Nat Genet 1999;21:99e102.