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Seborrheic Keratoses: The Rodney Dangerfield of Skin lesions, and Why They Should Get Our Respect

2016; Elsevier BV; Volume: 136; Issue: 3 Linguagem: Inglês

10.1016/j.jid.2015.12.019

1523-1747

Jack L. Arbiser, Michael Y. Bonner,

Genetic and rare skin diseases.

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. 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. 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., 1997Chesi M. Nardini E. Brents L.A. 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: 260-264Crossref PubMed Scopus (578) Google Scholar, Shayesteh et al., 1999Shayesteh L. Lu Y. Kuo W.L. et al.PIK3CA is implicated as an oncogene in ovarian cancer.Nat Genet. 1999; 21: 99-102Crossref PubMed Scopus (1008) Google Scholar); 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 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 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., 2016Neel V.A. 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: 696-705Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar 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., 2002Arbiser J.L. 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 tuberous sclerosis.Am J Pathol. 2002; 161: 781-786Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar). Neel et al., 2016Neel V.A. 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: 696-705Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar 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., 2016Neel V.A. 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: 696-705Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar). 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 Akt-mediated apoptosis was dependent on p53 and FoxO3, a target of Akt. What are the implications of this study for dermatology and oncology? 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., 2009Mandinova 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: 3127-3137Crossref PubMed Scopus (49) Google Scholar) (Figure 1). The inhibition of Akt might lead to an increase in reactive oxygen specifically in seborrheic keratosis, which has wild-type 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., 2015Martincorena I. Roshan A. Gerstung M. et al.Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin.Science. 2015; 348: 880-886Crossref PubMed Scopus (1005) Google Scholar). 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, 2012Bonner M.Y. Arbiser J.L. Targeting NADPH oxidases for the treatment of cancer and inflammation.Cell Mol Life Sci. 2012; 69: 2435-2442Crossref PubMed Scopus (68) Google Scholar). 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., 2015Karlsson I. Zhou X. Thomas R. et al.Solenopsin A and analogs exhibit ceramide-like biological activity.Vasc Cell. 2015; 7: 5Crossref PubMed Scopus (16) Google Scholar). 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. 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. Sustained Akt Activity Is Required to Maintain Cell Viability in Seborrheic Keratosis, a Benign Epithelial TumorJournal of Investigative DermatologyVol. 136Issue 3PreviewSeborrheic keratoses (SKs) are common benign skin tumors that share many morphological features with their malignant counterpart, squamous cell carcinoma. SKs frequently have acquired oncogenic mutations in the receptor tyrosine kinase/phosphatidylinositol 3-kinase/Akt signaling cascade. We developed a reliable culture system to study SKs in vitro and screened these cells using a library of selective kinase inhibitors to evaluate effects on cell survival. These benign tumors are sensitive to inhibition by ATP-competitive Akt inhibitors, including A-443654 and GSK690693. Full-Text PDF Open Archive