Proliferation, Apoptosis, and Survivin Expression in Keratinocytic Neoplasms and Hyperplasias

Abstract

The dysregulation of apoptosis occurs in many cutaneous disease states. Several apoptosis inhibitors have been shown elevated in neoplasms and in some inflammatory conditions, but their relation to proliferative and apoptotic states has not been defined. We examined the expression of the apoptosis inhibitor survivin in a panel of keratinocytic neoplasms and hyperproliferative skin lesions using both immunohistochemistry and a newly developed in situ hybridization technique. Proliferation and apoptotic indices were also assessed by immunohistochemical staining for proliferating cell nuclear antigen and TUNEL, respectively. We found the highest rate of proliferation in verrucae and psoriasis followed by actinic keratosis, squamous and basal cell carcinoma, lichen simplex chronicus, and seborrheic keratosis; all were significantly (P < 0.05) higher than normal skin. Apoptotic rate was increased in squamous (P = 0.05) and basal cell carcinoma (P = 0.03), but not significantly different from normal skin in the other lesions tested. Survivin expression was seen in most neoplasms and hyperproliferative lesions, but not normal skin. Survivin expression was often restricted to the upper third of the epidermis in psoriasis and lichen simplex chronicus, whereas all the other lesions stained diffusely. Survivin expression appears to be a consistent feature of keratinocytic neoplasms and hyperproliferative lesions and may contribute to the formation of epidermal hyperplasia seen in all of these disease states. KeywordsApoptosis; Keratinocyte; Proliferating cell nuclear antigen; TUNEL; Survivin Maintenance of homeostasis in the skin requires a delicate balance among proliferation, differentiation, and apoptosis. Disruption of the regulatory mechanisms governing these normal processes likely occurs in neoplastic and hyperproliferative disease states. The expression of various inhibitors of apoptosis, primarily of the Bcl-2 family, has been examined in multiple epidermal tumors and inflammatory conditions. For example, the apoptosis inhibitors bcl-2 and bcl-X L are expressed in melanoma 1-4 and nonmelanoma skin cancer. 5-9 In basal and squamous cell carcinoma (SCC), bcl-2 expression was detectable in the malignant keratinocytes but not in adjacent nonmalignant cells. 6 Weak bcl-2 expression was consistently found in keratinocytes comprising lesions of contact dermatitis, psoriasis, and seborrheic keratosis. 6 Dummer et al 10 examined bcl-2 expression in both benign and malignant cutaneous T-cell infiltrates and found significantly higher bcl-2 expression in the Address correspondence to Huntsman Cancer Institute, Suite 5243, 2000, Circle of Hope, Salt Lake City, Utah, 84112 (e-mail: doug.grossman@hci.utah.edu). Keratinocyte proliferation has been assessed in a number of benign and malignant skin conditions by immunohistochemical staining for proliferating cell nuclear antigen (PCNA) or Ki-67. Increased proliferation compared with normal skin was shown in psoriasis, 12,13 ichthyosis, 12 chronic dermatitis, 12,13 and verr...

Melanocyte Expression of Survivin Promotes Development and Metastasis of UV-Induced Melanoma in HGF-Transgenic Mice

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Does Notch play a tumor suppressor role across diverse squamous cell carcinomas?

“…Lack of caspase 3 resulted in increased proliferation and decreased differentiation of embryonic keratinocytes 36. However, the possible involvement of this pathway in CSCC remains to be clarified, although increased expression of survivin, an apoptosis inhibitor targeting caspase 3 and caspase 7, was observed in CSCC tumors 37, 38, 39.…”

Expression pattern of anti-apoptotic protein survivin in dysplastic nev

“…In such way, survivin is undetectable in the G0 phase cells of normal differentiated tissues, but frequently expressed in fetal tissues, in pre-neoplastic and early neoplastic lesions, as well as in developed malignancies [19]. Survivin has also been demonstrated in common nevi, in malignant melanoma, in epithelial skin tumors and tumor-like lesions; however, its expression was very rarely studied in dysplastic nevi [10,11,12,16,20].…”