Whereas accepted models of tumorigenesis exist for genetic lesions, the timing of epigenetic alterations in cancer is not clearly understood. We have analyzed the profile of aberrations in DNA methylation occurring in cells lines and primary tumors of one of the best-characterized mouse carcinogenesis systems, the multistage skin cancer progression model. Initial analysis using high-performance capillary electrophoresis and immunolocalization revealed a loss of genomic 5-methylcytosine associated with the degree of tumor aggressiveness. Paradoxically, this occurs in the context of a growing number of hypermethylated CpG islands of tumor suppressor genes at the most malignant stages of carcinogenesis. We have observed this last phenomenon using two approaches, a candidate gene approach, studying genes with well-known methylation-associated silencing in human tumors, and a mouse cDNA microarray expression analysis after treatment with DNA demethylating drugs. The transition from epithelial to spindle cell morphology is particularly associated with major epigenetic alterations, such as E-cadherin methylation, demethylation of the Snail promoter, and a decrease of the global DNA methylation. Analysis of data obtained from the cDNA microarray strategy led to the identification of new genes that undergo methylation-associated silencing and have growth-inhibitory effects, such as the insulin-like growth factor binding protein-3. Most importantly, all of the above genes were also hypermethylated in human cancer cell lines and primary tumors, underlining the value of the mouse skin carcinogenesis model for the study of aberrant DNA methylation events in cancer cells.

Human papillomavirus (HPV) is the most common sexually transmitted disorder in young, sexually active populations in the USA and Europe. Giant condyloma acuminatum (GCA) is a unique variant of condyloma acuminata, characterized by local aggressive behaviour despite benign histology. It carries a substantial risk of squamous cell carcinoma. Various treatments have been used, but response is often poor and recurrence rates high. We present a case of GCA successfully treated with a combination of surgical excision, oral acitretin and topical imiquimod. The diagnosis was based on histological examination, immunohistochemical analysis and in situ hybridization for HPV 6 and 11. We recommend a trial of oral retinoid and topical imiquimod in selected cases of GCA.

These findings indicate a discordant expression of bcl-2 and bax/bcl-x in psoriatic epidermis. Increased bcl-x expression might contribute to the antiapoptotic response in psoriatic keratinocytes. The presence of strong bax expression with a concomitant decrease in bcl-2 expression suggests either a functional defect in bax protein or an inherent/acquired resistance to bax-mediated apoptosis in psoriatic keratinocytes.

The purpose of this study was to evaluate the distribution and frequency of apoptosis-related proteins and their correlation with estrogen, progesterone, and androgen receptors in endometrial tissues. Immunohistochemical analyses of bcl-2, bax, bcl-x, and steroid receptors were performed in 22 endometrial carcinomas, 26 endometrial hyperplasias, and 19 cases of normal cyclical endometrium. Bcl-2 was expressed in 45.4% of carcinomas and 92.3% of hyperplasias. Bax immunostaining was found in 90.9% of carcinomas and 76.9% of hyperplasias. Bcl-x positivity was similar in carcinomas (68.1%) and endometrial hyperplasias (76.9%). In normal cyclical endometria, bcl-2 staining was intense and diffuse in the proliferative phase, but decreased dramatically in the early and mid-secretory phase to reappear in the late secretory phase. Bax was expressed throughout the menstrual cycle but more strongly in the secretory phase. Bcl-x displayed a similar degree of expression in proliferative and secretory endometria. Nineteen carcinomas (86.3%), 25 hyperplasias (96.1%), and 18 normal cyclical endometria (94.7%) were positive for estrogen receptor (ER). Progesterone receptor (PR) was observed in 20 carcinomas (90.9%), all hyperplasias (100%), and 18 normal cyclical endometria (94.7%). Androgen receptor (AR) positivity was seen in 7 carcinomas (31.8%), 6 hyperplasias (23.0%), and 3 normal cyclical endometria (15.7%). There was a statistically positive correlation between bcl-x and ER and a tendency toward significant correlation between bcl-x and PR and between ER and PR in carcinomas. In hyperplasias, there was a significant positive correlation between bcl-2 and PR and between bcl-2 and bax and a negative correlation between ER and bax. There was a statistically significant difference for bcl-2 (p = 0.001) and bax (p = 0.001) between the hyperplasia and carcinoma groups. There was increased expression of bax, decreased expression of bcl-2, and persistence of bcl-x protein in advanced endometrial carcinomas. Our findings show that ovarian hormones have a regulatory role on bcl-2 protein and that there is a correlation between other members of the bcl-2 family (bcl-x and bax) and steroid hormone receptors. Bax/bcl-x may be the major control mechanisms of apoptosis in advanced carcinomas; other members of the bcl-2 family may also be under hormonal control.