ABSTRACT
The most commonly occurring cutaneous malignancies are basal cell and squamous cell carcinoma. There are, however, other rare malignancies that are encountered and should be included in the differential, in which both the clinical and the histological diagnosis may be difficult. Here, the clinical and histological features, management, and prognostic factors of merkel cell carcinoma, microcystic adnexal carcinoma, leiomyosarcoma, dermatofibrosarcoma protuberans, and angiosarcoma are reviewed.
Subject(s)
Carcinoma/diagnosis , Sarcoma/diagnosis , Skin Neoplasms/diagnosis , Adenocarcinoma/diagnosis , Adenocarcinoma/therapy , Biopsy , Carcinoma/therapy , Carcinoma, Basal Cell/diagnosis , Carcinoma, Merkel Cell/diagnosis , Carcinoma, Merkel Cell/therapy , Carcinoma, Squamous Cell/diagnosis , Dermatofibrosarcoma/diagnosis , Dermatofibrosarcoma/therapy , Diagnosis, Differential , Female , Hemangiosarcoma/diagnosis , Hemangiosarcoma/therapy , Humans , Leiomyosarcoma/diagnosis , Leiomyosarcoma/therapy , Male , Microscopy, Electron , Mohs Surgery/methods , Neoplasm Staging , PUVA Therapy/methods , Prognosis , Recurrence , Risk Factors , Sarcoma/therapy , Skin Neoplasms/therapyABSTRACT
We have previously shown that in the rat osteoblastic osteosarcoma cell line-UMR 106-01-PTH induces maximal collagenase mRNA levels at 4 hours. Since this response to PTH requires de novo protein synthesis, it may be mediated by the combined temporal expression of members of the activator protein-1 (AP-1) gene family. We have demonstrated that maximal mRNA levels of two of the members of this family, c-fos and c-jun, occur 30 min after stimulation by PTH. Phorbol myristate acetate (PMA) elicits a similar increase in c-fos and c-jun mRNAs, but is unable to stimulate transcription of collagenase in these cells. To investigate further the involvement of the AP-1 gene family, we examined PTH and PMA stimulation of jun-B, jun-D, fos B, and fra-1 mRNAs in UMR 106-01 cells. The mRNA for jun-D was abundant under control conditions and showed no variation in response to PTH (10(-8) M). The fos B transcripts were not detected under control conditions, whereas jun-B and fra-1 mRNAs were present at low basal levels. PTH caused an increase in fos B mRNA that reached a maximal 4- to 5-fold plateau between 45 and 60 min. An increase in jun-B mRNA in response to PTH was detectable at 30 min, but reached a maximal 6- to 7-fold increase at 2 hours. After PTH stimulation, the fra-1 transcript showed a 10- to 11-fold peak at 4 hours. PMA (2.6 x 10(-7) M) stimulated fos B mRNA to maximal abundance at 1 hour, similar to PTH. In contrast, PMA caused a maximal increase in jun-B mRNA at 30 min and fra-1 mRNA at 2 hours, which was earlier than the response to PTH. To determine whether an increase in jun-B at the same time as c-fos and c-jun would inhibit collagenase gene transcription, we cotransfected an expression vector for jun-B with a rat collagenase promoter-reporter gene construct. This resulted in a decrease in PTH-stimulation of promoter activity. Thus, it appears that the differential temporal stimulation of the AP-1 genes by PTH and PMA, particularly an increase in jun-B at the same time as c-fos and c-jun, explains the difference seen in their ability to induce transcription of collagenase.
Subject(s)
Bone Neoplasms/genetics , Carcinogens/toxicity , Osteosarcoma/genetics , Teriparatide/toxicity , Tetradecanoylphorbol Acetate/toxicity , Transcription Factor AP-1/genetics , Animals , Blotting, Northern , Bone Neoplasms/pathology , Chloramphenicol O-Acetyltransferase/metabolism , Collagenases/drug effects , Collagenases/genetics , Gene Expression Regulation, Neoplastic/drug effects , Gene Expression Regulation, Neoplastic/genetics , Genes, Reporter/drug effects , Genes, Reporter/genetics , Genes, fos/drug effects , Genes, fos/genetics , Genes, jun/drug effects , Genes, jun/genetics , Osteoblasts/drug effects , Osteoblasts/enzymology , Osteosarcoma/pathology , Promoter Regions, Genetic/genetics , Proto-Oncogene Proteins c-fos/drug effects , Proto-Oncogene Proteins c-fos/genetics , RNA, Messenger/biosynthesis , Rats , Transcription Factor AP-1/metabolism , Transcription, Genetic/drug effects , Transcription, Genetic/genetics , Transfection , Tumor Cells, CulturedABSTRACT
Rat tissue inhibitor of metalloproteinases-2 (TIMP-2) was cloned from a UMR 106-01 rat osteoblastic osteosarcoma cDNA library. The 969-bp full-length clone demonstrates 98 and 86% sequence identity to human TIMP-2 at the amino acid and nucleic acid levels, respectively. Parathyroid hormone (PTH), at 10(-8) M, stimulates an approximately twofold increase in both the 4.2- and 1.0-kb transcripts over basal levels in UMR cells after 24 h of exposure. The PTH stimulation of TIMP-2 transcripts was not affected by the inhibitor of protein synthesis, cycloheximide (10(-5) M), suggesting a primary effect of the hormone. This is in contradistinction to regulation of interstitial collagenase (matrix metalloproteinase-1) by PTH in these same cells. Nuclear run-on assays demonstrate that PTH causes an increase in TIMP-2 transcription that parallels the increase in message levels. Parathyroid hormone, in its stimulation of TIMP-2 mRNA, appears to act through a signal transduction pathway involving protein kinase A (PKA) since the increase in TIMP-2 mRNA is reproduced by treatment with the cAMP analogue, 8-bromo-cAMP (5 x 10(-3) M). The protein kinase C and calcium pathways do not appear to be involved due to the lack of effect of phorbol 12-myristate 13-acetate (2.6 x 10(-6) M) and the calcium ionophore, ionomycin (10(-7) M), on TIMP-2 transcript abundance. In this respect, regulation of TIMP-2 and collagenase in osteoblastic cells by PTH are similar. However, we conclude that since stimulation of TIMP-2 transcription is a primary event, the PKA pathway must be responsible for a direct increase in transcription of this gene.