transforming-growth-factor-alpha and Salivary-Gland-Neoplasms

Quantitative assessment is more sensitive as a measure of cellular protein content as compared with standard optical density measurements. The data support the hypothesis that increased epidermal growth factor receptor (EGFR) and transforming growth factor (TGF)-alpha expression is associated with early events in malignant transformation of pleomorphic adenoma (PA).. In the present study, we attempted to identify EGFR and TGF-alpha expression and Ki-67 index in carcinoma ex-pleomorphic adenoma (Ca ex-PA) and PA. We also compared the presence of EGFR and TGF-alpha and Ki-67 index with clinical data.. The tissues were stained with monoclonal antibodies to EGFR, TGF-alpha and Ki-67. The results were analysed using quantitative immunohistochemical analysis. We also analysed the association of patients' prognosis with clinical parameters and the histological classification of the carcinomatous component.. As regards the association of patients' prognosis with EGFR staining and Ki-67 index, a significant increase was observed in patients who died or had residual disease compared with patients who were alive without disease. In the immunohistochemical analysis of EGFR and TGF-alpha and Ki67 index, a significant increase was observed in Ca ex-PA, especially with adenocarcinoma, compared with PA and sialadenitis.

Topics: Adenoma, Pleomorphic; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Cell Transformation, Neoplastic; ErbB Receptors; Female; Follow-Up Studies; Humans; Immunohistochemistry; Ki-67 Antigen; Male; Middle Aged; Neoplasm Staging; Prognosis; Retrospective Studies; Salivary Gland Neoplasms; Transforming Growth Factor alpha

Salivary duct carcinoma (SDC) is a rare, highly aggressive neoplasm that primarily affects the major salivary glands. It is a distinct clinicopathological entity characterized by its morphologic resemblance to ductal carcinoma of the breast, a high incidence of regional lymph node metastasis, and distant dissemination. Frequent expression of androgen receptor (AR) but not estrogen receptor or progesterone receptor in SDCs suggests that SDC bears a close immunophenotypic homology with prostatic carcinoma. An AR-mediated autocrine growth pathway consisting of epidermal growth factor receptor (EGFR) and its ligand, transforming growth factor alpha (TGF-alpha), has been implicated in the carcinogenesis of prostatic carcinoma. Androgens, in the presence of AR, mediate their mitogenic effects on prostatic cancer cells by up-regulating the transcriptional and translational activities of EGFR and TGF-alpha. Through an autocrine mode of action, TGF-alpha produced in the tumor cells binds to its receptor, EGFR, which is also expressed by these cells, resulting in a proliferative response.. To investigate whether a TGF-alpha/EGFR autocrine pathway is present in SDCs.. Retrospective analysis of the expression of AR, EGFR, and TGF-alpha in 12 SDCs.. An academic medical center.. Salivary duct carcinoma expresses AR, TGF-alpha, and EGFR in 11 (92%), 8 (67%), and 11 (92%) of 12 cases, respectively.. An AR-mediated TGF-alpha/EGFR autocrine pathway may be implicated in the tumorigenesis of SDC.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma; ErbB Receptors; Female; Humans; Male; Middle Aged; Receptors, Androgen; Retrospective Studies; Salivary Gland Neoplasms; Transforming Growth Factor alpha

Transforming growth factor-alpha (TGF-alpha) is expressed in both normal and malignant epithelial cells. Although the expression of TGF-alpha has been extensively studied in some human epithelial neoplasms, its expression in adenoid cystic carcinomas (ACCs) of the salivary gland has not been reported.. This study used an immunohistochemical technique to assess the expression of TGF-alpha in 40 ACC specimens from the salivary glands, seven specimens from labial minor salivary glands adjacent to mucoceles, and five specimens from normal submandibular glands.. In the normal submandibular gland specimens, positive TGF-alpha staining was found in all ductal segments as well as in serous and some mucous acinar cells. In labial minor salivary glands adjacent to mucoceles, positive TGF-alpha staining was found in ductal, serous acinar, serous demilune, and a few mucous acinar cells. Positive TGF-alpha immunostaining was observed in all five salivary gland ACC specimens with a solid histologic pattern, and 31 of the 35 salivary gland ACC specimens with a tubulo-cribriform histologic pattern. Overall, 36 of 40 ACCs of the salivary gland expressed TGF-alpha. Positive TGF-alpha staining was found in the salivary gland ACC specimens with solid, tubular, duct-like, and pseudocystic structures. No significant correlation was found between TGF-alpha expression in ACCs of the salivary gland and age, sex, primary cancer location, TNM status, clinical stage, prognosis, histologic type, perivascular or perineural invasion, focal necrosis of the tumor, or cellular atypia.. This study demonstrated that ductal and acinar cells of the normal submandibular gland and of labial minor salivary glands adjacent to mucoceles are the major sites of TGF-alpha synthesis and secretion. Furthermore, TGF-alpha is biosynthesized in salivary gland ACC tumor cells, forming solid, tubular, duct-like, and pseudocystic structures. Our data suggest that TGF-alpha may play an important biologic role as a mitogen in the growth of salivary gland ACC.

Topics: Adult; Aged; Carcinoma, Adenoid Cystic; ErbB Receptors; Female; Humans; Immunohistochemistry; Male; Middle Aged; Salivary Gland Neoplasms; Transforming Growth Factor alpha

The c-myc oncogene is commonly amplified in breast cancer and is known to interact synergistically with transforming growth factor alpha (TGF alpha) in vitro to promote phenotypic transformation of mammary epithelial cells. In addition, both genes are under sex steroid hormone regulation in breast cancer. We have used a bitransgenic mouse approach to test the relevance of Myc-TGF alpha interaction in mammary gland tumorigenesis of virgin animals in vivo. We mated single transgenic TGF alpha and c-myc mouse strains to yield double transgenic offspring for TGF alpha and c-myc. All (20 of 20) double transgenic TGF alpha/c-myc animals developed synchronous mammary tumors at a mean age of 66 days. An unexpected finding was that tumor latency and frequency in males and virgin females were identical. Thus, two gene products that are known to be coinduced in breast cancer by the sex hormones estrogen and progesterone strongly synergize to induce synchronous mammary tumors, independent of sex. The tumors, despite being estrogen receptor positive, were readily transplanted as highly malignant s.c. cancers in ovariectomized nude mice. Although approximately one-half of single transgenic c-myc virgin females also eventually developed mammary gland tumors, these were stochastic and arose after a long latency period of 9-12 months. Single transgenic virgin TGF alpha females and males, c-myc males, and transgene-negative littermates did not develop tumors (ages up to 15 months). The salivary glands of double transgenic animals also coexpress the two transgenes and show pathological abnormalities ranging from hyperplasias to frank adenocarcinomas. In contrast, the salivary glands of single transgenic and wild-type animals showed only mild hyperplasias or metaplasias, but tumors were not observed. In situ hybridization analysis of mammary and salivary glands revealed that hyperplastic and tumorous areas colocalize with regions that overexpress both the TGF alpha and c-myc transgenes. This indicates that there is a requirement for the presence of both proteins for transformation of these glands. In summary, TGF alpha and c-Myc synergize in an extremely powerful way to cause breast and salivary gland tumorigenesis in males and virgin females without a requirement for pregnancies.

Topics: Adenocarcinoma; Animals; Base Sequence; Cell Transformation, Neoplastic; Cocarcinogenesis; Crosses, Genetic; Estrogens; Female; Gene Expression Regulation, Neoplastic; Genes, myc; Hyperplasia; Male; Mammary Neoplasms, Experimental; Mammary Tumor Virus, Mouse; Metaplasia; Mice; Mice, Nude; Mice, Transgenic; Molecular Sequence Data; Neoplasm Proteins; Neoplasm Transplantation; Neoplasms, Hormone-Dependent; Ovariectomy; Progesterone; Proto-Oncogene Proteins c-myc; Receptors, Estrogen; Repetitive Sequences, Nucleic Acid; Salivary Gland Neoplasms; Salivary Glands; Sex Factors; Transforming Growth Factor alpha