epidermal-growth-factor and Fibroma

Calcifying aponeurotic fibroma (CAF) is a soft tissue neoplasm with a predilection for the hands and feet in children and adolescents. Its molecular basis is unknown. We used chromosome banding analysis, fluorescence in situ hybridization (FISH), mRNA sequencing (RNA-seq), RT-PCR, and immunohistochemistry to characterize a series of CAFs. An insertion ins(2;4)(q35;q25q?) was identified in the index case. Fusion of the FN1 and EGF genes, mapping to the breakpoint regions on chromosomes 2 and 4, respectively, was detected by RNA-seq and confirmed by RT-PCR in the index case and two additional cases. FISH on five additional tumours identified FN1-EGF fusions in all cases. CAFs analysed by RT-PCR showed that FN1 exon 23, 27 or 42 was fused to EGF exon 17 or 19. High-level expression of the entire FN1 gene in CAF suggests that strong FN1 promoter activity drives inappropriate expression of the biologically active portion of EGF, which was detected immunohistochemically in 8/9 cases. The FN1-EGF fusion, which has not been observed in any other neoplasm, appears to be the main driver mutation in CAF. Although further functional studies are required to understand the exact pathogenesis of CAF, the composition of the chimera suggests an autocrine/paracrine mechanism of transformation. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Topics: Adolescent; Child; Child, Preschool; Chromosome Banding; Epidermal Growth Factor; Exons; Female; Fibroma; Fibronectins; Gene Fusion; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Male; Recurrence; Soft Tissue Neoplasms

Palmar and plantar fibromatoses are disease processes in which the presence of certain growth factors has not been defined. Monoclonal antibodies against transforming growth factor-beta, epidermal growth factor, procollagen type 1, fibronectin, phosphotyrosine residues, and CD41 platelet antigen were used in standard immunoperoxidase staining to study 36 nodules and 24 cords obtained from patients with fibromatoses. The specimens were studied via light microscopy, and staining intensity was quantitated using a computer-enhanced video system. Transforming growth factor-beta staining paralleled procollagen I, fibronectin, and phosphotyrosine staining within the nodule (early stages) but not the cord (late stages) tissue. These factors showed significant increased staining in the early stage of fibromatosis when compared to the late stage. This study is a preliminary demonstration of the presence of transforming growth factor-beta in palmar and plantar fibromatoses.

Topics: Adult; Epidermal Growth Factor; Female; Fibroma; Fibronectins; Foot Dermatoses; Growth Substances; Hand Dermatoses; Humans; Immunohistochemistry; Male; Middle Aged; Phosphotyrosine; Procollagen; Transforming Growth Factor beta; Tyrosine

The role of endogenous growth inhibitors in the regulation of cell proliferation is unclear. Although there are numerous studies on the stimulatory effect of peptide hormones such as insulin, the somatomedins and epidermal growth factor (EGF) on cell proliferation, little is known about the existence of hormones that might exert an antiproliferative effect on cells. Somatostatin (SS), a cyclic tetradecapeptide hormone that is widely distributed in the body, exerts an inhibitory effect on numerous cellular processes. We observed that SS at concentrations of 10(-8) - 10(13M), inhibited EGF-induced centrosomal separation, which recent evidence suggests is necessary for DNA synthesis in response to EGF. This SS effect was associated with inhibition of DNA synthesis and cell replication induced by EGF in gerbil fibroma and HeLa cells. Inhibition of centrosomal separation and the consequent antiproliferative effect of SS may represent a biologically significant action of this ubiquitous hormone.

Topics: Animals; Cell Division; Cell Line; DNA; Epidermal Growth Factor; Fibroma; Gerbillinae; HeLa Cells; Humans; Interphase; Somatostatin