transforming-growth-factor-beta and Fibroma

We encountered two unique cases of papillary carcinoma of the thyroid gland forming fibroma-like nodular tumors. The two cases showed well-defined nodules composed largely of fibromatosis-like stroma with small foci of papillary carcinoma. This type of tumor is relatively rare and has been reported with the name of 'papillary carcinoma of the thyroid with fibromatosis-like stroma or nodular fasciitis-like stroma'. The stromal cells have had myofibroblastic features in all reported cases, including the present cases. The pathogenesis of this tumor is still unknown. We must be careful to differentiate this type of thyroid tumor from fibrosarcomatous anaplastic carcinoma, particularly in the intraoperative consultation. We speculate that this unique tumor is an autonomous proliferation of stromal cells, based on the immunohistochemical analyses of early stromal changes in usual-type papillary carcinoma of the thyroid. The present names of this disease may not represent the proper features of this tumor because all the reported cases formed fibroma-like nodules. We propose the name 'papillary carcinoma forming myofibroblastic nodular tumors'.

Topics: Activin Receptors, Type I; Adult; Carcinoma, Papillary; Diagnosis, Differential; Fibroma; Humans; Immunohistochemistry; Male; Middle Aged; Protein Serine-Threonine Kinases; Receptor, Platelet-Derived Growth Factor alpha; Receptor, Platelet-Derived Growth Factor beta; Receptor, Transforming Growth Factor-beta Type I; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Thyroid Neoplasms; Transforming Growth Factor beta

Ovarian cancer is the most common and lethal type of gynecological malignancy, due to its invasiveness. The present study aimed to analyze the molecular mechanism underlying chemoresistance in ovarian carcinoma cells, which may lead to local migration toward adjacent tissues and long‑distance metastasis to other organs. A total of 12 patients with ovarian fibroma were used to evaluate chemoresistance and chemosensitivity. The sensitivity and resistance of ovarian carcinoma cells was measured using apoptosis analysis, morphological observation, survival rate analysis, immunohistochemistry and immunostaining. The mechanism underlying the interaction between the epithelial‑mesenchymal transition (EMT) and liver kinase B1 (LKB1)‑salt‑inducible kinase 1 (SIK1) signaling pathways was additionally investigated in ovarian carcinoma. The results of the present study demonstrated that ovarian carcinoma cells isolated from patients exhibited apoptosis resistance. Inhibition of TGF‑β expression led to an inhibition of growth, migration and invasion, in addition to a promotion of apoptosis, in ovarian carcinoma cells treated with paclitaxel. Studies have indicated that the LKB1‑SIK1 signaling pathway may be suppressed in ovarian carcinoma cells compared with normal ovarian cells, leading to activation of the EMT signaling pathway. The results of the present study demonstrated that upregulation of LKB1 promoted SIK1 expression and markedly suppressed the growth and aggressiveness of ovarian cancer cells. Upregulation of LKB1 additionally promoted apoptosis in ovarian carcinoma cells. In addition, the results of the present study demonstrated that the knockdown of LKB1 further promoted the expression of transforming growth factor‑β and EMT, which downregulated the chemosensitivity of ovarian carcinoma cells. Additionally, overexpression of LKB1 in ovarian carcinoma cells increased chemosensitivity, resulting in a significant inhibition of migration and invasion. The present findings indicated that the enhancement of LKB1‑SIK1 suppressed the growth and aggressiveness of ovarian carcinoma cells isolated from clinical patients, which subsequently contributed to an inhibition of metastatic potential. In conclusion, targeting the LKB1‑SIK1 signaling pathway to inhibit EMT may provide potential therapeutic benefits in ovarian carcinoma.

Topics: Adult; AMP-Activated Protein Kinase Kinases; Apoptosis; Epithelial-Mesenchymal Transition; Female; Fibroma; Humans; Middle Aged; Ovarian Neoplasms; Ovary; Protein Serine-Threonine Kinases; Signal Transduction; Transforming Growth Factor beta

Elastofibroma is a rare neoplasm. In this article, we report our study of the pathogenesis of fibrosis in elastofibroma. Three tumors obtained from two patients were selected. One patient was a 57-year-old Japanese woman who had a bilateral tumor, and the other patient was a 83-year-old Japanese man. All tumors occurred in the infrascapular region. Macroscopically, the cut surface of all tumors showed a poorly defined and whitish mass with yellowish foci. Microscopically, the tumor consisted of collagen fiber bundles, abnormal elastic fibers, and spindle cells suggestive of fibroblasts. Elastica-van Gieson and Masson-trichrome stain identified abnormal elastic fibers and abundant collagen fibers, respectively, in elastofibroma. Immunohistochemically, fibroblasts were positive for CD34 but negative for alpha-smooth muscle actin and h-caldesmon. Additionally, the cytoplasm of many fibroblasts was positive for TGF-beta in all tumors. Ultrastructurally, some fibroblasts with abundant organelles in one tumor were observed in the adjacent area to amorphous elastic mass and bundles of collagen fibers. However, no myofibroblasts were ultrastructurally identified in the tumor. Finally, our study supplies further evidence that elastofibroma may show the proliferation of CD34-positive fibroblasts and contain no myofibroblasts, and that fibroblasts may produce both abnormal elastic fibers and collagen fibers through the secretion of TGF-beta.

Topics: Aged, 80 and over; Antigens, CD34; Elastic Tissue; Female; Fibroma; Humans; Japan; Male; Middle Aged; Soft Tissue Neoplasms; Transforming Growth Factor beta

To determine how toremifene, an anti-oestrogen triphenylethylene derivate, reduces tumour mass, we investigated its modulation of TGF-beta1 and TNF-alpha in fibroma fibroblasts. Normal and fibroma fibroblasts, isolated from patients affected by Gardner's syndrome without or with fibroma manifestation, were cultured in vitro. Secretion of GAG, collagen and TGF-beta1 was increased in fibroma fibroblasts compared to healthy cells. The increase in TGF-beta1 secretion into the medium was associated with a parallel increase in TGF-beta1 gene expression and receptor number. Receptor cross-linking studies using radiolabelled TGF-beta1 revealed more receptors, particularly types I and II, in fibroma fibroblasts than in normal cells. Normal and fibroma fibroblasts did not synthesise TNF-alpha, but they had TNF-alpha membrane receptors, as shown by TNF-alpha assay. TNF-alpha secreted by human monocytes, which may be present in the peritumoral area, increased cell proliferation and GAG accumulation and was, in turn, enhanced by TGF-beta1 treatment. Both growth factors increased angiogenesis, as shown by the CAM assay. Toremifene reduced TGF-beta1 secretion by fibroma fibroblasts and TNF-alpha secretion by monocytes, thus downregulating cell proliferation, ECM macromolecule accumulation and angiogenic progression. We hypothesise that increased TGF-beta1 gene expression and TGF-beta1 secretion in fibroma fibroblasts as well as the subsequent rise in TNF-alpha production by monocytes may facilitate fibroma growth and that toremifene inhibits autocrine and paracrine growth factor production.

Topics: Animals; Antineoplastic Agents, Hormonal; Blotting, Northern; Cells, Cultured; Chickens; Collagen; Fibroblasts; Fibroma; Gardner Syndrome; Glycosaminoglycans; Humans; Receptors, Estrogen; Receptors, Transforming Growth Factor beta; RNA, Messenger; RNA, Neoplasm; Skin Neoplasms; Toremifene; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

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