dinoprost and Fibrosarcoma

Metastasis is a complex process, almost a cascade, involving multiple steps and activities. However, an important factor is that malignant cells are able to penetrate through the multiple basement membrane barriers surrounding tissues, blood vessels, nerves and muscle that would otherwise block their dissemination. Penetration of malignant tumor cells through basement membrane is an active process requiring proteolysis. We report here that inhibitors of both the cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolism convert mouse melanoma and human fibrosarcoma cells to a non invasive state by reducing the production of MMP-2, an enzyme required for the degradation of basement membranes. Specific metabolites of each pathway, i.e. PGF2 alpha and 5-HPETE, are able to transcend the block and restore collagenase production, invasiveness in vitro and metastatic activity in vivo. These studies indicate a key role for arachidonic acid metabolites in metastasis and suggest novel therapeutic approaches for inhibiting the spread of cancer.

Topics: Animals; Arachidonic Acid; Caffeine; Collagen; Cyclooxygenase Inhibitors; Dinoprost; Drug Combinations; Extracellular Matrix; Fibrosarcoma; Gelatinases; Humans; Indoles; Indomethacin; Laminin; Leukotrienes; Lipoxygenase Inhibitors; Masoprocol; Matrix Metalloproteinase 2; Melanoma; Metalloendopeptidases; Mice; Neoplasm Metastasis; Proteoglycans; Tumor Cells, Cultured; Umbelliferones

Prostaglandins may inhibit or promote tumor cell replication, depending on the cell system that is investigated. In our laboratory, we have established and characterized four different specific human cancer cell lines. The objectives of this study were to examine and compare the prostaglandin endoperoxide synthase (PG synthase, EC 1.14.99.1) activity of these cell lines by measuring the conversion of arachidonate to 3H-PGE2 and 3H-PGF2 alpha. We found that the oral epidermal carcinoma cell line (OEC-M1) had a moderate degree of PG synthase activity. Enzyme activity could be partially blocked (statistically significant) by the addition of epidermal growth factor (EGF) at 20 ng/mL and almost completely inhibited by platelet-derived growth factor at (PDGF) 20 mU/mL. By contrast, we discovered that the human breast adenocarcinoma cell line (BC-M1) did not contain significant PG synthase, and enzyme activity could be significantly activated by the addition of epidermal growth factor at 20 ng/mL and platelet-derived growth factor at 20 mU/mL. We also found that the human stomach adenocarcinoma cell line (SCM-1) had a significant amount of PG synthase activity, and these PG synthase activities were not activated or inhibited by EGF at 20 ng/mL or PDGF at 20 mU/mL. Furthermore, the human fibrosarcoma (FS-M1) cell line also contained a moderate degree of PG synthase activity, which could be significantly inhibited by PDGF at 20 mU/mL but was not inhibited by EGF at 20 ng/mL. The results suggest that EGF and PDGF may be involved in the regulation of the PG synthase activities of human oral, breast, stomach, and fibrosarcoma cancer cells.

Topics: Adenocarcinoma; Breast Neoplasms; Buttocks; Carcinoma, Squamous Cell; Chromatography, Thin Layer; Cyclooxygenase Inhibitors; Dinoprost; Dinoprostone; Enzyme Activation; Epidermal Growth Factor; Female; Fibrosarcoma; Gingival Neoplasms; Humans; Organ Specificity; Platelet-Derived Growth Factor; Prostaglandin-Endoperoxide Synthases; Stomach Neoplasms; Tumor Cells, Cultured

Nontransformed (Ob1771) and polyoma virus-transformed (Ob17PY) mouse cells from the preadipocyte Ob17 clonal line have been compared in their ability to release prostaglandins in vitro as well as in vivo as assayed by in situ microdialysis. Prostaglandin FE2, prostaglandin-2 alpha and mainly prostacyclin are released in larger amounts (4- to 10-fold) by Ob17PY cells in vitro and Ob17PY-induced tumors in vivo as compared to Ob1771 preadipocytes in vitro and periepididymal adipose tissue in vivo. In contrast to Ob1771 preadipocytes, none of these prostanoids appear to be involved in the control of proliferation or differentiation of Ob17PY cells in serum-free culture medium. However, prostacyclin, the level of which is the most affected by transformation, might be considered as a valuable indicator of fibrosarcoma development.

Topics: Adipocytes; Adipose Tissue; Animals; Cell Differentiation; Cell Division; Cell Transformation, Viral; Cells, Cultured; Dialysis; Dinoprost; Dinoprostone; Epoprostenol; Extracellular Space; Fibrosarcoma; Male; Mice; Mice, Nude; Prostaglandins

The purpose of this investigation was to determine whether cells transformed by herpes simplex virus type 2 (HSV-2) can be stimulated to synthesize prostaglandins (PG). Stimulation was determined by measuring the release of PG into overlay fluids from cell monolayers prelabeled with [3H]arachidonic acid. Results showed that Ca2+ ionophore A-23187 markedly stimulated arachidonic acid release starting 30 min after treatment of HSV-2-transformed and nontransformed rat embryo fibroblast cells. However, only HSV-2-transformed cells were stimulated in production of PG. HSV-2-transformed, nontumorigenic, rat embryo fibroblast, line G, clone 2.0 cells synthesize nearly equal amounts of prostaglandin E2 (PGE2) and prostaglandin F2 alpha, while tumor (rat fibrosarcoma) cells synthesize primarily PGE2. Stimulation of PGE2 synthesis by Ca2+ ionophore A-23187 or 12-O-tetradecanoyl-phorbol-13-acetate decreased as rat fibrosarcoma cells were serially passaged in tissue culture. At low passage of parental rat fibrosarcoma cells, four distinct morphological clonal cell lines were isolated, which varied markedly in their capacity to be stimulated in PG synthesis by 12-O-tetradecanoyl-phorbol-13-acetate. There was correlation between the capacity of clone 1 cells to be stimulated in PGE2 synthesis by serum alone and capacity of the tumors produced by the clone 1 cells to metastasize to the lungs of syngeneic tumor-bearing rats. In summary, cell transformation by HSV-2 appears to be essential for stimulation of PG synthesis in cells. The capacity to be stimulated in arachidonic acid metabolism and PG synthesis may be important in the process of carcinogenesis by a putative human cancer virus.

Topics: Animals; Calcimycin; Cell Division; Cell Transformation, Neoplastic; Clone Cells; Dinoprost; Dinoprostone; Embryo, Mammalian; Fibrosarcoma; Kinetics; Neoplasm Metastasis; Phorbols; Prostaglandins; Prostaglandins E; Prostaglandins F; Rats; Simplexvirus; Tetradecanoylphorbol Acetate