thymosin and Fibrosarcoma

Topics: Animals; Fibrosarcoma; Lung Neoplasms; Male; Thymic Factor, Circulating; Thymosin; Thymus Hormones

Nanoparticles are prevalent in both commercial and medicinal products; however, the contribution of nanomaterials to carcinogenesis remains unclear. We therefore examined the effects of nano-sized titanium dioxide (TiO(2)) on poorly tumorigenic and nonmetastatic QR-32 fibrosarcoma cells. We found that mice that were cotransplanted subcutaneously with QR-32 cells and nano-sized TiO(2), either uncoated (TiO(2)-1, hydrophilic) or coated with stearic acid (TiO(2)-2, hydrophobic), did not form tumors. However, QR-32 cells became tumorigenic after injection into sites previously implanted with TiO(2)-1, but not TiO(2)-2, and these developing tumors acquired metastatic phenotypes. No differences were observed either histologically or in inflammatory cytokine mRNA expression between TiO(2)-1 and TiO(2)-2 treatments. However, TiO(2)-2, but not TiO(2)-1, generated high levels of reactive oxygen species (ROS) in cell-free conditions. Although both TiO(2)-1 and TiO(2)-2 resulted in intracellular ROS formation, TiO(2)-2 elicited a stronger response, resulting in cytotoxicity to the QR-32 cells. Moreover, TiO(2)-2, but not TiO(2)-1, led to the development of nuclear interstices and multinucleate cells. Cells that survived the TiO(2) toxicity acquired a tumorigenic phenotype. TiO(2)-induced ROS formation and its related cell injury were inhibited by the addition of antioxidant N-acetyl-l-cysteine. These results indicate that nano-sized TiO(2) has the potential to convert benign tumor cells into malignant ones through the generation of ROS in the target cells.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Cell Line, Tumor; Cell Transformation, Neoplastic; Cytokines; Deoxyguanosine; Dinoprostone; Female; Fibrosarcoma; Intercellular Signaling Peptides and Proteins; Mice; Mice, Inbred C57BL; Nanoparticles; Neoplasm Invasiveness; Particle Size; Reactive Oxygen Species; Thymosin; Titanium; Vascular Endothelial Growth Factor A

We identified a thymosin-beta4 gene overexpression in malignant mouse fibrosarcoma cells (QRsP-30) that were derived from clonal weakly tumorigenic and nonmetastatic QR-32 cells by using a differential display method. Thymosin-beta4 is known as a 4.9-kd polypeptide that interacts with G-actin and functions as a major actin-sequestering protein in cells. All of the six malignant fibrosarcoma cell lines that have been independently converted from QR-32 cells expressed high levels of thymosin-beta4 mRNA and its expression in tumor cells was correlated with tumorigenicity and metastatic potential. Up-regulation of thymosin-beta4 in QR-32 cells (32-S) transfected with sense thymosin-beta4 cDNA converted the cells to develop tumors and formed numerous lung metastases in syngeneic C57BL/6 mice. In contrast, antisense thymosin-beta4 cDNA-transfected QRsP-30 (30-AS) cells reduced thymosin-beta4 expression, and significantly lost tumor formation and metastases to distant organs. Vector-alone transfected cells (32-V or 30-V cells) behaved like their parental cells. We observed that tumor cell motility, cell shape, and F-actin organization is regulated in proportion to the level of thymosin-beta4 expression. These findings indicate that thymosin-beta4 molecule regulates fibrosarcoma cell tumorigenicity and metastasis through actin-based cytoskeletal organization.

Topics: Animals; Cell Movement; Fibrosarcoma; Gene Expression Regulation, Neoplastic; Lung Neoplasms; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Thymosin; Transfection; Tumor Cells, Cultured

We have shown the in vivo usefulness of a novel chimera tumor necrosis factor (TNF), called rTNF-STH, which was constituted with human thymosin beta 4 and recombinant human TNF-SAM1. Tumor necrosis was induced by intravenous injection of a smaller amount of rTNF-STH (1 x 10(3) U/mouse, 0.67 microgram/mouse) than rTNF-alpha or rTNF-S (1 x 10(4) U/mouse, 2.5-5 micrograms/mouse). Significant antitumor effects of rTNF-STH to Meth A fibrosarcoma, B16 melanoma, MH134 hepatoma, or Lewis lung carcinoma (3LL) were observed by systemic injection of rTNF-STH at the maximum tolerable dose of 1 x 10(4) U/mouse (6.7 micrograms/mouse); this dose did not cause regression of tumors by conventional rTNF-alpha. rTNF-STH showed a significant prolongation of its half-life in serum. The average calculated half-life of the chimera protein is about 110 min, which is 15 times longer than that of original TNF-SAM1 (7.5 min). On the basis of this prolongation of half-life of rTNF-STH and its efficient hemorrhagic necrotic activity, the antitumor effect of rTNF-STH--as compared with that of the known TNF species--is discussed. Findings indicate that use of the chimera protein to alter the N-terminal region of TNF may be a promising approach to obtain molecules that more favorably attack tumors and other diseases than conventional rTNFs.

Topics: Animals; Fibrosarcoma; Half-Life; Liver Neoplasms, Experimental; Lung Neoplasms; Melanoma, Experimental; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Necrosis; Neoplasm Transplantation; Neoplasms, Experimental; Recombinant Fusion Proteins; Recombinant Proteins; Thymosin; Tumor Necrosis Factor-alpha

In this report we describe the characterization of the immunomodulatory efficiency and therapeutic properties of thymosin fraction five (F5). We consistently observed the immunostimulation of T-cell activity in assays of allogeneic mixed lymphocyte response (MLR) and the development of cytotoxic effector cells in an allogeneic mixed lymphocyte tumor response-cell-mediated cytotoxicity assay (MLTR-CMC). No induction of suppressor cell activity was observed. Thymosin F5 also acted successfully as an adjuvant when admixed with irradiated tumor cells. We were unable to demonstrate either NK cell or macrophage activation by thymosin F5. Therapeutic protocols using thymosin F5 and directed against pre-existing experimental and spontaneous metastases, had a significant immunotherapeutic potential.

Topics: Animals; Cell Line; Fibrosarcoma; Immunotherapy; Leukemia, Experimental; Lymphocyte Culture Test, Mixed; Male; Melanoma; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasms, Radiation-Induced; T-Lymphocytes; Thymosin; Ultraviolet Rays