Suppression of growth and dissemination in human pre-B leukemia cells by tumor necrosis factor-alpha in scid mice.
Tumor necrosis factor (TNF) has been shown to inhibit the growth of ALL cells. Since the systemic administration of TNF for malignancy results in poor response and severe toxicity, future efforts should concentrate on local treatment. Here we examined the suppressive effect of TNF alpha on leukemic cells engrafted in scid mice. NALM6 cells derived from pre-B ALL were injected in scid mice subcutaneously with or without Matrigel. In mice with Matrigel, subcutaneous tumors rapidly increased with time, whereas none of the mice without Matrigel showed any obvious signs of disease or apparent tumors. High levels of leukemic infiltration were observed in peripheral organs in mice with Matrigel by flow cytometry and PCR for human beta-actin mRNA expression, while mice without Matrigel showed low or undetectable infiltration in these organs. Human TNF alpha was also coinjected subcutaneously with NALM6 cells and Matrigel into scid mice. Mice with 10 ng of TNF alpha showed small subcutaneous tumors at 8 weeks, which slowly increased. They were found to have a small number of leukemic cells in peripheral organs by flow cytometry. By PCR, all organs with the exception of lung and brain showed low or undetectable expression of beta-actin. However, a large dose of TNF alpha (100 ng) had no suppressive effect on tumor growth and leukemic infiltration in mouse organs. Similar results were obtained in colony formation of leukemic cells in vitro. To examine the mechanism of the suppressive effect of TNF alpha, the expression of TNF receptors in tumor cells was analyzed by flow cytometry. Parental NALM6 expressed both TNF alpha receptors I (TNFR60) and II (TNFR80), but these expressions were suppressed in tumor cells from mice with Matrigel. Only TNFR80 expression was induced in tumor cells of mice with 10 ng of TNF alpha. The induction of Fas expression was also detected, whereas neither DNA fragmentation nor apoptotic change in histology was observed in tumor cells of mice with TNF alpha. These results suggest that the suppressive effect of TNF alpha on the growth of leukemic cells in scid mice is mediated through the activation of TNFR80 without apoptotic signal.
Yoshida
N
N
Department of Pediatrics, Saga Medical School, Japan.
Ishii
E
E
Mohri
S
S
Nagumo
F
F
Yoshidomi
S
S
Miyazaki
S
S
D000818:Animals; D017209:Apoptosis; D002455:Cell Division / Q000187:drug effects; D003094:Collagen / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005434:Flow Cytometry; D006801:Humans; D016023:Integrins / Q000096:biosynthesis; D007797:Laminin / Q000502:physiology; D007942:Leukemia, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017254:Leukemic Infiltration / Q000188:drug therapy; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D016133:Polymerase Chain Reaction; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011509:Proteoglycans / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use*; D014410:Tumor Stem Cell Assay
D004338:Drug Combinations; D016023:Integrins; D007797:Laminin; D011509:Proteoglycans; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; C059485:matrigel; D003094:Collagen