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 cel ls. Since the systemic administration of TNF for malignancy results in poor response and severe toxicity, future efforts should concentrate on local t reatment. Here we examined the suppressive effect of TNF alpha on leukemic cells engrafted in scid mice. NALM6 cells derived from pre-B ALL were injec ted in scid mice subcutaneously with or without Matrigel. In mice with Matr igel, subcutaneous tumors rapidly increased with time, whereas none of the mice without Matrigel showed any obvious signs of disease or apparent tumor s. High levels of leukemic infiltration were observed in peripheral organs in mice with Matrigel by flow cytometry and PCR for human beta-actin mRNA e xpression, while mice without Matrigel showed low or undetectable infiltrat ion in these organs. Human TNF alpha was also coinjected subcutaneously wit h NALM6 cells and Matrigel into scid mice. Mice with 10 ng of TNF alpha sho wed small subcutaneous tumors at 8 weeks, which slowly increased. They were found to have a small number of leukemic cells in peripheral organs by flo w cytometry. By PCR, all organs with the exception of lung and brain showed low or undetectable expression of p-actin. However, a large dose of TNF al pha (100 ng) had no suppressive effect on tumor growth and leukemic infiltr ation in mouse organs. Similar results were obtained in colony formation of leukemic cells in vitro. To examine the mechanism of the suppressive effec t of TNF alpha, the expression of TNF receptors in tumor cells was analyzed by flow cytometry. Parental NALM6 exp ressed both TNFa receptors I (TNFR60 ) and II (TNFR80), but these expressions were suppressed in tumor cells fro m 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 dete cted, whereas neither DNA fragmentation nor apoptotic change in histology w as observed in tumor cells of mice with TNF alpha. These results suggest th at the suppressive effect of TNF alpha on the growth of leukemic cells in s cid mice is mediated through the activation of TNFR80 without apoptotic sig nal.