In vitro selection of NIH-3T3 cells for resistance to lymphotoxin induces resistance to activated macrophages and enhances tumorigenicity in vivo.
It is well known that expression of certain growth factors leads to tumorigenesis. However, the role of growth inhibitory molecules in this process is less certain. During the last few years several cytokines with growth inhibitory properties have been identified. In spite of the production of these cytokines by the body's immune system, the growth and progression of the tumor continue. In order to understand the mechanisms by which tumor escapes the host defense system, we have used lymphotoxin (LT), a lymphocyte-derived cytokine that is known to selectively inhibit the growth of certain tumor cells. The effect of LT was investigated on NIH-3T3 mouse fibroblast cells that are highly sensitive to its cytotoxic effects and are also tumorigenic in nude mice. On exposure to 10 units/ml of LT, 50% of these cells are killed within 24 h. A stable variant of NIH-3T3 cells that is completely resistant (LT-R) to even 10,000-fold higher concentration of the cytokine than that of sensitive cells (LT-S) was isolated in vitro by repeated exposure to LT. Both LT-S and LT-R displayed similar characteristics when grown both as a monolayer and in soft agar. No significant difference in LT receptor number or affinity between the two cell types was observed. It was not possible to overcome the resistance to LT by the addition of interferon-gamma but the resistance could be overcome by the presence of various chemotherapeutic agents suggesting a difference in the mechanism of action of these two agents.(ABSTRACT TRUNCATED AT 250 WORDS)
Totpal
K
K
Cytokine Research Laboratory, Department of Clinical Immunology and Biological Therapy, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Lapushin
R
R
Ananthaswamy
H N
HN
Aggarwal
B B
BB
D016475:3T3 Cells / Q000187:drug effects* / Q000276:immunology / Q000637:transplantation; D000818:Animals; D002470:Cell Survival; D003601:Cytotoxicity Tests, Immunologic; D004351:Drug Resistance / Q000276:immunology; D008233:Lymphotoxin-alpha / Q000494:pharmacology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000276:immunology* / Q000473:pathology
D008233:Lymphotoxin-alpha