Constitutive activation of the interleukin 2 gene in the induction of spontaneous in vitro transformation and tumorigenicity of T cells.
There is growing evidence to suggest that tumorigenic transformation of cells may result from aberrant regulation of autocrine growth factor production. In the current study we describe the spontaneous in vitro transformation of T-lymphocyte cell lines during routine cell culture as evidenced by autonomous growth without any requirement for stimulation or exogenous interleukin 2 (IL-2). These cells constitutively expressed the IL-2 gene and were inhibited from proliferating by addition of antibodies against IL-2, the IL-2 receptor, or IL-2 antisense oligonucleotides, thereby suggesting that the cell transformation resulted from IL-2-mediated autocrine growth. The transformed cells when injected into nude but not normal mice induced tumors that were inhibited by antibodies against IL-2 and the IL-2 receptor as well as by immunosuppressive drugs such as cyclosporin A. These studies demonstrate that aberrant regulation of IL-2 production can lead to spontaneous transformation of T cells in vitro, capable of inducing tumors in vivo. Our studies not only provide evidence for the important role played by autocrine growth factors in tumorigenicity but also stress the need to use caution while performing immunotherapy using in vitro-cultured T cells against cancer and viral infections, particularly in an immunodeficient host, to exclude any possible transfer of transformed mutant cells.
Nagarkatti
M
M
Department of Biology, Virginia Polytechnic Institute, Blacksburg 24061.
Hassuneh
M
M
Seth
A
A
Manickasundari
K
K
Nagarkatti
P S
PS
D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D005260:Female; D007376:Interleukin-2 / Q000235:genetics* / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000235:genetics*; D013601:T-Lymphocytes / Q000473:pathology*
D007376:Interleukin-2