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Our studies and those of others (11, 25) indicated that IL-2R and endogenous IL-2 are ubiquitously expressed in human carcinomas both in culture and in situ. Data available from various laboratories provide evidence for the presence of IL-2R on melanoma cell lines and other tumour cell lines. Furthermore, the IL-2/IL-2R pathway appears to be operative in normal non-hematopoietic tissues, e.g., fibroblasts and keratinocytes (5, 26). Thus, this pathway appears to be active in vivo and in vitro in the regulation of growth in a broad range of tumour/tissue cells. Endogenous IL-2 produced by tumour cells in culture, in the absence of any exogenous IL-2, behaved like a cell-cycle associated protein and was shown to promote cell cycle progression. Similar to its role in lymphocytes, IL-2 produced in tumour cells and shown to be localized to the Golgi complex (36, 38) promoted their growth as evidenced by: a) increased expression of both IL-2 and IL-2R (at the protein and mRNA levels) in mitotic tumour cells (36, 38); b) an association between increased IL-2 expression and a decreased level of p27 CDK inhibitor in pre-mitotic cells (38); c) inhibition of IL-2 production by IL-2 specific antisense oligonucleotide, which not only resulted in the inhibition of tumour growth but led to its apoptosis (36). Thus, in carcinoma cells, endogenous IL-2 behaves like a growth-promoting factor, and it also protects tumour cells from apoptosis (36).

In our studies, IL-2 emerges as a growth regulatory hormone not only for hematopoietic but all cells, which is capable of regulating tumour cell proliferation as well as its death. This concept is entirely consistent with the role played by IL-2 in the hematopoietic system (42).

The evidence for the presence of the endogenous or intracrine/autocrine IL-2 pathway in human carcinomas and its involvement in tumour cell survival has important biological and therapeutic implications. The possibility exists for modulating or disrupting the intracrine/ autocrine pathway by various strategies, so that it no longer benefits the tumour. Such strategies might involve the use of exogenous IL-2 at the high ligand/receptor molecular ratios to induce a negative growth signal in tumour cells or the application of IL-2-specific antisense oligonucleotides to induce the cell cycle arrest. Alternatively, it is possible to envision elimination of tumour cells by targeted delivery of, e.g., IL-2 fused with a diphtheria toxin (43). Upon IL-2 mediated internalization and endocytosis of such modified IL-2, IL-2R-positive tumour cells are selectively killed (43). It has been observed in various animal models of tumour growth that delivery of exogenous IL-2 exerts an inhibitory effect on tumour growth, although in most instances, this has been interpreted as an immunologic effects of IL-2 up-regulating the host

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