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
1. Salomon DS, Brandt R, Ciardello R, Normanno N. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 1995; 19:183-232
2. Waldmann TA, White JD, Goldman CK. The interleukin-2 receptor: a target for monoclonal antibody treatment of human T-cell lymphotropic virus I-induced adult T-cell leukemia. Blood 1993; 82:1701-1712
3. Baserga R. The IGF-I receptor: a key to tumour growth? Cancer Res 1995; 55:249-252
4. Weidman E, Sacchi M, Plaisance S, Heo DS, Yasamura S, Lin WC, Johnson JT, Herberman RB, Azzarone B, Whiteside TL. Receptors for interleukin-2 on human squamous cell carcinoma cell lines and tumour in situ. Cancer Res. 1992; 149:340-349
5. Plaisance S, Rubenstein E, Alileche A, Sahraoui Y, Krief P, Augery-Bourget Y, Jasmin C, Suarez H, Azzarone B. Expression of the interleukin-2 receptor on human fibroblasts and its biological significance. Int Immunol 1992; 4:739-746
6. Rimoldi D, Salvi S, Hartmann F, Schreyer M, Blum S, Zografos L, Plaissance S, Azzarone B, Carrel S. Expression of IL-2 receptors in human melanoma cells. Anticancer Res 1993; 13:555-564
7. Plaisance S, Rubenstein E, Alileche A, Benoit P, Jasmin C, Azzarone B. The IL-2 receptor present on human embryonic fibroblasts is functional in the absence of P64/IL-2R gamma chain. Int Immunol 1993; 843-848
8. Saneto RP, Altman A, Knobler RL, Johnson HM, De Vellis Y. Interleukin-2 mediates the antitumour defenses (17). We suggest that beyond activation of immune mechanisms, therapeutically-delivered IL-2 directly inhibits tumour growth possibly via competing with endogenous IL-2 for IL-2R on tumour cells or other as yet unknown mechanisms. It is also likely, and already demonstrated in animal tumour models, that exogenous IL-2 makes tumour cells more sensitive to radiotherapy (44). This possibility deserves close attention as it has an important and widely applicable therapeutic potential.
inhibition of oligodendrocyte progenitor cell proliferation in vitro. PNAS USA 1986; 83:9221-9225
9. Arzt E, Stelzer G, Renner U, Lange M, Muller OA, Stalla GK. Interleukin-2 and interleukin-2 receptors on intestinal epithelial cells. J Clin Invest 1992; 90:1944-1955
10. Ciacci C, Mahida YR, Dignass A, Koizuma M, Podolsky DK. Functional interleukin-2 receptors on intestinal epithelial cells. J Clin Invest 1993; 92:527-532
11. McMillan DN, Kernohan NM, FlettME, Heys SD, Deehan DJ, Sewell HF, Walker F, Eremin O. Interleukin-2 receptor expression and interleukin-2 localization in human solid tumour cells in situ and in vitro: evidence for a direct role in the regulation of tumour cell proliferation. Int J Cancer 1995; 60:766-772
12. Alileche A, Plaisance S, Han DS, Rubinstein E, Mingari C, Bellomo R, Jasmin C, Azzarone B. Human melanoma cell line M14 secretes a functional interleukin-2. Oncogene 1993; 8:1791-1796
13. Azzarone B, Pottin-Clemenceau C, Krief P, Rubinstein E, Jasmin C, Scudeletti M, Indiveri F. Are interleukin-2 and interleukin-15 tumour promoting factors for human non-hematopoietic cells? Eur Cytokine Newt 1996; 7:27-35
14. Van Parejis L, Ibraghimov A, Abbas AK. The roles of costimulation and Fas in T cell apoptosis and peripheral tolerance. Immunity 1996; 4:321-328
15. Morgan DA, Ruscetti FW, Gallo RC. Selective in vitro growth of T lymphocytes from normal human bone marrow. Science 1976; 193:10071008
16. Robb RJ, Kitny RM, Chowhry V. Purification and partial sequence analysis of human T-cell growth factor. PNAS USA 1993; 80:59905994
17. Waldmann TA. The interleukin-2 receptor. J Biol Chem 1991; 266:2681-2684
18. Taniguchi T, Minami Y. The IL-2/IL-2 receptor system: a current overview. Cell 1993; 73:5-8
19. Minami Y, Kono T, Miyazaki T, Taniguchi T. The IL-2 receptor complex its structure, function and target genes. Ann Rev Immunol 1993; 11:245-267
20. Takeshita T, Ohtani K, Asao H, Kumaki S, Nakamura M, Sugamura K. An associated molecule, p64, with IL-2 receptor chain. Its possible involvement in the formation of the functional intermediate affinity IL-2 receptor complex. J Immunol 1992; 148:2154-2158
21. Kindig T, Schorle H, Backman M, Hengartner H, Zinkernagel R, Morak I. Immune responses in IL-2 deficient mice. Science 1993; 262:1059-1061
22. Voss SD, Hong R, Sondel PM. Sever combined immune deficiency, interleukin-2 and the IL-2 receptor. Experiments of nature continue to point the way. Blood 1994; 83:626-635.
23. Sznol M, Parkinson DR. Clinical applications of IL-2. Oncology 1994; 8:61-71
24. Sondel PM, Kohler PC, Hank JA, Moore KH, Rosenthal NS, Sosman JA, Beckhofer R, Storer B. Clinical and immunological effects of recombinant interleukin-2 given by repetitive weekly cycles to patients with cancer. Cancer Res 1988; 48:2561-2567
25. Rosenberg SA. Perspectives on the use of interleukin-2 in cancer treatment. Cancer J Sci Am 1997; 3:52-56
26. Yasumura S, Lin WC, Weidmann E, Hebda P, Whiteside TL. Expression of interleukin-2 receptors on human carcinoma cell lines and tumour growth inhibition by interleukin-2. Int J Cancer 1994; 59:225-234
27. Rabinowich H, Vitolo D, Altarac S, Herberman RB, Whiteside TL. Role of cytokines in the adoptive immunotherapy of an experimental model of human head and neck cancer by human IL-2-activated natural killer cells. J Immunol 1992; 4:739-746
28. Lenardo M, Ka-Ming Chan F, Hornung F, McFarland H, Siegel R, Wang J, Zheng L. "Mature T lymphocyte apoptosis-immune regulation in a dynamic and unpredictable antigenic environment." In Annual Review of Immunology, Vol 17, William E. Paul, C.
Garrison Fathman, Laurie H. Glimcher, Eds. Palo Alto, CA: Annual Reviews, 1999.
29. Atkins MB. Interleukin-2 in metastatic melanoma: establishing a role. Cancer J Sci Am 1997; 3:57-58
30. Figlin R, Gitlitz B, Franklin J, Dorey F, et al. Interleukin-2-based immunotherapy for the treatment of metastatic renal carcinoma: an analysis of 203 consecutively treated patients. Cancer J Sci Am 1997; 3:592-597
31. Resnicoff M, Burgand J-L, Rotman H, Abraham D, Baserga R. Correlation between apoptosis, tumourgenesis and levels of insulinlike growth factor I receptors. Cancer Res 1995; 55:3739-3741
32. Lin W-C, Yasamura S, Suminami Y, Sung MW, Nagashima S, Stanson J, Whiteside TL. Consitutitve production of IL-2 by human carcinoma cells, expression of IL-2 receptor, and tumour growth. J Immunol 1995; 155:4805-4816
33. Reichert TE, Watkins S, Stanson J, Johnson JT, Whiteside TL. Endogeneous IL-2 in cancer cells - a marker of cellular proliferation. J. Histochem.Cytochem.1998; 46:603 -611
34. Lin W-C, Yasamura S, Whiteside TL. Transfer of interleukin-2 receptor genes into squamous cell carcinoma: Modification of tumour cell growth. Arch Otolaryngol Head Neck Surg 1993; 119:1229-1235
35. Heo DS, Park J-G, Hata K, Day R, Herberman RB, Whiteside TL. Evaluation of tetrazolium-based semi-automatic colorimetric assay for measurement of antitumour cytotoxicity. Cancer Res 1990; 50:3681-3690
36. Reichert TE, Kashii Y, Stanson J, Zeevi A, Whiteside TL. The role of endogenous interleukin-2 (IL-2) in proliferation of human carcinoma cell lines. Br J Cancer 1999; 81(5):822-831
37. Suminami K, Kashii Y, Law JC, Lin W-C, Stanson J, Reichert TE, Rabinowich H, Whiteside TL. Molecular analysis of the IL-2 receptor chain gene expressed in human tumour cells. Oncogene 1998;16: 1309-1317
38. Reichert TE, Nagashima S, Kashii Y, Stanson J, Dou QP, Whiteside TL. Interleukin-2 expression in human carcinoma cell lines and its role in cell cycle progression. Oncogene 2000;19:514-525
39. Nagashima S, Reichert TE, Kashii Y, Suminami Y, Suzuki T, Whiteside TL. In vitro characteristics of human squamous cell carcinoma of the head and neck cells engineered to secrete interleukin-2. Cancer Gene Therapy 1997;4:366-376
40. Nagashima S, Kashii Y, Reichert TE, Suminami Y, Suxuki T, Whiteside TL. Human gastric carcinoma transduced with the IL-2 gene: Increased sensitivity to immune effector cells in vitro and in vivo. Int J Cancer 1997; 72: 174-183
41. Hemar A, Subtil A, Lieb M, Morelon E, Hellio R, Dautry-Varsat A. Endocytosis of interleukin 2 receptors in human T lymphocytes: distinct intra cellular localization and fate of the receptor n, and y chains. J.Cell.Biol 1995:5564
42. Abbas AK. Die and let live: eliminating dangerous lymphocytes. Cell 1996; 84:655657
43. Duvic M, Gather J, Maize J, Frankel AE. l.'Aii.,-,. IL-2 diphtheria fusion toxin produces clinical responses in tumour stage cutaneous T-cell lymphoma. Am J Hematol 1998; 58:87-90
44. Lee J, Moran JP, Fenton BM, Koch CJ, Frelinger JG, Keng PC, Lord EM. Alteration of tumour response to radiation by interleukin-2 gene transfer. Br J Cancer 2000; 82:937
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