RGD Reference Report - Gene transfer of secreted-type modified interleukin-18 gene to B16F10 melanoma cells suppresses in vivo tumor growth through inhibition of tumor vessel formation.

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Gene transfer of secreted-type modified interleukin-18 gene to B16F10 melanoma cells suppresses in vivo tumor growth through inhibition of tumor vessel formation.
Authors:	Nagai, H Hara, I Horikawa, T Oka, M Kamidono, S Ichihashi, M
Citation:	Nagai H, etal., J Invest Dermatol. 2002 Sep;119(3):541-8.
RGD ID:	8655870
Pubmed:	PMID:12230493 (View Abstract at PubMed)
DOI:	DOI:10.1046/j.1523-1747.2002.01866.x (Journal Full-text)
Interleukin-18 is a novel cytokine identified as a strong inducer of interferon-gamma. Interleukin-18 has been shown to have similar bioactivities to interleukin-12 and to have antitumor efficacy in experimental models. In this study, we investigated whether the introduction of the interleukin-18 gene to B16F10 melanoma cells can induce antitumor response or not. Before the transfection, we modified the interleukin-18 gene to enable transfected tumor cells to secrete bioactive interleukin-18, because interleukin-18 does not have a signal sequence and requires processing by the interleukin-1 converting enzyme to attain the mature form. We found that B16 melanoma cells transduced with hybrid cDNA consisting of the interferon-beta signal sequence and mature interleukin-18 sequence, but not native interleukin-18, secreted a large amount of interleukin-18 and exhibited retarded tumor growth when injected in syngeneic mice. The antitumor effect was mostly abrogated by administration of anti-interferon-gamma antibody, but was not affected by in vivo depletion of CD8+ T cells or natural killer cells. Histologic analysis revealed that vascularization was markedly reduced and that necrosis was extensively induced in interleukin-18-secreting B16F10 melanoma (B16/IL18) tissues, whereas abundant tumor vessel formation was observed in B16/IL18 tissues of interferon-gamma-neutralized mice. We also found that chemokines, interferon-inducible protein-10 and monokine induced by interferon-gamma, were produced in B16/IL18 tissues and that the expression of both chemokines was dependent on that of interferon-gamma in the tumor tissues. Further, we showed that B16 melanoma cells secreted both chemokines in response to interferon-gamma. In addition, the expression of angiogenin, an angiogenic factor of melanoma, in B16 melanoma cells was reduced by interferon-gamma treatment. These results indicate that gene transfer of secreted-type interleukin-18 to B16F10 melanoma cells is a useful method of triggering an antitumor response without any systemic adverse effects and that the antitumor efficacy is mainly mediated by antiangiogenic activity, which is possibly involved in at least two dynamic changes induced by interferon-gamma inside B16 melanoma cells: the upregulation of antiangiogenic chemokines, interferon-inducible protein-10 and monokine induced by interferon-gamma, and the downregulation of angiogenic factor, angiogenin.

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
IL18	Human	Experimental Melanoma	treatment	ISO	Il18 (Mus musculus)		RGD
Il18	Rat	Experimental Melanoma	treatment	ISO	Il18 (Mus musculus)		RGD
Il18	Mouse	Experimental Melanoma	treatment	IMP			RGD

Objects Annotated

Genes (Rattus norvegicus)

Il18 (interleukin 18)

Genes (Mus musculus)

Il18 (interleukin 18)

Genes (Homo sapiens)

IL18 (interleukin 18)

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Gene transfer of secreted-type modified interleukin-18 gene to B16F10 melanoma cells suppresses in vivo tumor growth through inhibition of tumor vessel formation.