Endogenous IL-12 triggers an antiangiogenic program in melanoma cells.
The IL12RB2 gene acts as a tumor suppressor in human B cell malignancies. Indeed, Il12rb2 knockout (KO) mice develop spontaneously B cell tumors, but also lung epithelial tumors. This latter phenotype may be related to (i) impairment of host IL-12-mediated immunosurveillance and/or (ii) IL-12 inability to inhibit directly the growth of IL-12 unresponsive malignant cells. To address this issue, we transplanted IL-12R(+) B16 melanoma cells into syngeneic Il12rb2 KO mice with the following rationale: (i) these mice have severe defects in IFN-gamma production, as well as in cytotoxic T lymphocyte and natural killer cell cytotoxicity, and (ii) they produce but do not use IL-12 that can potentially bind to and target tumor cells only. Il12rb2 KO mice displayed higher endogenous serum levels of IL-12 and developed smaller B16 tumors than WT animals. These tumors showed reduced proliferation, increased apoptosis, and defective microvessel formation related to down-regulated expression of a set of proangiogenic genes previously unrelated to IL-12. Such effects depended on direct activity of endogenous IL-12 on tumor cells in KO mice, and hydrodynamic delivered IL-12 caused further reduced tumorigenicity of B16 cells in these mice. A previously undescribed mechanism of the IL-12 antitumor activity has been here identified and characterized.
Airoldi
Irma
I
Laboratory of Oncology, G. Gaslini Institute, Largo G. Gaslini 5, 16148 Genoa, Italy. irmaairoldi@ospedale-gaslini.ge.it
Di Carlo
Emma
E
Cocco
Claudia
C
Taverniti
Giuseppe
G
D'Antuono
Tommaso
T
Ognio
Emanuela
E
Watanabe
Morihiro
M
Ribatti
Domenico
D
Pistoia
Vito
V
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D002645:Chickens; D016147:Genes, Tumor Suppressor; D018664:Interleukin-12 / Q000378:metabolism / Q000502:physiology*; D008545:Melanoma / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic; D053707:Receptors, Interleukin-12 / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D053707:Receptors, Interleukin-12; D011994:Recombinant Proteins; D018664:Interleukin-12