Tumor cell responses to IFNgamma affect tumorigenicity and response to IL-12 therapy and antiangiogenesis.
Expression of a dominant negative mutant IFNgammaR1 in murine SCK and K1735 tumor cells rendered them relatively unresponsive to IFNgamma in vitro and more tumorigenic and less responsive to IL-12 therapy in vivo. IL-12 induced histologic evidence of ischemic damage only in IFNgamma-responsive tumors, and in vivo Matrigel vascularization assays revealed that while IFNgamma-responsive and -unresponsive tumor cells induced angiogenesis equally well, IL-12 and its downstream mediator IFNgamma only inhibited angiogenesis induced by the responsive cells. IL-12 induced angiogenesis inhibitory activity in the responsive cells, which may be attributable to production of the chemokine IP-10. Thus, IL-12 and IFNgamma inhibit tumor growth by inducing tumor cells to generate antiangiogenic activity.
Biomedical Graduate Program, University of Pennsylvania, Philadelphia 19104, USA.
C M
CM
Coughlin
K E
KE
Salhany
M S
MS
Gee
D C
DC
LaTemple
S
S
Kotenko
X
X
Ma
G
G
Gri
M
M
Wysocka
J E
JE
Kim
L
L
Liu
F
F
Liao
J M
JM
Farber
S
S
Pestka
G
G
Trinchieri
W M
WM
Lee
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D005260:Female; D015870:Gene Expression; D007371:Interferon-gamma / Q000494:pharmacology*; D018664:Interleukin-12 / Q000627:therapeutic use*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D008546:Melanoma, Experimental / Q000188:drug therapy*; D051379:Mice; D008805:Mice, Inbred A; D008809:Mice, Inbred C3H; D016296:Mutagenesis; D009389:Neovascularization, Pathologic; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins; D014407:Tumor Cells, Cultured; D000096743:Interferon gamma Receptor
D000970:Antineoplastic Agents; D007371:Interferon-gamma; D018664:Interleukin-12; D017471:Receptors, Interferon; D011994:Recombinant Proteins; D000096743:Interferon gamma Receptor