Here, we describe that microenvironmental
IL-1 beta and, to a lesser extent,
IL-1 alpha are required for in vivo angiogenesis and invasiveness of different
tumor cells. In
IL-1 beta knockout (KO) mice, local
tumor or lung
metastases of
B16 melanoma cells were not observed compared with WT mice. Angiogenesis was assessed by the recruitment of blood vessel networks into
Matrigel plugs containing
B16 melanoma cells; vascularization of the plugs was present in WT mice, but was absent in
IL-1 beta KO mice. The addition of exogenous
IL-1 into B16-containing
Matrigel plugs in
IL-1 beta KO mice partially restored the angiogenic response. Moreover, the incorporation of
IL-1 receptor antagonist to B16-containing plugs in WT mice inhibited the ingrowth of blood vessel networks into
Matrigel plugs. In
IL-1 alpha KO mice, local
tumor development and induction of an angiogenic response in
Matrigel plugs was less pronounced than in WT mice, but significantly higher than in
IL-1 beta KO mice. These effects of host-derived
IL-1 alpha and
IL-1 beta were not restricted to the
melanoma model, but were also observed in DA/3 mammary and
prostate cancer cell models. In addition to the in vivo findings,
IL-1 contributed to the production of vascular endothelial cell
growth factor and
tumor necrosis factor in cocultures of peritoneal macrophages and
tumor cells. Host-derived
IL-1 seems to control
tumor angiogenesis and invasiveness. Furthermore, the anti-angiogenic effects of
IL-1 receptor antagonist, shown here, suggest a possible therapeutic role in
cancer, in addition to its current use in
rheumatoid arthritis.