Tumorigenicity of IL-1alpha- and IL-1beta-deficient fibrosarcoma cells.
Analyzing the growth of fibrosarcoma lines derived from IL-1alpha-, IL-1beta- , or IL-1alphabeta-knockout (-/-) mice in the immunocompetent host revealed that tumor-derived IL-1alpha and IL-1beta exert strong and opposing effects on immune response induction, which prohibited the evaluation of a potential impact on tumorigenicity. Therefore, in vivo growth of IL-1-deficient tumor lines was evaluated in nu/nu mice and was compared with in vitro growth characteristics. All IL-1-deficient fibrosarcoma lines grow in immunocompromised mice. However, IL-1alpha(-/-)beta-competent (comp) lines grow more aggressively, efficiently induce angiogenesis, and recruit inflammatory cells. Despite stronger tumorigenicity of IL-1beta(comp) lines, IL-1alpha strengthens anchorage-independent growth, but both IL-1alpha and IL-1beta support drug resistance. Corresponding to the aggressive growth, IL-1beta(comp) cells display increased matrix adhesion, motility, and cable formation on matrigel, likely supported by elevated alpha(v)/beta3 and matrix metalloroteinase expression. Recruitment of myeloid cells requires IL-1beta but is regulated by IL-1alpha, because inflammatory chemokine and cytokine expression is stronger in IL-1alpha(-/-)beta(comp) than in IL-1(wt) lines. This regulatory effect of tumor-derived IL-1alpha is restricted to the tumor environment and does not affect systemic inflammatory response induction by tumor-derived IL-1beta. Both sarcoma cell-derived IL-1alpha and IL-1beta promote tumor growth. However, IL-1alpha exerts regulatory activity on the tumor cell-matrix cross-talk, and only IL-1beta initiates systemic inflammation.
Department of Tumor Progression and Tumor Defense, German Cancer Research Center, Heidelberg, Germany.
Irina
I
Nazarenko
Rachid
R
Marhaba
Eli
E
Reich
Elena
E
Voronov
Mario
M
Vitacolonna
Dagmar
D
Hildebrand
Elena
E
Elter
Mohini
M
Rajasagi
Ron N
RN
Apte
Margot
M
Zöller
D000818:Animals; D017209:Apoptosis; D002465:Cell Movement; D049109:Cell Proliferation; D018925:Chemokines / Q000378:metabolism; D005354:Fibrosarcoma / Q000378:metabolism*; D005434:Flow Cytometry; D007249:Inflammation; D053582:Interleukin-1alpha / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008954:Models, Biological
D018925:Chemokines; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D020782:Matrix Metalloproteinases