Tumorigenicity of IL-1α- and IL-1β-deficient fibrosarcoma cells

Analyzing the growth of fibrosarcoma lines derived from IL-1 alpha-, IL-1 beta-, or IL-1 alpha beta-knockout((-/-)) mice in the immunocompetent host revealed that tumor-derived IL-1 alpha and IL-1 beta 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-1 alpha(-/-)beta-competent ( comp) lines grow more aggressively, efficiently induce angiogenesis, and recruit inflammatory cells. Despite stronger tumorigenicity of IL-1 beta(comp) lines, IL-1 alpha strengthens anchorage-independent growth, but both IL-1a and IL-1 beta support drug resistance. Corresponding to the aggressive growth, IL-1 beta(comp) cells display increased matrix adhesion, motility, and cable formation on matrigel, likely supported by elevated alpha(v)/beta(3) and matrix metalloproteinase expression. Recruitment of myeloid cells requires IL-1 beta but is regulated by IL-1 alpha, because inflammatory chemokine and cytokine expression is stronger in IL-1 alpha(-/-)beta(comp) than in IL-1(wt) lines. This regulatory effect of tumor-derived IL-1 alpha is restricted to the tumor environment and does not affect systemic inflammatory response induction by tumor-derived IL-1 beta. Both sarcoma cell-derived IL-1 alpha and IL-1 beta promote tumor growth. However, IL- 1 alpha exerts regulatory activity on the tumor cell-matrix cross-talk, and only IL-1 beta initiates systemic inflammation.