TY - JOUR
T1 - Tumorigenicity of IL-1α- and IL-1β-deficient fibrosarcoma cells
AU - Nazarenko, Irina
AU - Marhaba, Rachid
AU - Reich, Eli
AU - Voronov, Elena
AU - Vitacolonna, Mario
AU - Hildebrand, Dagmar
AU - Elter, Elena
AU - Rajasagi, Mohini
AU - Apte, Ron N.
AU - Zöller, Margot
N1 - Funding Information:
Abbreviations: BMC, bone marrow cells; IL-1α−/−/IL-1β−/−/IL-1αβ−/− fibrosarcoma, tumors derived from mice with a targeted deletion of the corresponding genes; IL-1comp, IL-1 competent; IL-1Ra, IL-1 receptor antagonist; i.v., intravenously; MDSC, myeloid-derived suppressor cells; MMP, matrix metalloproteinase; RPMI-s, RPMI 1640, supplemented with 10% fetal calf serum, antibiotics, L-glutamine; SC, spleen cells; s.c., subcutaneously; wt, wild type Address all correspondence to: Margot Zöller, Department of Tumor Progression and Immune Defense, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. E-mail: [email protected] 1This work was supported by the Israel Ministry of Science in cooperation with the German Cancer Research Center, Heidelberg, Germany (M.Z., R.N.A.), the Tumorzentrum Heidelberg/Mannheim (M.Z.), the United States–Israel Binational foundation (R.N.A.), the Israel Science Foundation founded by the Israel Academy of Sciences and Humanities (R.N.A.), the Israel Ministry of Health Chief Scientist’s Office (R.N.A., E.V.), Association for International Cancer Research (R.N.A.), the German–Israeli DIP collaborative program (R.N.A.), the Israel Cancer Association (E.V.), the Concern Foundation (E.V.), and the Israel Cancer Association (E.V.). R.N.A. is an incumbent of the Irving Isaac Sklar Chair in Endocrinology and Cancer. 2These authors equally contributed to this study. Received 8 February 2008; Revised 29 March 2008; Accepted 29 March 2008 Copyright © 2008 Neoplasia Press, Inc. All rights reserved 1522-8002/08/$25.00 DOI 10.1593/neo.08286
PY - 2008/1/1
Y1 - 2008/1/1
N2 - Analyzing the growth of fibrosarcoma lines derived from IL-1α-, IL-1β-, or IL-1αβ-knockout (-/-) mice in the immunocompetent host revealed that tumor-derived IL-1α and IL-1β 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-1α-/- β-competent (comp) lines grow more aggressively, efficiently induce angiogenesis, and recruit inflammatory cells. Despite stronger tumorigenicity of IL-βcomp lines, IL-1α strengthens anchorage-independent growth, but both IL-1α and IL-1β support drug resistance. Corresponding to the aggressive growth, IL-1βcomp cells display increased matrix adhesion, motility, and cable formation on matrigel, likely supported by elevated αv/β3 and matrix metalloproteinase expression. Recruitment of myeloid cells requires IL-1β but is regulated by IL-1α, because inflammatory chemokine and cytokine expression is stronger in IL-1α-/- βcomp than in IL-1wt lines. This regulatory effect of tumor-derived IL-1α is restricted to the tumor environment and does not affect systemic inflammatory response induction by tumor-derived IL-1β. Both sarcoma cell-derived IL-1α and IL-1β promote tumor growth. However, IL-1α exerts regulatory activity on the tumor cell-matrix cross-talk, and only IL-1β initiates systemic inflammation.
AB - Analyzing the growth of fibrosarcoma lines derived from IL-1α-, IL-1β-, or IL-1αβ-knockout (-/-) mice in the immunocompetent host revealed that tumor-derived IL-1α and IL-1β 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-1α-/- β-competent (comp) lines grow more aggressively, efficiently induce angiogenesis, and recruit inflammatory cells. Despite stronger tumorigenicity of IL-βcomp lines, IL-1α strengthens anchorage-independent growth, but both IL-1α and IL-1β support drug resistance. Corresponding to the aggressive growth, IL-1βcomp cells display increased matrix adhesion, motility, and cable formation on matrigel, likely supported by elevated αv/β3 and matrix metalloproteinase expression. Recruitment of myeloid cells requires IL-1β but is regulated by IL-1α, because inflammatory chemokine and cytokine expression is stronger in IL-1α-/- βcomp than in IL-1wt lines. This regulatory effect of tumor-derived IL-1α is restricted to the tumor environment and does not affect systemic inflammatory response induction by tumor-derived IL-1β. Both sarcoma cell-derived IL-1α and IL-1β promote tumor growth. However, IL-1α exerts regulatory activity on the tumor cell-matrix cross-talk, and only IL-1β initiates systemic inflammation.
UR - http://www.scopus.com/inward/record.url?scp=44449176257&partnerID=8YFLogxK
U2 - 10.1593/neo.08286
DO - 10.1593/neo.08286
M3 - Article
C2 - 18516292
AN - SCOPUS:44449176257
SN - 1522-8002
VL - 10
SP - 549
EP - 562
JO - Neoplasia
JF - Neoplasia
IS - 6
ER -