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Vol. 15, No. 11, pp. 1373-1382, June 1, 2001
1 Institut André Lwoff, Centre National de la Recherche
Scientifique UPR 9079, 94801 Villejuif, France; 2 Department
of Urology, and 3 Robert H. Lurie Comprehensive Cancer Center,
Northwestern University Medical School, Chicago, Illinois 60611, USA;
4 Institut National de la Santé et de la Recherche
Médicale U403, Faculté de Médecine Laënnec, 69372 Lyon,
France; 5 Department of Microbiology-Immunology, Northwestern
University Medical School, Chicago, Illinois 60611, USA
Thrombospondin 1 (TSP1) is a multifunctional protein able to
activate TGF
and to inhibit angiogenesis in vivo. Although usually thought of as an inhibitor of tumor growth, TSP1 may sometimes be
present at high levels during tumor progression, suggesting that tumors
can eventually overcome their anti-tumor effects. Using a
tet-repressible expression system, we demonstrate that murine TSP1
delayed the onset of tumor growth when produced in the tumor bed by rat
fibrosarcoma tumor cells or by stromal fibroblasts coinjected with
unmodified C6 glioma tumor cells. Yet upon prolonged exposure to TSP1,
tumors came to grow at the same rate in the presence as in the absence
of TSP1 and transplantation experiments showed that they had become
insensitive to inhibition by TSP1 in both syngeneic and immune
compromised hosts. Tumor resistance to TSP1 developed as a result of
the in vivo outgrowth of pre-existing tumor cell variants that (1)
secreted increased amounts of angiogenic factors that counterbalanced
the inhibitory effect of TSP1 on neovascularization and (2) grew more
efficiently in the presence of TSP1-activated TGF. These results
indicate that prolonged and continuous local delivery of a single
multifunctional angiogenesis inhibitor like TSP1 to fast-growing tumors
can lead to tumor resistance in vivo by fostering the outgrowth of
subpopulations that are a by-product of the genetic instability of the
tumor cells themselves.
[Key Words:
Angiogenesis; inhibition; cancer; TGF; resistance; tetracyclin]
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