Fibrosarcomas show a high incidence of recurrence and general resistance to apoptosis. Limiting
tumor regrowth and increasing their sensitivity to
chemotherapy and apoptosis represent key issues in developing more effective treatments of these
tumors.
Tissue inhibitor of metalloproteinase 1 (TIMP-1) broadly blocks
matrix metalloproteinase (
MMP) activity and can moderate
tumor growth and
metastasis. We previously described generation of a
recombinant fusion protein linking
TIMP-1 to glycosylphophatidylinositol (GPI) anchor (TIMP-1-GPI) that efficiently directs the inhibitor to cell surfaces. In the present report, we examined the effect of TIMP-1-GPI treatment on
fibrosarcoma biology. Exogenously applied TIMP-1-GPI efficiently incorporated into surface membranes of human HT1080
fibrosarcoma cells. It inhibited their proliferation, migration, suppressed
cancer cell clone formation, and enhanced apoptosis.
Doxorubicin, the standard chemotherapeutic
drug for
fibrosarcoma, was tested alone or in combination with TIMP-1-GPI. In parallel, the influence of treatment on HT1080 side population cells (exhibiting tumor stem cell-like characteristics) was investigated using
Hoechst 33342 staining. The sequential combination of TIMP-1-GPI and
doxorubicin showed more than additive effects on apoptosis, while TIMP-1-GPI treatment alone effectively decreased "stem-cell like" side population cells of HT1080. TIMP-1-GPI treatment was validated using HT1080
fibrosarcoma murine xenografts. Growing
tumors treated with repeated local
injections of TIMP-1-GPI showed dramatically inhibited
fibrosarcoma growth and reduced angiogenesis. Intraoperative peritumoral application of GPI-anchored
TIMP-1 as an adjuvant to surgery may help maintain
tumor control by targeting microscopic residual
fibrosarcoma cells and increasing their sensitivity to
chemotherapy.