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In vivo mechanisms by which tumors producing thrombospondin 1 bypass its inhibitory effects
S Filleur1, O V Volpert, A Degeorges
1Institut André Lwoff, Centre National de la Recherche Scientifique UPR 9079, 94801 Villejuif, France.
Abstract:
Thrombospondin 1 (TSP1) is a multifunctional protein able to activate TGFbeta 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 TGFbeta. 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.
Insights
Thrombospondin 1 (TSP1) initially delays tumor growth but fast-growing tumors develop resistance. This resistance arises from tumor cell variants overcoming TSP1
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Thrombospondin 1 (TSP1) is a protein known to activate TGF-beta and inhibit angiogenesis.
- While typically viewed as an anti-tumor agent, TSP1's presence during tumor progression suggests tumors can overcome its effects.
Purpose of the Study:
- To investigate the long-term effects of TSP1 production in the tumor microenvironment.
- To understand the mechanisms by which tumors develop resistance to TSP1.
Main Methods:
- Utilized a tet-repressible expression system to control murine TSP1 production in rat fibrosarcoma and C6 glioma tumor models.
- Assessed tumor growth rates and performed transplantation experiments in syngeneic and immune-compromised hosts.
- Analyzed the molecular basis of TSP1 resistance in tumor cell variants.
Main Results:
- Murine TSP1 initially delayed tumor growth when produced in the tumor bed.
- Prolonged TSP1 exposure led to tumors growing at rates similar to controls, indicating resistance.
- Transplantation studies confirmed TSP1-insensitive tumor growth in various hosts.
- Tumor resistance was attributed to outgrowth of variants secreting angiogenic factors and utilizing TSP1-activated TGF-beta for growth.
Conclusions:
- Continuous local delivery of TSP1 can paradoxically lead to tumor resistance.
- Tumor resistance is driven by genetic instability and the selection of pre-existing resistant subpopulations.
- This highlights the challenge of using single-agent angiogenesis inhibitors against aggressive tumors.