Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice

Santos AM et al. J Clin Invest. 119(12), 3613–3625, 2009

Speaker: Wen-Hsin Yao (姚文欣)                                 Time: 15:10~16:00, Mar. 24, 2010

Commentator: Dr. Cheng-Chan Lu (呂政展 教授)     Place: Room 601

Abstract:

In addition to genetic mutations in tumor cells, the changes of tumor microenvironment also contribute to tumorigenesis. Proteases serve as an executive in stromagenesis and agiogenesis¹. Therefore, targeting or inhibiting these proteases and their activity is a potential way in cancer therapy. Among the proteases, fibroblast activation protein (FAP) is selectively expressed on tumor-associated fibroblasts and pericytes in epithelial tumors. Previous studies have shown that targeting FAP attenuates tumor growth. However, its function in tumor progression is unclear. To understand the effect of FAP on tumorigenesis, K-ras^G12D-driven endogenous lung adenocarcinoma and syngeneic transplanted CT26 tumor model were used in this study. In both models, when FAP gene of mice was disrupted by LacZ knockin (FAP-null), the tumor burden and tumor cell proliferation of FAP-null mice were less than that in littermate control. When treating FAP inhibitor PT630, tumors in these two models appeared to grow slower than vehicle control. Tumor sections staining showed that the CT26 tumor nodules from PT630-treated mice were less organized and dense than that in control mice. FAP might affect tumor growth by degrading collagen², and cause ECM remodeling and lead to alternative integrin-mediated signaling. Indeed, the collegen content of tumors in FAP-null mice was higher than that in control mice. Besides, the authors demonstrated that FAP deletion caused activation of FAK -ERK signaling pathway and lead to the expression of p21^WAF1, a cell cycle inhibitor, and this might slow down the proliferation rate of tumor cells. Since ECM remodeling is required for angiogenesis, the authors found that blood vessels in CT26 tumors from PT630-treated mice were less than control mice. In conclusion, FAP protease activity can enhance tumor growth by at least remodeling collagen that induces growth-promoting integrin-mediated signaling and angiogenesis in tumor.

References

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2.      Aggarwal, S., et al. Effect of fibroblast activation protein and [alpha]2-antiplasmin cleaving enzyme on collagen types I, III, and IV. Arch, Biochem. Biophys. 457, 177–186 (2007)