Abstract 11: Absence of TGFBI favors tumor angiogenesis

TGFBI, a circulating extracellular matrix protein, modulates several integrin-mediated cellular functions. The protein contains an N-terminal EMI domain, four consecutive FAS1 domains, and the RGD motif in the C-terminal domain. The fourth FAS1 domain of TGFBI exerts anti-angiogenic activity through interactions with αvβ3 integrin. Here, we used TGFBI-deficient mice and TGFBI transgenic mice to investigate the role of TGFBI in tumor growth in vivo. The absence of TGFBI led to enhanced tumor angiogenesis and a 3.6-fold increase in tumor growth. In contrast, a 1.7-fold increase in circulating levels of TGFBI in TGFBI transgenic mice induced a 2.4-fold decrease in tumor growth. We found that the binding affinity (Kd) of TGFBI for αvβ3 integrin was approximately 3.8 × 10 8 M, a value ∼2300-fold higher than that of a single FAS1 domain, and demonstrated that this greater affinity was due to the cooperative action of four FAS1 domains and the RGD motif. Moreover, TGFBI exhibited potent anti-angiogenic and anti-tumorigenic activities and specifically targeted the tumor vasculature and accumulated at the tumor site. Collectively, our results support the theory that TGFBI acts as a potent endogenous anti-tumor and anti-angiogenic molecule by targeting αvβ3 integrin, and highlight the importance of physiological circulating TGFBI levels in inhibiting tumor growth. Citation Format: Jun-Young Seo, Hae Uk Jung, Hye-Nam Son, Soyoun Kim, Eunsung Jun, Ju-Ock Nam, Jung-Eun Kim, In-San Kim. Absence of TGFBI favors tumor angiogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 11. doi:10.1158/1538-7445.AM2014-11