FIG. 5.

Summary mechanism. Both cells become sensitive to the IGF-1Ri in the transition from static (A) to flow perfusion conditions (B) due to the shear stress-mediated upregulation of IGF-1. Mechanosensitive promotion of IL-6 secretion also results in acquired sensitivity to Stat3i in MSCs. (C) On co-culturing, sensitivity to IGF-1Ri is lost, because tumor cells coerce MSCs into secreting higher levels of IL-6, and ES proliferation relies on IL-6/Stat3 signaling rather than IGF-1/IGF-1R signaling cascade. ES-acquired drug resistance to IGF-1R blockade is overcome only in the presence of Stat3i. (D) On a macroscopic level, IGF-1Ri will have minimal impact on solid ES tumors, Stat3i will primarily target local stroma, and significant shrinkage of tumor growth will likely occur only on dual targeting of IGF-1Ri+Stat3i.