Figure 6

Preventive Trk inhibition reduces CGRP⁺ and NF200⁺ nerve fiber sprouting and the formation of neuroma-like structures in the periosteum of tumor-injected mice. Representative confocal images of periosteum from sham (A, D), sarcoma + vehicle (B, E), and sarcoma + early/sustained ARRY-470 (C, F) mice. Periosteum sections were immunostained with an antibody against CGRP (A-C) and NF200 (D-F). Note that at day 20 post-tumor cell injection there is significant sprouting and neuroma formation by CGRP⁺ (B) and NF200⁺ (E) nerve fibers in sarcoma + vehicle mice. Preventive and maintained administration of ARRY-470 ( 30 mg/kg; p.o., BID) initiated at day 6 through day 20 post cell injection significantly reduces the pathological tumor-induced reorganization of sensory CGRP⁺ (C) and NF200⁺ (F) nerve fibers. Confocal images were acquired from bone sections (20 μm in thickness) and were projected from 80 optical sections at 0.25 μm intervals with a 40x objective.