Pro‐tumorigenic Effects of Transforming Growth Factor Beta 1 in Canine Osteosarcoma

Background Transforming growth factor beta 1 ( TGF β1) is a pleiotropic cytokine that contributes to reparative skeletal remodeling by inducing osteoblast proliferation, migration, and angiogenesis. Organic bone matrix is the largest bodily reservoir for latent TGF β1, and active osteoblasts express cognate receptors for TGF β1 ( TGF β RI and TGF β RII ). During malignant osteolysis, TGF β1 is liberated from eroded bone matrix and promotes local progression of osteotropic solid tumors by its mitogenic and prosurvival activities. Hypothesis Canine osteosarcoma ( OS ) cells will possess TGF β1 signaling machinery. Blockade of TGF β1 signaling will attenuate pro‐tumorigenic activities in OS cells. Naturally occurring primary OS samples will express cognate TGF β1 receptors; and in dogs with OS , focal malignant osteolysis will contribute to circulating TGF β1 concentrations. Animals Thirty‐three dogs with appendicular OS . Methods Expression of TGF β1 and its cognate receptors, as well as the biologic effects of TGF β1 blockade, was characterized in OS cells. Ten spontaneous OS samples were characterized for TGF β RI / II expressions by immunohistochemistry. In 33 dogs with OS , plasma TGF β1 concentrations were quantified and correlated with bone resorption. Results Canine OS cells secrete TGF β1, express cognate receptors, and TGF β1 signaling blockade decreases proliferation, migration, and vascular endothelial growth factor secretion. Naturally occurring OS samples abundantly and uniformly express TGF β RI / II , and in OS ‐bearing dogs, circulating TGF β1 concentrations correlate with urine N ‐telopeptide excretion. Conclusions and Clinical Importance Canine OS cells possess TGF β1 signaling machinery, potentially allowing for the establishment of an autocrine and paracrine pro‐tumorigenic signaling loop. As such, TGF β1 inhibitors might impede localized OS progression in dogs.