Targeting Insulin-Like Growth Factor 1 Receptor Restricts Development and Severity of Secondary Lymphedema in Mice

Secondary lymphedema is a debilitating chronic tissue swelling in a limb caused by inadequate interstitial fluid drainage due to dysfunctional lymphatic vessels. Pathological enlargement of small lymphatics contributes to lymphatic dysfunction in secondary lymphedema, but the molecular mechanisms driving this remodelling are unclear. Here, using a surgical mouse model of secondary lymphedema and whole-genome microarray, we identified the transcript for insulin-like growth factor binding protein 5 (IGFBP5), a negative regulator of IGF signaling, as the most profoundly down-regulated mRNA in lymphedematous tissue. Notably, IGF signalling via IGF1 receptor (IGF1R) was previously shown to promote lymphatic remodelling. We therefore targeted IGF1R in the mouse model using the small molecule IGF1R inhibitor linsitinib. Linsitinib was effective in restricting enlargement of small lymphatics and tissue swelling during lymphedema development. Importantly, linsitinib profoundly reduced tissue swelling in mice with chronic lymphedema suggesting that IGF signalling could be a therapeutic target in clinical secondary lymphedema. Gene candidates involved in pathological lymphatic remodelling in lymphedema were identified by whole-genome microarray analysis for mouse lymphedema model and non-operated control groups. The effects of inhibiting IGF1R signalling during lymphedema development in the model were then assessed by treating the mice with linsitinib. In addition, whether linsitinib could restrict tissue swelling in established lymphedema was assessed.