Combined targeting of TGF-β1 and integrin β3 impairs lymph node metastasis in a mouse model of non-small-cell lung cancer

Background: Transforming Growth Factor beta (TGF-beta) acts as a tumor suppressor early in carcinogenesis but turns into tumor promoter in later disease stages. In fact, TGF-beta is a known inducer of integrin expression by tumor cells which contributes to cancer metastatic spread and TGF-beta inhibition has been shown to attenuate metastasis in mouse models. However, carcinoma cells often become refractory to TGF-beta-mediated growth inhibition. Therefore identifying patients that may benefit from anti-TGF-beta therapy requires careful selection. Methods: We performed in vitro analysis of the effects of exposure to TGF-beta in NSCLC cell chemotaxis and adhesion to lymphatic endothelial cells. We also studied in an orthotopic model of NSCLC the incidence of metastases to the lymph nodes after inhibition of TGF-beta signaling, beta 3 integrin expression or both. Results: We offer evidences of increased beta 3-integrin dependent NSCLC adhesion to lymphatic endothelium after TGF-beta exposure. In vivo experiments show that targeting of TGF-beta and beta 3 integrin significantly reduces the incidence of lymph node metastasis. Even more, blockade of beta 3 integrin expression in tumors that did not respond to TGF-beta inhibition severely impaired the ability of the tumor to metastasize towards the lymph nodes. Conclusion: These findings suggest that lung cancer tumors refractory to TGF-beta monotherapy can be effectively treated using dual therapy that combines the inhibition of tumor cell adhesion to lymphatic vessels with stromal TGF-beta inhibition.