Inhibition of Tumor Growth and Angiogenesis by a Lysophosphatidic Acid Antagonist in an Engineered Three-Dimensional Lung Cancer Xenograft Model

BACKGROUND: We developed an engineered three-dimensional (3D) tumor xenograft model of nonsmall cell lung cancer (NSCLC) in nude mice, and we used this model to evaluate a dual-activity inhibitor of lysophosphatidic acid (LPA) biosynthesis and receptor activation. METHODS: First, BrP-LPA, a pan-antagonist for 4 LPA receptors and inhibitor of the lyosphospholipase D activity of autotaxin, was examined for inhibition of cell migration and cell invasion by human NSCLC A549 cells. Second, A549 cells were encapsulated in 3D in 3 semisynthetic extracellular matrices (ECMs) based on chemically modified glycosaminoglycans, and injected subcutaneously in nude mice. Tumor volume and vascularity were determined as a function of semisynthetic ECMs composition. Third, engineered NSCLC xenografts were formed from A549 cells in either Extracel-HP or Matrigel, and mice were treated with 4 intraperitoneal injections of 3 mg/kg of BrP-LPA. RESULTS: First, BrP-LPA inhibited cell migration and invasiveness of A549 cells in vitro. Second, tumor growth and microvessel formation for 3D encapsulated A549 cells in vivo in nude mice increased in the following order: buffer only < Extracel < Extracel-HP < Extracel-HP containing growth factorss plus laminin. Third, tumor volumes increased rapidly in both Matrigel and Extracel-HP encapsulated A549 cells, and tumor growth was markedly inhibited by BrP-LPA treatment. Finally, tumor vascularization was dramatically reduced in the A549 tumors treated with BrP-LPA. CONCLUSIONS: Engineered A549 lung tumors can be created by 3D encapsulation in an ECM substitute with user controlled composition. The engineered tumors regress and lose vascularity in response to a dual activity inhibitor of the LPA signaling pathway. Cancer 2010;116:1739-50. (C) 2070 American Cancer Society.