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Tissue-Engineered “Metastases”: Treatment of Hepatic Colon Tumors with a Dual Action Autotaxin Inhibitor-Lysophosphatidic Acid Receptor Antagonist - Pages 69-77

Guanghui Yang, Honglu Zhang and Glenn D. Prestwich

Department of Medicinal Chemistry and The Center for Therapeutic Biomaterials, The University of Utah, 419 Wakara Way, Suite 205, Salt Lake City, Utah 84108-1257, USA





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    Abstract: Lysophosphatidic acid (LPA) acts via G protein coupled receptors (GPCRs) to regulate critical cellular functions and pathophysiological levels of LPA or its receptors are linked to cancer initiation, progression and metastasis. LPA is biosynthesized by the lysophospholipase D activity of autotaxin (ATX/lysoPLD), a known factor for tumorigenesis. By attenuating both LPA signaling and LPA production, we expected to observe synergistic anti-cancer therapeutic effects. In vitro, treatment of human colon cancer cells (HCT 116) with BrP-LPA, a potent dual action ATX inhibitor and pan-LPA GPCR antagonist, significantly reduced cell proliferation, migration and invasion. Next, a tissue-engineered xenograft model to mimic hepatic metastasis of colon cancer was used to evaluate BrP-LPA efficacy in vivo. HCT 116 cells were suspended in Extracel™, a synthetic extracellular matrix (sECM), and injected directly into the livers of nude mice (n = 8). After 1 week, BrP-LPA in saline buffer was administered for two weeks by intraperitoneal injection (10 mg/kg) twice per week. Controls were injected with saline buffer only. The BrP-LPA treated group showed reduced liver tumor weight (p < 0.05) and reduced tumor volume (p < 0.05) relative to controls. This study is the first demonstration of the effects of a dual action ATX inhibitor/LPA antagonist on colon cancer cells, and the first example of a tissue-engineered hepatic colon cancer “metastases” as a platform for anti-cancer drug evaluation. The results suggest that attenuation of signaling through the LPA pathway offers a promising therapeutic target for reducing colon cancer growth and metastasis.

    Keywords: LPA, signal transduction modifier, lysolipid, cell encapsulation, Extracel™, tumor engineering, injectable hydrogel, hyaluronic acid, HA.


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