Tissue-Engineered “Metastases”: Treatment of Hepatic Colon Tumors with a Dual Action Autotaxin Inhibitor-Lysophosphatidic Acid Receptor Antagonist
Keywords:LPA, signal transduction modifier, lysolipid, cell encapsulation, Extracel™, tumor engineering, injectable hydrogel, hyaluronic acid, HA.
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.
Espey DK, Wu XC, Swan J, et al. Annual report to the nation on the status of cancer, 1975-2004, featuring cancer in American Indians and Alaska Natives. Cancer 2007; 110(10): 2119-52. http://dx.doi.org/10.1002/cncr.23044
Ballantyne GH, Quin J. Surgical treatment of liver metastases in patients with colorectal cancer. Cancer 1993; 71(12 Suppl): 4252-66. http://dx.doi.org/10.1002/1097-0142(19930615)71:12+<4252::AID-CNCR2820711815>3.0.CO;2-6
Wolpin BM, Meyerhardt JA, Mamon HJ, Mayer RJ. Adjuvant treatment of colorectal cancer. CA Cancer J Clin 2007; 57(3): 168-85. http://dx.doi.org/10.3322/canjclin.57.3.168
Russell AH, Tong D, Dawson LE, Wisbeck W. Adenocarcinoma of the proximal colon. Sites of initial dissemination and patterns of recurrence following surgery alone. Cancer 1984; 53(2): 360-7. http://dx.doi.org/10.1002/1097-0142(19840115)53:2<360::AID-CNCR2820530232>3.0.CO;2-U
Dizon DS, Kemeny NE. Intrahepatic arterial infusion of chemotherapy: clinical results. Semin Oncol 2002; 29(2): 126-35. http://dx.doi.org/10.1053/sonc.2002.31680
Silen W. Hepatic resection for metastases from colorectal carcinoma is of dubious value. Arch Surg 1989; 124: 1021-22. http://dx.doi.org/10.1001/archsurg.1989.01410090027004
van Corven EJ, Groenink A, Jalink K, Eichholtz T, Moolenaar WH. Lysophosphatidate-induced cell proliferation: identification and dissection of signaling pathways mediated by G proteins. Cell 1989; 59(1): 45-54. http://dx.doi.org/10.1016/0092-8674(89)90868-4
Moolenaar WH. Lysophosphatidic acid, a multifunctional phospholipid messenger. J Biol Chem 1995; 270(22): 12949-52.
Mills GB, Moolenaar WH. The emerging role of lysophosphatidic acid in cancer. Nat Rev Cancer 2003; 3(8): 582-91. http://dx.doi.org/10.1038/nrc1143
Luquain C, Sciorra VA, Morris AJ. Lysophosphatidic acid signaling: how a small lipid does big things. TIBS 2003; 28(7): 377-83. http://dx.doi.org/10.1016/S0968-0004(03)00139-7
Murph M, Tanaka T, Liu S, Mills GB. Of spiders and crabs: the emergence of lysophospholipids and their metabolic pathways as targets for therapy in cancer. Clin Cancer Res 2006; 12(22): 6598-602. http://dx.doi.org/10.1158/1078-0432.CCR-06-1721
An S, Bleu T, Hallmark OG, Goetzl EJ. Characterization of a novel subtype of human G protein-coupled receptor for lysophosphatidic acid. J Biol Chem 1998; 273(14): 7906-10. http://dx.doi.org/10.1074/jbc.273.14.7906
Aoki J, Bandoh K, Inoue K. A novel human G-protein-coupled receptor, EDG7, for lysophosphatidic acid with unsaturated fatty-acid moiety. Ann N Y Acad Sci 2000; 905: 263-6. http://dx.doi.org/10.1111/j.1749-6632.2000.tb06556.x
Yang M, Zhong W, Srivastava N, et al. G-protein coupled lysophosphatidic acid receptors stimulate proliferation of colon cancer cells through the beta-catenin pathway. Proc Natl Acad Sci USA 2005; 102: 6027-32. http://dx.doi.org/10.1073/pnas.0501535102
Yun CC, Sun H, Wang D, et al. LPA2 receptor mediates mitogenic signals in human colon cancer cells. Am J Physiol Cell Physiol 2005; 289(1): C2-11. http://dx.doi.org/10.1152/ajpcell.00610.2004
Feng L, Mills GB, Prestwich GD. Modulators of lysophosphatidic acid signaling. Expert Opin Therap Patents 2003; 13: 1619-34.
Umezu-Goto M, Tanyi J, Lahad J, et al. Lysophosphatidic acid production and action: validated targets in cancer? J Cell Biochem 2004; 92(6): 1115-40. http://dx.doi.org/10.1002/jcb.20113
Tigyi G, Parrill AL. Molecular mechanisms of lysophosphatidic acid action. Prog Lipid Res 2003; 42(6): 498-526. http://dx.doi.org/10.1016/S0163-7827(03)00035-3
Panupinthu N, Lee H, Mills G. Lysophosphatidic acid production and action: critical new players in breast cancer initiation and progression. Br J Cancer 2010; 102: 941-46. http://dx.doi.org/10.1038/sj.bjc.6605588
Tokumura A, Majima E, Kariya Y, et al. Identification of human plasma lysophospholipase D, a lysophosphatidic acid-producing enzyme, as autotaxin, a multifunctional phosphodiesterase. J Biol Chem 2002; 277(42): 39436-42. http://dx.doi.org/10.1074/jbc.M205623200
Umezu-Goto M, Kishi Y, Taira A, et al. Autotaxin has lysophospholipase D activity leading to tumor cell growth and motility by lysophosphatidic acid production. J Cell Biol 2002; 158(2): 227-33. http://dx.doi.org/10.1083/jcb.200204026
Rivera-Lopez CM, Tucker AL, Lynch KR. Lysophosphatidic acid (LPA) and angiogenesis. Angiogenesis 2008; 11(3): 301-10. http://dx.doi.org/10.1007/s10456-008-9113-5
van Meeteren L, Moolenaar W. Regulation and biological activities of the autotaxin-LPA axis. Prog Lipid Res 2007; 46: 145-60. http://dx.doi.org/10.1016/j.plipres.2007.02.001
van Meeteren LA, Ruurs P, Christodoulou E, et al. Inhibition of autotaxin by lysophosphatidic acid and sphingosine 1-phosphate. J Biol Chem 2005; 280(22): 21155-61. http://dx.doi.org/10.1074/jbc.M413183200
Zhang H, Xu X, Gajewiak J, et al. Dual activity lysophosphatidic acid receptor pan-antagonist/autotaxin inhibitor reduces breast cancer cell migration in vitro and causes tumor regression in vivo. Cancer Res 2009; 69: 5441-49. http://dx.doi.org/10.1158/0008-5472.CAN-09-0302
North E, Howard A, Wanjala I, Pham T, Baker D, Parrill A. Pharmacophore Development and Application Toward the Identification of Novel, Small-Molecule Autotaxin Inhibitors. J Med Chem 2010; 53: 3095-105. http://dx.doi.org/10.1021/jm901718z
Parrill A, Baker D. Autotaxin inhibition: challenges and progress toward novel anticancer agents. Anticancer Agents Med Chem 2008; 8: 917-23.
Albers HM, Dong A, van Meeteren LA, et al. Boronic acid-based inhibitor of autotaxin reveals rapid turnover of LPA in the circulation. Proc Natl Acad Sci USA 2010; 107: 7257-62. http://dx.doi.org/10.1073/pnas.1001529107
Nishimasu H, Okudaira S, Hama K, et al. Crystal structure of autotaxin and insight into GPCR activation by lipid mediators. Nat Struct Mol Biol. 2011. http://dx.doi.org/10.1038/nsmb.1998
Hausmann J, Kamtekar S, Christodoulou E, et al. Structural basis of substrate discrimination and integrin binding by autotaxin. Nat Struct Mol Biol 2011. http://dx.doi.org/10.1038/nsmb.1980
Jiang G, Xu Y, Fujiwara Y, et al. α-Substituted phosphonate analogues of lysophosphatidic acid (LPA) selectively inhibit production and action of LPA. Chem Med Chem 2007; 2: 679-90. http://dx.doi.org/10.1002/cmdc.200600280
Xu X, Yang G, Zhang H, Prestwich G. Evaluating dual activity LPA pan-antagonist/autotaxin inhibitors as anti-cancer agents in vivo using engineered human tumors. Prostagland. Other Lipid Med 2009; 89: 140-46. http://dx.doi.org/10.1016/j.prostaglandins.2009.07.006
Xu X, Prestwich GD. Inhibition of tumor growth and angiogenesis by a lysophosphatidic acid antagonist in a engineered three-dimensional lung cancer xenograft model. Cancer 2010; 116: 1739-50. http://dx.doi.org/10.1002/cncr.24907
Guo Y, Higazi AA, Arakelian A, et al. A peptide derived from the nonreceptor binding region of urokinase plasminogen activator (uPA) inhibits tumor progression and angiogenesis and induces tumor cell death in vivo. FASEB J 2000; 14(10): 1400-10. http://dx.doi.org/10.1096/fj.14.10.1400
Liu Y, Shu XZ, Prestwich GD. Tumor engineering: orthotopic cancer models in mice using cell-loaded, injectable, cross-linked hyaluronan-derived hydrogels. Tissue Eng 2007; 13(5): 1091-101. http://dx.doi.org/10.1089/ten.2006.0297
Stoeltzing O, Ahmad SA, Liu W, et al. Angiopoietin-1 inhibits vascular permeability, angiogenesis, and growth of hepatic colon cancer tumors. Cancer Res 2003; 63(12): 3370-7.
Polizzi D, Pratesi G, Tortoreto M, et al. A novel taxane with improved tolerability and therapeutic activity in a panel of human tumor xenografts. Cancer Res 1999; 59(5): 1036-40.
Prestwich G. Evaluating drug toxicity and efficacy in three dimensions: using synthetic extracellular matrices in drug discovery. Acc Chem Res 2008; 41: 139-48. http://dx.doi.org/10.1021/ar7000827
Prestwich G. Hyaluronic acid-based clinical biomaterials for cell and molecule delivery in regenerative medicine. J Controlled Release 2011(155): 193-99. http://dx.doi.org/10.1016/j.jconrel.2011.04.007
Scaife CL, Shea JE, Dai Q, Firpo MA, Prestwich GD, Mulvihill SJ. Synthetic extracellular matrix enhances tumor growth and metastasis in an orthotopic mouse model of pancreatic adenocarcinoma. J Gastrointest Surg 2008; 12: 1074-80. http://dx.doi.org/10.1007/s11605-007-0425-3
Fidler I. Critical factors in the biology of human cancer metastasis. Cancer Res 1990; 50: 6130-38.
Bibby M. Orthotopic models of cancer for preclinical drug evaluation: advantages and disadvantages. Eur J Cancer 2004; 40: 852-57. http://dx.doi.org/10.1016/j.ejca.2003.11.021
Fidler I. The organ microenvironment and cancer metastasis. Differentiation 2002; 70: 498-505. http://dx.doi.org/10.1046/j.1432-0436.2002.700904.x