Cytosolic Phospholipase A2 and Lysophospholipids in Tumor Angiogenesis

Overview

Journal J Natl Cancer Inst

Publisher Oxford University Press

Specialty Oncology

Date 2010 Aug 24

PMID 20729478

Citations 41

Authors

Amanda G Linkous

Eugenia M Yazlovitskaya

Dennis E Hallahan

Affiliations

Soon will be listed here.

Abstract

Background: Lung cancer and glioblastoma multiforme are highly angiogenic and, despite advances in treatment, remain resistant to therapy. Cytosolic phospholipase A2 (cPLA(2)) activation contributes to treatment resistance through transduction of prosurvival signals. We investigated cPLA(2) as a novel molecular target for antiangiogenesis therapy.

Methods: Glioblastoma (GL261) and Lewis lung carcinoma (LLC) heterotopic tumor models were used to study the effects of cPLA(2) expression on tumor growth and vascularity in C57/BL6 mice wild type for (cPLA(2)α(+/+)) or deficient in (cPLA(2)α(-/-)) cPLA(2)α, the predominant isoform in endothelium (n = 6-7 mice per group). The effect of inhibiting cPLA(2) activity on GL261 and LLC tumor growth was studied in mice treated with the chemical cPLA(2) inhibitor 4-[2-[5-chloro-1-(diphenylmethyl)-2-methyl-1H-indol-3-yl]-ethoxy]benzoic acid (CDIBA). Endothelial cell proliferation and function were evaluated by Ki-67 immunofluorescence and migration assays in primary cultures of murine pulmonary microvascular endothelial cells (MPMEC) isolated from cPLA(2)α(+/+) and cPLA(2)α(-/-) mice. Proliferation, invasive migration, and tubule formation were assayed in mouse vascular endothelial 3B-11 cells treated with CDIBA. Effects of lysophosphatidylcholine, arachidonic acid, and lysophosphatidic acid (lipid mediators of tumorigenesis and angiogenesis) on proliferation and migration were examined in 3B-11 cells and cPLA(2)α(-/-) MPMEC. All statistical tests were two-sided.

Results: GL261 tumor progression proceeded normally in cPLA(2)α(+/+) mice, whereas no GL261 tumors formed in cPLA(2)α(-/-) mice. In the LLC tumor model, spontaneous tumor regression was observed in 50% of cPLA(2)α(-/-) mice. Immunohistochemical examination of the remaining tumors from cPLA(2)α(-/-) mice revealed attenuated vascularity (P ≤ .001) compared with tumors from cPLA(2)α(+/+) mice. Inhibition of cPLA(2) activity by CDIBA resulted in a delay in tumor growth (eg, LLC model: average number of days to reach tumor volume of 700 mm(3), CDIBA vs vehicle: 16.8 vs 11.8, difference = 5, 95% confidence interval = 3.6 to 6.4, P = .04) and a decrease in tumor size (eg, GL261 model: mean volume on day 21, CDIBA vs vehicle: 40.1 vs 247.4 mm(3), difference = 207.3 mm(3), 95% confidence interval = 20.9 to 293.7 mm(3), P = .021). cPLA(2) deficiency statistically significantly reduced MPMEC proliferation and invasive migration (P = .002 and P = .004, respectively). Compared with untreated cells, cPLA(2)α(-/-) MPMEC treated with lysophosphatidylcholine and lysophosphatidic acid displayed increased cell proliferation (P = .011) and invasive migration (P < .001).

Conclusions: In these mouse models of brain and lung cancer, cPLA(2) and lysophospholipids have key regulatory roles in tumor angiogenesis. cPLA(2) inhibition may be a novel effective antiangiogenic therapy.

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References

Keshet E, Ben-Sasson S . Anticancer drug targets: approaching angiogenesis. J Clin Invest. 1999; 104(11):1497-501. PMC: 409872. DOI: 10.1172/JCI8849. View

Suh J, Barnett G . Brachytherapy for brain tumor. Hematol Oncol Clin North Am. 1999; 13(3):635-50, viii-ix. DOI: 10.1016/s0889-8588(05)70080-0. View

Navarro-Tito N, Soto-Guzman A, Castro-Sanchez L, Martinez-Orozco R, Salazar E . Oleic acid promotes migration on MDA-MB-231 breast cancer cells through an arachidonic acid-dependent pathway. Int J Biochem Cell Biol. 2009; 42(2):306-17. DOI: 10.1016/j.biocel.2009.11.010. View

Shweiki D, Neeman M, Itin A, Keshet E . Induction of vascular endothelial growth factor expression by hypoxia and by glucose deficiency in multicell spheroids: implications for tumor angiogenesis. Proc Natl Acad Sci U S A. 1995; 92(3):768-72. PMC: 42701. DOI: 10.1073/pnas.92.3.768. View

Folkman J . A new link in ovarian cancer angiogenesis: lysophosphatidic acid and vascular endothelial growth factor expression. J Natl Cancer Inst. 2001; 93(10):734-5. DOI: 10.1093/jnci/93.10.734. View

Aoki J, Inoue A, Okudaira S . Two pathways for lysophosphatidic acid production. Biochim Biophys Acta. 2008; 1781(9):513-8. DOI: 10.1016/j.bbalip.2008.06.005. View

Fainaru O, D Hornstein M, Folkman J . Doxycycline inhibits vascular leakage and prevents ovarian hyperstimulation syndrome in a murine model. Fertil Steril. 2008; 92(5):1701-5. DOI: 10.1016/j.fertnstert.2008.08.129. View

Yazlovitskaya E, Linkous A, Thotala D, Cuneo K, Hallahan D . Cytosolic phospholipase A2 regulates viability of irradiated vascular endothelium. Cell Death Differ. 2008; 15(10):1641-53. DOI: 10.1038/cdd.2008.93. View

Kishi Y, Okudaira S, Tanaka M, Hama K, Shida D, Kitayama J . Autotaxin is overexpressed in glioblastoma multiforme and contributes to cell motility of glioblastoma by converting lysophosphatidylcholine to lysophosphatidic acid. J Biol Chem. 2006; 281(25):17492-17500. DOI: 10.1074/jbc.M601803200. View

10.

Ptaszynska M, Pendrak M, Bandle R, Stracke M, Roberts D . Positive feedback between vascular endothelial growth factor-A and autotaxin in ovarian cancer cells. Mol Cancer Res. 2008; 6(3):352-63. PMC: 2442564. DOI: 10.1158/1541-7786.MCR-07-0143. View

11.

Rucker H, Wynder H, THOMAS W . Cellular mechanisms of CNS pericytes. Brain Res Bull. 2000; 51(5):363-9. DOI: 10.1016/s0361-9230(99)00260-9. View

12.

Hirabayashi T, Shimizu T . Localization and regulation of cytosolic phospholipase A(2). Biochim Biophys Acta. 2000; 1488(1-2):124-38. DOI: 10.1016/s1388-1981(00)00115-3. View

13.

Mounier C, Ghomashchi F, Lindsay M, James S, Singer A, Parton R . Arachidonic acid release from mammalian cells transfected with human groups IIA and X secreted phospholipase A(2) occurs predominantly during the secretory process and with the involvement of cytosolic phospholipase A(2)-alpha. J Biol Chem. 2004; 279(24):25024-38. DOI: 10.1074/jbc.M313019200. View

14.

Wong E, Brem S . Taming glioblastoma: targeting angiogenesis. J Clin Oncol. 2007; 25(30):4705-6. DOI: 10.1200/JCO.2007.13.1037. View

15.

McKew J, Foley M, Thakker P, Behnke M, Lovering F, Sum F . Inhibition of cytosolic phospholipase A2alpha: hit to lead optimization. J Med Chem. 2006; 49(1):135-58. DOI: 10.1021/jm0507882. View

16.

Gerhardt H, Betsholtz C . Endothelial-pericyte interactions in angiogenesis. Cell Tissue Res. 2003; 314(1):15-23. DOI: 10.1007/s00441-003-0745-x. View

17.

Farooqui A, Ong W, Horrocks L . Inhibitors of brain phospholipase A2 activity: their neuropharmacological effects and therapeutic importance for the treatment of neurologic disorders. Pharmacol Rev. 2006; 58(3):591-620. DOI: 10.1124/pr.58.3.7. View

18.

Weiser-Evans M, Wang X, Amin J, Van Putten V, Choudhary R, Winn R . Depletion of cytosolic phospholipase A2 in bone marrow-derived macrophages protects against lung cancer progression and metastasis. Cancer Res. 2009; 69(5):1733-8. PMC: 2653105. DOI: 10.1158/0008-5472.CAN-08-3766. View

19.

Videtic G, Gaspar L, Zamorano L, Fontanesi J, Levin K, Kupsky W . Use of the RTOG recursive partitioning analysis to validate the benefit of iodine-125 implants in the primary treatment of malignant gliomas. Int J Radiat Oncol Biol Phys. 1999; 45(3):687-92. DOI: 10.1016/s0360-3016(99)00244-8. View

20.

Fujita Y, Yoshizumi M, Izawa Y, Ali N, Ohnishi H, Kanematsu Y . Transactivation of fetal liver kinase-1/kinase-insert domain-containing receptor by lysophosphatidylcholine induces vascular endothelial cell proliferation. Endocrinology. 2005; 147(3):1377-85. DOI: 10.1210/en.2005-0644. View