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Autotaxin: a secreted autocrine/paracrine factor that promotes glioma invasion

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Glioblastoma multiforme (GBM) is inherently invasive, and it is from the invasive cell population that the tumor recurs. The GBM invasion transcriptome reveals over-expression of various autocrine factors that could act as motility drivers, such as autotaxin (ATX). Some of these factors could also have paracrine roles, modulating the behavior of cells in the peri-tumoral brain parenchyma. ATX generates lysophosphatidic acid (LPA), which signals through LPA receptors expressed by GBM as well as in astrocytes, oligodendrocytes (ODC) and microglia; their activation manifest cell specific effects. ATX stimulates invasion of GBM cells in vitro and ex vivo invasion assays. ATX activity enhances GBM adhesion in cells expressing the LPA1 receptor, as well as stimulating rac activation. GBM secreted ATX can also have paracrine effects: ATX activity results in reduced ODC adhesion. ODC monolayer invasion showed that U87 and U251 GBM cells expressing ATX invaded through an ODC monolayer significantly more than cells depleted of ATX or cells expressing inactive ATX, suggesting that GBM cells secreting ATX find ODCs less of a barrier than cells that do not express ATX. Secreted factors that drive GBM invasion can have autocrine and paracrine roles; one stimulates GBM motility and the other results in ODC dis-adhesion.

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Glioblastoma multiforme




Central nervous system






Lysophosphatidic acid.


  1. Wesseling P, Ruiter DJ, Burger PC (1997) Angiogenesis in brain tumors; pathobiological and clinical aspects. J Neurooncol 32:253–265

    Article  PubMed  CAS  Google Scholar 

  2. Nakada M, Nakada S, Demuth T, Tran NL, Hoelzinger DB, Berens ME (2007) Molecular targets of glioma invasion. Cell Mol Life Sci 64(4):458–478

    Google Scholar 

  3. Colin C, Baeza N, Bartoli C, Fina F, Eudes N, Nanni I, Martin PM, Ouafik L, Figarella-Branger D (2006) Identification of genes differentially expressed in glioblastoma versus pilocytic astrocytoma using Suppression Subtractive Hybridization. Oncogene 25:2818–2826

    Article  PubMed  CAS  Google Scholar 

  4. Hoelzinger D, Mariani L, Weis J, Woyke T, Berens T, McDonough W, Sloan A, Coons S, Berens M (2005) Gene expression profile of glioblastoma multiformes invasive phenotype points to new therapeutic targets. Neoplasia 7:7–16

    Article  PubMed  CAS  Google Scholar 

  5. Mariani L, Beaudry C, McDonough WS, Hoelzinger DB, Kaczmarek E, Ponce F, Coons SW, Giese A, Seiler RW, Berens ME (2001) Death-associated protein 3 (Dap-3) is overexpressed in invasive glioblastoma cells in vivo and in glioma cell lines with induced motility phenotype in vitro. Clin Cancer Res 7:2480–2489

    PubMed  CAS  Google Scholar 

  6. Mariani L, McDonough WS, Hoelzinger DB, Beaudry C, Kaczmarek E, Coons SW, Giese A, Moghaddam M, Seiler RW, Berens ME (2001) Identification and validation of P311 as a glioblastoma invasion gene using laser capture microdissection. Cancer Res 61:4190–4196

    PubMed  CAS  Google Scholar 

  7. Hoelzinger DB, Demuth D, Berens ME (2007) Autocrine factors that sustain glioma invasion and paracrine biology in the brain microenvironment. JNCI 99(21)

  8. Barallobre MJ, Pascual M, Del Rio JA, Soriano E (2005) The Netrin family of guidance factors: emphasis on Netrin-1 signalling. Brain Res Brain Res Rev 49:22–47

    Article  PubMed  CAS  Google Scholar 

  9. Huot J (2004) Ephrin signaling in axon guidance. Prog Neuropsychopharmacol Biol Psychiatry 28:813–818

    Article  PubMed  CAS  Google Scholar 

  10. Fox MA, Colello RJ, Macklin WB, Fuss B (2003) Phosphodiesterase-Ialpha/autotaxin: a counteradhesive protein expressed by oligodendrocytes during onset of myelination. Mol Cell Neurosci 23:507–519

    Article  PubMed  CAS  Google Scholar 

  11. Narita M, Goji J, Nakamura H, Sano K (1994) Molecular cloning, expression, and localization of a brain-specific phosphodiesterase I/nucleotide pyrophosphatase (PD-I alpha) from rat brain. J Biol Chem 269:28235–28242

    PubMed  CAS  Google Scholar 

  12. Fuss B, Baba H, Phan T, Tuohy VK, Macklin WB (1997) Phosphodiesterase I, a novel adhesion molecule and/or cytokine involved in oligodendrocyte function. J Neurosci 17:9095–9103

    PubMed  CAS  Google Scholar 

  13. Fox MA, Alexander JK, Afshari FS, Colello RJ, Fuss B (2004) Phosphodiesterase-I alpha/autotaxin controls cytoskeletal organization and FAK phosphorylation during myelination. Mol Cell Neurosci 27:140–150

    Article  PubMed  CAS  Google Scholar 

  14. Scherer H (1940) The forms of growth in gliomas and their practical significance. Brain 63:1–35

    Article  Google Scholar 

  15. Giese A, Westphal M (1996) Glioma invasion in the central nervous system. Neurosurgery 39:235–250; discussion 250–232

    Google Scholar 

  16. Yang Y, Mou L, Liu N, Tsao MS (1999) Autotaxin expression in non-small-cell lung cancer. Am J Respir Cell Mol Biol 21:216–222

    PubMed  Google Scholar 

  17. Stracke ML, Krutzsch HC, Unsworth EJ, Arestad A, Cioce V, Schiffmann E, Liotta LA (1992) Identification, purification, and partial sequence analysis of autotaxin, a novel motility-stimulating protein. J Biol Chem 267:2524–2529

    PubMed  CAS  Google Scholar 

  18. Yang SY, Lee J, Park CG, Kim S, Hong S, Chung HC, Min SK, Han JW, Lee HW, Lee HY (2002) Expression of autotaxin (NPP-2) is closely linked to invasiveness of breast cancer cells. Clin Exp Metastasis 19:603–608

    Article  PubMed  CAS  Google Scholar 

  19. Kawagoe H, Stracke ML, Nakamura H, Sano K (1997) Expression and transcriptional regulation of the PD-Ialpha/autotaxin gene in neuroblastoma. Cancer Res 57:2516–2521

    PubMed  CAS  Google Scholar 

  20. Kishi Y, Okudaira S, Tanaka M, Hama K, Shida D, Kitayama J, Yamori T, Aoki J, Fujimaki T, Arai H (2006) Autotaxin is overexpressed in glioblastoma multiforme and contributes to cell motility of glioblastoma by converting lysophosphatidylcholine to lysophosphatidic acid. J Biol Chem 281:17492–17500

    Article  PubMed  CAS  Google Scholar 

  21. Umezu-Goto M, Kishi Y, Taira A, Hama K, Dohmae N, Takio K, Yamori T, Mills GB, Inoue K, Aoki J, Arai H (2002) Autotaxin has lysophospholipase D activity leading to tumor cell growth and motility by lysophosphatidic acid production. J Cell Biol 158:227–233

    Article  PubMed  CAS  Google Scholar 

  22. Tokumura A, Majima E, Kariya Y, Tominaga K, Kogure K, Yasuda K, Fukuzawa K (2002) Identification of human plasma lysophospholipase D, a lysophosphatidic acid-producing enzyme, as autotaxin, a multifunctional phosphodiesterase. J Biol Chem 277:39436–39442

    Article  PubMed  CAS  Google Scholar 

  23. Dennis J, Nogaroli L, Fuss B (2005) Phosphodiesterase-Ialpha/autotaxin (PD-Ialpha/ATX): a multifunctional protein involved in central nervous system development and disease. J Neurosci Res 82:737–742

    Article  PubMed  CAS  Google Scholar 

  24. Kleihues P, Cavenee WK (eds) (2000) World Health Organization Classification of Tumors. Pathology & Genetics. Tumors of the Nervous System. Lyon, France: IARC Press

  25. Koh E, Clair T, Woodhouse EC, Schiffmann E, Liotta L, Stracke M (2003) Site-directed mutations in the tumor-associated cytokine, autotaxin, eliminate nucleotide phosphodiesterase, lysophospholipase D, and motogenic activities. Cancer Res 63:2042–2045

    PubMed  CAS  Google Scholar 

  26. Nakada M, Yamashita J, Okada Y, Sato H (1999) Ets-1 positively regulates expression of urokinase-type plasminogen activator (uPA) and invasiveness of astrocytic tumors. J Neuropathol Exp Neurol 58:329–334

    Article  PubMed  CAS  Google Scholar 

  27. Wegener J, Keese CR, Giaever I (2000) Electric cell-substrate impedance sensing (ECIS) as a noninvasive means to monitor the kinetics of cell spreading to artificial surfaces. Exp Cell Res 259:158–166

    Article  PubMed  CAS  Google Scholar 

  28. Sharma KV, Koenigsberger C, Brimijoin S, Bigbee JW (2001) Direct evidence for an adhesive function in the noncholinergic role of acetylcholinesterase in neurite outgrowth. J Neurosci Res 63:165–175

    Article  PubMed  CAS  Google Scholar 

  29. Chuang YY, Tran NL, Rusk N, Nakada M, Berens ME, Symons M (2004) Role of synaptojanin 2 in glioma cell migration and invasion. Cancer Res 64:8271–8275

    Article  PubMed  CAS  Google Scholar 

  30. Nakada M, Niska JA, Miyamori H, McDonough WS, Wu J, Sato H, Berens ME (2004) The phosphorylation of EphB2 receptor regulates migration and invasion of human glioma cells. Cancer Res 64:3179–3185

    Article  PubMed  CAS  Google Scholar 

  31. Valster A, Tran NL, Nakada M, Berens ME, Chan AY, Symons M (2005) Cell migration and invasion assays. Methods 37:208–215

    Article  PubMed  CAS  Google Scholar 

  32. Keese CR, Bhawe K, Wegener J, Giaever I (2002) Real-time impedance assay to follow the invasive activities of metastatic cells in culture. Biotechniques 33:842–844, 846, 848–850

    Google Scholar 

  33. Ren J, Xiao YJ, Singh LS, Zhao X, Zhao Z, Feng L, Rose TM, Prestwich GD, Xu Y (2006) Lysophosphatidic acid is constitutively produced by human peritoneal mesothelial cells and enhances adhesion, migration, and invasion of ovarian cancer cells. Cancer Res 66:3006–3014

    Article  PubMed  CAS  Google Scholar 

  34. Saxena NK, Sharma D, Ding X, Lin S, Marra F, Merlin D, Anania FA (2007) Concomitant activation of the JAK/STAT, PI3K/AKT, and ERK signaling is involved in leptin-mediated promotion of invasion and migration of hepatocellular carcinoma cells. Cancer Res 67:2497–2507

    Article  PubMed  CAS  Google Scholar 

  35. Mischel PS, Shai R, Shi T, Horvath S, Lu KV, Choe G, Seligson D, Kremen TJ, Palotie A, Liau LM, Cloughesy TF, Nelson SF (2003) Identification of molecular subtypes of glioblastoma by gene expression profiling. Oncogene 22:2361–2373

    Article  PubMed  CAS  Google Scholar 

  36. Chun J (2005) Lysophospholipids in the nervous system. Prostaglandins Other Lipid Mediat 77:46–51

    Article  PubMed  CAS  Google Scholar 

  37. Moolenaar WH, van Meeteren LA, Giepmans BN (2004) The ins and outs of lysophosphatidic acid signaling. Bioessays 26:870–881

    Article  PubMed  CAS  Google Scholar 

  38. Malchinkhuu E, Sato K, Horiuchi Y, Mogi C, Ohwada S, Ishiuchi S, Saito N, Kurose H, Tomura H, Okajima F (2005) Role of p38 mitogen-activated kinase and c-Jun terminal kinase in migration response to lysophosphatidic acid and sphingosine-1-phosphate in glioma cells. Oncogene 24:6676–6688

    Article  PubMed  CAS  Google Scholar 

  39. Steiner MR, Urso JR, Klein J, Steiner SM (2002) Multiple astrocyte responses to lysophosphatidic acids. Biochim Biophys Acta 1582:154–160

    PubMed  CAS  Google Scholar 

  40. Tham CS, Lin FF, Rao TS, Yu N, Webb M (2003) Microglial activation state and lysophospholipid acid receptor expression. Int J Dev Neurosci 21:431–443

    Article  PubMed  CAS  Google Scholar 

  41. Yu N, Lariosa-Willingham KD, Lin FF, Webb M, Rao TS (2004) Characterization of lysophosphatidic acid and sphingosine-1-phosphate-mediated signal transduction in rat cortical oligodendrocytes. Glia 45:17–27

    Article  PubMed  Google Scholar 

  42. Sato K, Malchinkhuu E, Muraki T, Ishikawa K, Hayashi K, Tosaka M, Mochiduki A, Inoue K, Tomura H, Mogi C, Nochi H, Tamoto K, Okajima F (2005) Identification of autotaxin as a neurite retraction-inducing factor of PC12 cells in cerebrospinal fluid and its possible sources. J Neurochem 92:904–914

    Article  PubMed  CAS  Google Scholar 

  43. Manning TJ Jr, Rosenfeld SS, Sontheimer H (1998) Lysophosphatidic acid stimulates actomyosin contraction in astrocytes. J Neurosci Res 53:343–352

    Article  PubMed  CAS  Google Scholar 

  44. Rao TS, Lariosa-Willingham KD, Lin FF, Palfreyman EL, Yu N, Chun J, Webb M (2003) Pharmacological characterization of lysophospholipid receptor signal transduction pathways in rat cerebrocortical astrocytes. Brain Res 990:182–194

    Article  PubMed  CAS  Google Scholar 

  45. Weiner JA, Hecht JH, Chun J (1998) Lysophosphatidic acid receptor gene vzg-1/lpA1/edg-2 is expressed by mature oligodendrocytes during myelination in the postnatal murine brain. J Comp Neurol 398:587–598

    Article  PubMed  CAS  Google Scholar 

  46. Friedl P, Brocker EB (2000) The biology of cell locomotion within three-dimensional extracellular matrix. Cell Mol Life Sci 57:41–64

    Article  PubMed  CAS  Google Scholar 

  47. Friedl P, Zanker KS, Brocker EB (1998) Cell migration strategies in 3-D extracellular matrix: differences in morphology, cell matrix interactions, and integrin function. Microsc Res Tech 43:369–378

    Article  PubMed  CAS  Google Scholar 

  48. Salhia B, Tran NL, Symons M, Winkles JA, Rutka JT, Berens ME (2006) Molecular pathways triggering glioma cell invasion. Expert Rev Mol Diagn 6:613–626

    Article  PubMed  CAS  Google Scholar 

  49. Seasholtz TM, Radeff-Huang J, Sagi SA, Matteo R, Weems JM, Cohen AS, Feramisco JR, Brown JH (2004) Rho-mediated cytoskeletal rearrangement in response to LPA is functionally antagonized by Rac1 and PIP2. J Neurochem 91:501–512

    Article  PubMed  CAS  Google Scholar 

  50. Baker DL, Fujiwara Y, Pigg KR, Tsukahara R, Kobayashi S, Murofushi H, Uchiyama A, Murakami-Murofushi K, Koh E, Bandle RW, Byun HS, Bittman R, Fan D, Murph M, Mills GB, Tigyi G (2006) Carba analogs of cyclic phosphatidic acid are selective inhibitors of autotaxin and cancer cell invasion and metastasis. J Biol Chem 281:22786–22793

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Michael E. Berens.

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Hoelzinger, D.B., Nakada, M., Demuth, T. et al. Autotaxin: a secreted autocrine/paracrine factor that promotes glioma invasion. J Neurooncol 86, 297–309 (2008).

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