Macrophage/microglial Cell Subpopulations in Glioblastoma Multiforme Relapses are Differentially Altered by Radiochemotherapy
Following surgical removal of glioblastoma multiforme (GBM), radiochemotherapy impedes neoplastic outgrowth and relapse formation. Macrophages/microglial cells are believed to be potent mediators of the host defense system in GBM. However, little is known about their alteration by postsurgical therapies.
We have now analyzed expression of LCA (leucocyte common antigen), CD68 (phagocytic cells), HLA-DR, -DP, -DQ (MHC class II), MRP-8 (myeloid-related protein, S100A8), MRP-14 (S100A9), LCF (lymphocyte chemoattractant factor, IL-16) and NOS II (inducible nitric oxide synthase) in macrophages/microglial cells in 39 GBM relapses and their matched primary tumors. Following surgery of the primary tumors, 15 patients received irradiation and chemotherapy, 17 irradiation and 7 no treatment. In irradiated relapses, we observed significantly more macrophages/microglial cells expressing MRP-14 compared to untreated GBM relapses. Furthermore, we observed a significant increase of CD68 expressing macrophages/microglial cells in patients without postsurgical treatment, but not in those with radiochemotherapy.
In conclusion, our findings suggest that radiochemotherapy alters the number of MRP-14 expressing cells. The lacking increase of CD68 expressing cells in patients with radiochemotherapy suggests depletion of this cell type by postsurgical therapy.
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- 1.Kleihues P, Burger PC, Scheithauer BW: The new classification of brain tumors. Brain Pathol 3: 255–268, 1993Google Scholar
- 2.Shapiro WR, Green SB, Burger PC, Mahaley MS Jr., Selker RG, VanGilder JC, Robertson JT, Ransohoff J, Mealey J Jr., Strike TA: Randomized trial of three chemotherapy regimens and two radiotherapy regimens and two radiotherapy regimens in postoperative treatment of malignant glioma. Brain Tumor Cooperative Group Trial 8001. J Neurosurg 71: 1–9, 1989Google Scholar
- 3.Huncharek M, Muscat J: Treatment of recurrent high grade astrocytoma; results of a systematic reviewof 1,415 patients. Anticancer Res 18: 1303–1311, 1998Google Scholar
- 4.Ramprasad MP, Terpstra V, Kondratenko N, Quehenberger O, Steinberg D: Cell surface expression of mouse macrosialin and human CD68 and their role as macrophage receptors for oxidized low density lipoprotein. Proc Natl Acad Sci USA 93: 14833–14838, 1996Google Scholar
- 5.Planting AS, Splinter TA, Ardizzoni A, Estape J, Giaccone G, Kirkpatrick A, Dalesio O, McVie JG: Phase II study of ACNU as second-line treatment in small-cell lung cancer. EORTC Lung Cancer Cooperative Group. Cancer Chemother Pharmacol 29: 409–411, 1992Google Scholar
- 6.Ganter S, Northoff H, Mannel D, Gebicke-Harter PJ: Growth control of cultured microglia. J Neurosci Res 33: 218–230, 1992Google Scholar
- 7.Kreutzberg GW: Microglia: a sensor for pathological events in the CNS. Trends Neurosci 19: 312–318, 1996Google Scholar
- 8.Leung SY, Wong MP, Chung LP, Chan AS, Yuen ST: Monocyte chemoattractant protein-1 expression and macrophage infiltration in gliomas. Acta Neuropathol 93: 518–527, 1997Google Scholar
- 9.Schoenberger SP, Toes RE, van-der-Voort EI, Offringa R, Melief CJ: T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature 393: 480–483, 1998Google Scholar
- 10.Morimura T, Neuchrist C, Kitz K, Budka H, Scheiner O, Kraft D, Lassmann H: Monocyte subpopulations in human gliomas: expression of Fc and complement receptors and correlation with tumor proliferation. Acta Neuropathol 80: 287–294, 1990Google Scholar
- 11.Morris CS, Esiri MM: Immunocytochemical study of macrophages and microglial cells and extracellular matrix components in human CNS disease. 1. Gliomas. J Neurol Sci. 101: 47–58, 1991Google Scholar
- 12.Roggendorf W, Strupp S, Paulus W: Distribution and characterization of microglia/macrophages in human brain tumors. Acta Neuropathol 92: 288–293, 1996Google Scholar
- 13.Schluesener HJ, Seid K, Kretzschmar J, Meyermann R: Leukocyte chemotactic factor, a natural ligand to CD4, is expressed by lymphocytes and microglial cells of the MS plaque. J Neurosci Res 44: 606–611, 1996Google Scholar
- 14.Pulford KA, Sipos A, Cordell JL, Stross WP, Mason DY: Distribution of the CD68 macrophage/myeloid associated antigen. Int Immunol 2: 973–980, 1990Google Scholar
- 15.Jadus MR, Williams CC, Avina MD, Ly M, Kim S, Liu Y, Narasaki R, Lowell CA, Wepsic HT: Macrophages kill T9 glioma tumor cells bearing the membrane isoform of macrophage colony stimulating factor through a phagocytosis-dependent pathway. J Immunol 160: 361–368, 1998Google Scholar
- 16.Lorusso L, Rossi ML: The phagocyte in human gliomas. Ann NY Acad Sci 832: 405–425, 1997Google Scholar
- 17.Rampling R, Steward W, Paul J, Macham MA, Harvey E, Eckley D: rhGM-CSF ameliorates neutropenia in patients with malignant glioma treated with BCNU. Br J Cancer 69: 541–545, 1994Google Scholar
- 18.Liau LM, Black KL, Prins RM, Sykes SN, DiPatre PL, Cloughesy TF, Becker DP, Bronstein JM: Treatment of intracranial gliomas with bone marrow-derived dendritic cells pulsed with tumor antigens. J Neurosurg 90: 1115–1124, 1999Google Scholar
- 19.Kerkhoff C, Klempt M, Sorg C:Novel insights into structure and function of MRP8 (S100A8) and MRP14 (S100A9). Biochim Biophys Acta 1448: 200–211, 1998Google Scholar
- 20.Rammes A, Roth J, Goebeler M, Klempt M, Hartmann M, Sorg C: Myeloid-related protein (MRP) 8 and MRP14, calcium-binding proteins of the S100 family, are secreted by activated monocytes via a novel, tubulin-dependent pathway. J Biol Chem 272: 9496–9502, 1997Google Scholar
- 21.Roth J, Goebeler M, van-den-Bos C, Sorg C: Expression of calcium-binding proteins MRP8 and MRP14 is associated with distinct monocytic differentiation pathways in HL-60 cells. Biochem Biophys Res Commun 191: 565–570, 1993Google Scholar
- 22.Propper C, Huang X, Roth J, Sorg C, Nacken W: Analysis of the MRP8–MRP14 protein–protein interaction by the twohybrid system suggests a prominent role of the C-terminal domain of S100 proteins in dimer formation. J Biol Chem 274: 183–188, 1999Google Scholar
- 23.Giorgi R, Pagano RL, Dias MA, Aguiar-Passeti T, Sorg C, Mariano M: Antinociceptive effect of the calcium-binding protein MRP-14 and the role played by neutrophils on the control of inflammatory pain. J Leukoc Biol 64: 214–220, 1998Google Scholar
- 24.Aguiar-Passeti T, Postol E, Sorg C, Mariano M: Epithelioid cells from foreign-body granuloma selectively express the calcium-binding protein MRP-14, a novel down-regulatory molecule of macrophage activation. J Leukoc Biol 62: 852–858, 1997Google Scholar
- 25.Siegenthaler G, Roulin K, Chatellard-Gruaz D, Hotz R, Saurat JH, Hellman U, Hagens G: A heterocomplex formed by the calcium-binding proteins MRP8 (S100A8) and MRP14 (S100A9) binds unsaturated fatty acids with high affinity. J Biol Chem 272: 9371–9377, 1997Google Scholar