. _:b472092378 . _:b472092151 . . _:b472092131 . _:b472092389 . _:b472092388 . _:b472092391 . . _:b472092390 . _:b472092087 . _:b472092385 . _:b472092384 . . _:b472092387 . _:b472092386 . . _:b472092397 . _:b472092396 . _:b472092399 . . _:b472092327 . _:b472092200 . _:b472092398 . _:b472092167 . _:b472092393 . _:b472092202 . _:b472092086 . _:b472092392 . _:b472092395 . _:b12444258 . _:b472092179 . _:b472092394 . _:b472092405 . _:b472092404 . . _:b472092559 . . _:b472092407 . _:b472092406 . _:b472092173 . . _:b472092401 . _:b472092400 . _:b12444220 . _:b472092403 . _:b12444221 . . _:b472092402 . . _:b12444222 . _:b472092413 . _:b472092596 . _:b12444223 . _:b472092412 . . _:b472092415 . . _:b472092253 . _:b472092414 . . _:b12444218 . _:b472092409 . . . _:b12444219 . _:b472092408 . _:b12444228 . _:b472092411 . _:b12444229 . _:b472092410 . . _:b12444230 . _:b472092161 . _:b12444231 . . _:b12444224 . . _:b12444225 . _:b12444263 . _:b12444226 . _:b12444227 . _:b12444236 . . _:b12444237 . _:b12444238 . _:b472092129 . _:b12444239 . _:b12444232 . _:b12444233 . _:b12444234 . _:b472092353 . . _:b12444235 . _:b472092176 . . . _:b12444244 . _:b12444245 . _:b472092499 . _:b12444246 . _:b472092128 . . _:b472092554 . _:b472092561 . _:b12444247 . _:b472092295 . _:b12444240 . _:b472092419 . _:b12444241 . _:b472092218 . _:b472092473 . _:b12444242 . _:b12444243 . . _:b12444252 . . _:b12444253 . _:b472092328 . _:b12444254 . _:b472092405 . _:b12444255 . _:b12444248 . _:b12444272 "Enhanced expression of Arg-1 associated with TAMs was found in 3LL murine lung carcinoma [39], in the human papillomavirus E6/E7-expressing murine tumors [>>40<<] and in CD11b+/CD14\u2212 myeloid cells from renal carcinoma patients [41]." . _:b12444249 . . _:b12444250 . _:b12444251 . _:b12444260 . _:b12444261 . . . _:b12444262 . . _:b12444247 "materials and methods" . _:b12444263 . _:b12444256 . . _:b12444257 . . _:b472092163 . _:b12444258 . _:b472092097 . _:b12444259 . . . _:b12444268 . . _:b12444269 . . _:b12444270 . . . _:b12444271 . _:b472092438 . _:b12444264 . _:b12444265 . . _:b12444266 . _:b472092484 . _:b472092412 . _:b12444267 . _:b472092281 . _:b12444276 . _:b12444277 . . _:b12444278 . . _:b472092567 . _:b12444279 . _:b472092578 . _:b12444272 . . _:b472092139 . _:b12444273 . _:b472092133 . _:b12444274 . _:b472092468 . . _:b12444275 . . _:b472092109 . _:b472092152 . _:b12444284 . _:b12444285 . . _:b12444223 "M2-type macrophages from experimental tumors and various types of cancers express arginase-1 (Arg1), IL-10 and transforming growth factor beta 1 (TGF-\u03B21), support tumor invasion, angiogenesis and matrix remodelling [2], [3], [>>4<<]. The stromal signals influencing glioma progression are poorly known and are likely distinct from those implicated in non-nervous system cancers." . _:b12444286 . . _:b12444287 . . _:b12444280 . _:b472092532 . _:b12444281 . . _:b12444225 . _:b12444282 . _:b472092435 . _:b12444283 . . . . _:b472092478 . _:b472092290 . . . . _:b472092367 . . _:b472092592 . _:b472092334 . _:b12444281 "Depleting macrophages in tumors in CSF-1 null mice (Csf1op) delayed the angiogenic switch and malignant transition, whereas restoration of macrophages rescued the vessel phenotype in these tumors [>>29<<]. High-grade gliomas demonstrate the highest levels of tumor angiogenesis when compared to non-neural solid cancers. Numbers of infiltrating macrophages have been found to correlate with small vessel density and tumor grade [49]. We" . . . _:b472092221 . . _:b472092063 . _:b472092106 . . . . _:b472092101 . . . . . . _:b472092275 . . . _:b472092507 . . . . . _:b472092560 . . . . . . . . . _:b472092427 . _:b12444239 . _:b12444237 "Several glioma-secreted factors have been characterized as promoting microglial chemotaxis: macrophage colony-stimulating factor 1 [12], [14], granulocyte/macrophage colony-stimulating factor [15], hepatocyte growth factor [>>16<<] and monocyte chemotactic protein 3 [17]." . . _:b12444284 "Previous studies showed an important role of microglia-derived MT1-MMP in regulation of MMP-2 activity [>>21<<], [23]." . _:b472092340 . _:b472092416 . . _:b472092359 . "10.1371%2Fjournal.pone.0023902" . _:b472092103 . _:b12444273 "Enhanced expression of Arg-1 associated with TAMs was found in 3LL murine lung carcinoma [39], in the human papillomavirus E6/E7-expressing murine tumors [40] and in CD11b+/CD14\u2212 myeloid cells from renal carcinoma patients [>>41<<]. Cyclooxygenase-2 (COX-2) expression and prostaglandins (PGE) have been implicated in the development of many cancers [42] serving as pro-inflammatory mediators under some conditions, but having anti-inflammatory and immunosuppressive" . . _:b12444256 "The concept that macrophages play instructive roles in tumor growth by regulating cell motility, invasion, angiogenesis and immunomodulation has gained great attention over last years. [2], [>>28<<], [29]. Tumor-derived cytokines such as IL-4, IL-10, TGF-\u03B2, and M-CSF are believed to polarise tumor-infiltrating macrophages towards an M2 anti-inflammatory phenotype [30], [31]." . . _:b12444255 "The concept that macrophages play instructive roles in tumor growth by regulating cell motility, invasion, angiogenesis and immunomodulation has gained great attention over last years. [>>2<<], [28], [29]. Tumor-derived cytokines such as IL-4, IL-10, TGF-\u03B2, and M-CSF are believed to polarise tumor-infiltrating macrophages towards an M2 anti-inflammatory phenotype [30], [31]." . . . . _:b472092143 . _:b472092181 . _:b472092124 . _:b472092117 . _:b472092045 . _:b472092174 . _:b472092250 . _:b472092242 . _:b472092612 . . _:b472092047 . . _:b472092046 . . . _:b472092396 . _:b472092449 . . _:b472092060 . _:b472092547 . _:b472092178 . _:b472092053 . . . . _:b472092052 . _:b12444219 . _:b472092320 . _:b472092055 . . _:b12444287 "Despite of developments of new therapeutics, glioblastomas are difficult to treat due to frequent dysfunctions of tumor suppressors and oncogenes; the mean survival of patients with glioblastomas ranges between 1\u20132 years [51], [>>52<<]. Counteracting of brain macrophage accumulation and activation should be taken into account when considering the development of more effective therapy against malignant gliomas." . . _:b472092054 . _:b472092595 . _:b472092440 . . _:b472092375 . _:b472092049 . _:b472092510 . . . _:b472092048 . _:b472092215 . _:b472092226 . _:b472092051 . _:b472092050 . _:b472092471 . _:b472092061 . _:b472092060 . . _:b472092063 . . . _:b472092062 . _:b472092600 . . _:b472092053 . _:b472092057 . _:b12444218 "introduction" . _:b472092068 . _:b472092056 . _:b472092208 . _:b472092299 . _:b472092059 . _:b472092058 . _:b472092069 . _:b472092068 . _:b472092150 . _:b472092071 . _:b472092070 . . . _:b472092065 . _:b472092064 . _:b472092406 . . _:b472092067 . _:b12444276 . _:b472092066 . _:b472092077 . _:b472092076 . _:b472092066 . _:b472092079 . _:b472092078 . _:b472092493 . _:b472092391 . _:b472092073 . _:b472092126 . _:b472092072 . . _:b472092075 . _:b472092521 . _:b472092094 . _:b472092074 . . _:b472092317 . _:b12444231 "Microglial cells in tumors do not secrete cytokines critical in developing effective innate immune responses and an anti-tumor immune response is suppressed in glioma patients [9], [10], [>>11<<]. The presence of cells positively stained for CD163 and CD204, putative markers for \u201CM2\u201D macrophages [12], as well as myeloid-derived suppressor cell-like cells have been detected in glioma patients [13]. Several glioma-secreted factors" . _:b472092085 . . _:b472092084 . _:b472092087 . . _:b12444277 . _:b472092086 . _:b472092081 . _:b12444263 "Several experimental studies demonstrated that microglia contribute to glioma progression by secreting growth factors, angiogenic molecules, extracellular matrix\u2013degrading enzymes, and immunosuppressive factors [21], [22], [23], [>>24<<]. However, Galarneau et al. showed that ablation of CD11b cells (ganciclovir-treated B6 mice expressing a mutant form of HSV-1 TKmt-30 under CD11b promoter) increases glioma growth [32], a recent study demonstrated that ablation of CD11b" . _:b472092080 . . _:b472092343 . _:b472092083 . . _:b472092082 . . _:b472092347 . _:b472092093 . _:b472092092 . . . _:b472092095 . _:b472092252 . _:b472092094 . _:b472092089 . _:b472092088 . . _:b472092091 . . _:b472092090 . . _:b472092101 . _:b472092314 . _:b472092100 . . . . . _:b472092103 . _:b472092102 . _:b12444230 . _:b472092097 . _:b472092466 . _:b472092096 . _:b472092099 . _:b12444227 . . _:b472092098 . _:b472092109 . _:b472092271 . _:b472092108 . _:b472092111 . . _:b472092110 . _:b472092539 . _:b472092105 . _:b472092357 . _:b472092104 . _:b472092197 . _:b472092107 . _:b472092479 . _:b472092106 . . _:b472092117 . _:b472092116 . . _:b472092270 . _:b472092214 . _:b472092077 . _:b472092119 . _:b472092122 . . _:b472092118 . _:b472092379 . _:b472092550 . _:b472092113 . _:b472092446 . _:b472092112 . _:b472092520 . _:b472092115 . _:b472092049 . _:b472092321 . _:b472092114 . _:b472092318 . _:b472092125 . . . _:b472092124 . _:b12444245 "Furthermore, microglial cells secrete active TGF-\u03B21, which stimulates glioblastoma invasion [>>24<<]." . . _:b472092127 . . _:b472092126 . _:b472092121 . _:b472092120 . _:b472092501 . _:b472092123 . _:b472092421 . . _:b472092122 . _:b472092601 . _:b472092133 . . . _:b472092132 . _:b12444221 "M2-type macrophages from experimental tumors and various types of cancers express arginase-1 (Arg1), IL-10 and transforming growth factor beta 1 (TGF-\u03B21), support tumor invasion, angiogenesis and matrix remodelling [>>2<<], [3], [4]." . _:b472092191 . _:b472092135 . . _:b472092134 . _:b472092129 . . _:b472092128 . . _:b472092394 . _:b472092131 . _:b12444239 "Immunosuppressive properties of glioma cancer stem cells, producing CSF-1, TGF-\u03B21 and macrophage inhibitory cytokine, and inducing polarisation of recruited macrophages/microglia have been demonstrated [>>18<<], [19], [20]." . _:b472092130 . . _:b472092141 . _:b472092382 . _:b472092140 . . . _:b472092143 . _:b472092142 . _:b472092437 . _:b12444268 . . _:b472092137 . . _:b472092136 . _:b472092139 . . . . . _:b472092138 . _:b472092057 . . _:b472092149 . . _:b472092307 . _:b472092148 . . _:b472092151 . . _:b472092150 . _:b12444252 "Differences in the surface expression of CD11b and CD45 antigens on microglia (CD11b+/CD45low) and blood-derived macrophages (CD11b+/CD45high) isolated from tumor tissue permitted distinction of the two populations by flow cytometry [>>27<<]. We determined the relative contribution of resident and blood-derived cells to the Iba1-positive population within the tumor." . _:b472092588 . _:b472092145 . _:b472092470 . _:b472092201 . _:b472092144 . . . _:b472092147 . _:b472092146 . . _:b472092495 . _:b472092157 . _:b472092337 . _:b472092156 . . _:b472092159 . _:b472092564 . . . _:b472092158 . . _:b472092528 . _:b472092153 . . _:b12444236 . . _:b472092152 . . _:b472092155 . _:b472092323 . . _:b472092154 . _:b472092070 . _:b472092291 . . . . . _:b472092586 . . . _:b472092315 . . _:b472092447 . _:b472092408 . _:b472092236 . _:b12444256 . . _:b472092444 . _:b472092230 . . . . _:b472092553 . _:b472092078 . _:b472092524 . _:b472092199 . . _:b472092138 . . . . . _:b472092603 . _:b472092488 . _:b472092607 . . _:b472092225 . _:b12444218 _:b12444220 . _:b12444218 _:b12444221 . _:b472092113 . _:b12444218 _:b12444222 . _:b12444218 _:b12444223 . . _:b472092552 . _:b12444218 _:b12444219 . _:b12444262 . _:b472092272 . _:b472092069 . _:b12444218 _:b12444236 . _:b472092141 . _:b12444218 _:b12444237 . _:b472092216 . _:b12444218 _:b12444238 . . . _:b12444218 _:b12444239 . _:b12444218 _:b12444232 . _:b12444218 _:b12444233 . _:b12444218 _:b12444234 . _:b472092247 . _:b12444218 _:b12444235 . . _:b12444218 _:b12444228 . _:b12444218 _:b12444229 . _:b12444218 _:b12444230 . _:b12444218 _:b12444231 . _:b12444218 _:b12444224 . _:b12444218 _:b12444225 . _:b12444218 _:b12444226 . _:b472092072 . _:b12444218 _:b12444227 . . _:b472092374 . _:b12444218 _:b12444244 . . _:b12444218 _:b12444245 . _:b12444218 _:b12444246 . _:b472092401 . _:b12444218 _:b12444240 . _:b12444218 _:b12444241 . _:b12444218 _:b12444242 . _:b472092159 . _:b12444218 _:b12444243 . . . _:b472092177 . . _:b472092254 . . . . _:b472092123 . _:b472092452 . . _:b472092534 . . _:b12444229 . _:b472092246 . . _:b12444228 . _:b12444287 . . _:b12444285 . _:b472092494 . _:b472092257 . _:b472092443 . _:b12444252 . . _:b472092411 . . _:b472092155 . . _:b12444264 . . . . . . . . . _:b12444229 "Microglial cells in tumors do not secrete cytokines critical in developing effective innate immune responses and an anti-tumor immune response is suppressed in glioma patients [>>9<<], [10], [11]." . . . . . . . . . _:b472092047 "19"^^ . _:b472092134 . _:b472092045 "22"^^ . _:b472092046 "19"^^ . . _:b472092055 "11"^^ . _:b12444251 "results" . _:b12444264 "However, Galarneau et al. showed that ablation of CD11b cells (ganciclovir-treated B6 mice expressing a mutant form of HSV-1 TKmt-30 under CD11b promoter) increases glioma growth [>>32<<], a recent study demonstrated that ablation of CD11b in vivo (ganciclovir-treated CD11b-HSVTK mice) decreases tumor size and improves survival [33]." . _:b472092048 "19"^^ . _:b472092049 "15"^^ . _:b472092054 "12"^^ . _:b472092050 "15"^^ . _:b472092053 "12"^^ . . _:b472092052 "13"^^ . _:b12444244 . _:b472092051 "13"^^ . _:b12444218 . . _:b472092378 . _:b472092062 "9"^^ . _:b472092063 "9"^^ . _:b472092060 "9"^^ . _:b472092061 "9"^^ . _:b472092362 . _:b472092059 "10"^^ . _:b472092372 . _:b472092145 . _:b472092058 "10"^^ . _:b472092057 "10"^^ . _:b472092056 "11"^^ . . . _:b472092399 . _:b472092070 "8"^^ . _:b472092071 "8"^^ . _:b472092068 "8"^^ . . _:b472092069 "8"^^ . _:b472092306 . _:b472092066 "8"^^ . _:b472092346 . _:b472092067 "8"^^ . . _:b472092064 "9"^^ . _:b472092065 "9"^^ . _:b472092078 "7"^^ . _:b472092172 . _:b472092233 . _:b472092582 . _:b472092079 "7"^^ . _:b472092234 . _:b472092076 "7"^^ . _:b472092562 . _:b472092077 "7"^^ . . _:b472092583 . _:b472092074 "8"^^ . _:b12444254 . . _:b472092075 "8"^^ . . _:b12444251 . _:b472092072 "8"^^ . _:b472092052 . _:b472092392 . . _:b12444249 "Primary cultures of astrocytes were prepared from cerebral cortex of 2-day-old C57BL/6 newborn mice as described previously [>>25<<]. Astrocytes were cultured in DMEM with high glucose (GlutaMAX\u2122, Gibco) supplemented with 10% FBS, 100 U/ml penicillin and 100 \u00B5g/ml streptomycin." . _:b12444247 . _:b472092073 "8"^^ . . . _:b472092086 "7"^^ . . _:b472092087 "6"^^ . _:b472092092 . _:b472092084 "7"^^ . . _:b472092509 . _:b472092085 "7"^^ . _:b472092082 "7"^^ . _:b472092083 "7"^^ . . _:b12444274 . _:b472092080 "7"^^ . . . _:b472092081 "7"^^ . _:b472092094 "6"^^ . _:b472092410 . _:b472092095 "6"^^ . _:b472092092 "6"^^ . . . _:b12444269 "Expression of iNos and Arg-1 define classically and alternatively activated macrophages in the context of Th2-polarised immune responses [>>37<<], [38]. Enhanced expression of Arg-1 associated with TAMs was found in 3LL murine lung carcinoma [39], in the human papillomavirus E6/E7-expressing murine tumors [40] and in CD11b+/CD14\u2212 myeloid cells from renal carcinoma patients [41]." . _:b472092093 "6"^^ . . _:b472092090 "6"^^ . . _:b472092091 "6"^^ . . _:b472092088 "6"^^ . . _:b472092502 . _:b472092089 "6"^^ . _:b472092062 . _:b472092102 "6"^^ . . _:b472092103 "6"^^ . _:b472092100 "6"^^ . _:b472092101 "6"^^ . . _:b472092047 . . _:b472092098 "6"^^ . _:b472092409 . _:b12444254 _:b12444255 . . _:b472092099 "6"^^ . . _:b472092096 "6"^^ . _:b12444224 "gamma - IFN\u03B3) they are characterized by increased chemotaxis, production of inflammation mediators and cytokines, activation of the respiratory burst, and they become immune effector cells mediating both innate and adaptive responses [>>5<<], [6]. Histopathologic and flow cytometry studies of human glioma tissue have shown high intratumoral microglia density which correlates with the grade of malignancy [7], [8], [9]." . . _:b472092097 "6"^^ . _:b12444251 _:b12444252 . _:b472092109 "5"^^ . _:b12444251 _:b12444253 . _:b472092515 . _:b472092108 "6"^^ . _:b12444271 . _:b472092111 "5"^^ . . . . _:b12444238 . _:b12444254 _:b12444284 . _:b12444247 _:b12444248 . _:b472092110 "5"^^ . _:b12444247 _:b12444249 . _:b12444254 _:b12444285 . _:b472092384 . _:b12444247 _:b12444250 . _:b12444254 _:b12444286 . . _:b472092106 "6"^^ . _:b12444254 _:b12444287 . _:b12444249 . _:b12444254 _:b12444280 . _:b12444254 _:b12444281 . _:b472092107 "6"^^ . _:b12444254 _:b12444282 . _:b12444254 _:b12444283 . _:b12444254 _:b12444276 . _:b12444254 _:b12444277 . _:b472092104 "6"^^ . _:b12444254 _:b12444278 . _:b12444254 _:b12444279 . . _:b472092355 . _:b12444254 _:b12444272 . _:b12444254 _:b12444273 . _:b472092105 "6"^^ . _:b12444254 _:b12444274 . _:b12444254 _:b12444275 . _:b12444254 _:b12444268 . . _:b12444254 _:b12444269 . _:b12444254 _:b12444270 . _:b12444254 _:b12444271 . _:b12444254 _:b12444264 . _:b472092117 "5"^^ . _:b12444254 _:b12444265 . _:b12444254 _:b12444266 . _:b12444254 _:b12444267 . _:b12444254 _:b12444260 . _:b472092116 "5"^^ . . _:b12444254 _:b12444261 . _:b12444254 _:b12444262 . _:b12444254 _:b12444263 . _:b12444254 _:b12444256 . _:b472092119 "5"^^ . _:b12444254 _:b12444257 . _:b12444254 _:b12444258 . . _:b12444254 _:b12444259 . _:b472092118 "5"^^ . _:b472092107 . _:b472092113 "5"^^ . _:b472092112 "5"^^ . _:b12444266 . _:b472092115 "5"^^ . _:b472092114 "5"^^ . . _:b472092125 "5"^^ . _:b472092120 . _:b472092529 . . _:b472092124 "5"^^ . _:b472092127 "5"^^ . . . _:b472092126 "5"^^ . _:b472092121 "5"^^ . _:b472092120 "5"^^ . _:b472092123 "5"^^ . _:b472092602 . _:b472092122 "5"^^ . _:b12444231 . . _:b472092133 "4"^^ . . _:b12444228 "Histopathologic and flow cytometry studies of human glioma tissue have shown high intratumoral microglia density which correlates with the grade of malignancy [7], [8], [>>9<<]. Microglial cells in tumors do not secrete cytokines critical in developing effective innate immune responses and an anti-tumor immune response is suppressed in glioma patients [9], [10], [11]. The presence of cells positively stained for" . _:b472092132 "4"^^ . _:b12444283 . _:b472092135 "4"^^ . . _:b472092134 "4"^^ . . _:b472092129 "4"^^ . _:b472092128 "5"^^ . _:b472092131 "4"^^ . . . _:b472092130 "4"^^ . _:b472092475 . _:b472092141 "4"^^ . _:b472092140 "4"^^ . . _:b472092195 . _:b472092143 "4"^^ . . _:b472092142 "4"^^ . . . . _:b472092137 "4"^^ . _:b472092462 . _:b472092538 . . . _:b472092136 "4"^^ . _:b472092139 "4"^^ . _:b472092138 "4"^^ . _:b472092474 . _:b472092149 "4"^^ . _:b472092148 "4"^^ . _:b472092151 "4"^^ . _:b472092203 . _:b472092150 "4"^^ . . _:b472092145 "4"^^ . _:b472092144 "4"^^ . _:b472092594 . _:b472092147 "4"^^ . _:b472092485 . _:b472092146 "4"^^ . _:b12444227 "Histopathologic and flow cytometry studies of human glioma tissue have shown high intratumoral microglia density which correlates with the grade of malignancy [7], [>>8<<], [9]. Microglial cells in tumors do not secrete cytokines critical in developing effective innate immune responses and an anti-tumor immune response is suppressed in glioma patients [9], [10], [11]. The presence of cells positively" . _:b12444248 "GL261-glioma cells stably expressing pEGFP-N1 [>>21<<] obtained from Prof." . _:b472092157 "4"^^ . _:b472092156 "4"^^ . _:b472092144 . _:b472092159 "4"^^ . _:b472092158 "4"^^ . _:b472092153 "4"^^ . _:b472092429 . _:b472092190 . . _:b472092084 . . . _:b472092587 . _:b472092152 "4"^^ . _:b472092135 . . _:b472092155 "4"^^ . _:b12444232 . _:b12444220 "Recent experimental and pre-clinical studies show an important role of tumor-infiltrating macrophages in tumor growth, metastasis and response to cancer treatments [1], [>>2<<]. Tumor-associated macrophages are attracted by tumor-released molecules which induce reprogramming/differentiation of macrophages into anti-inflammatory cells known as alternatively activated, in contrast to inflammatory M1-type" . _:b12444279 . _:b472092154 "4"^^ . _:b472092589 . _:b12444234 . _:b472092229 . _:b12444236 "Several glioma-secreted factors have been characterized as promoting microglial chemotaxis: macrophage colony-stimulating factor 1 [12], [14], granulocyte/macrophage colony-stimulating factor [>>15<<], hepatocyte growth factor [16] and monocyte chemotactic protein 3 [17]." . . . _:b472092227 . _:b12444267 "The macrophagic expression of Arg-1 is tightly regulated by exogenous stimuli such as IL-4 and IL-13 [>>35<<]. L-arginine depletion due to extensive myeloid arginase activity may suppress T cell immune responses [36]. Expression of iNos and Arg-1 define classically and alternatively activated macrophages in the context of Th2-polarised immune" . _:b472092326 . _:b472092115 . . _:b12444261 . . _:b472092288 . _:b12444250 . . _:b472092570 . . _:b472092577 . _:b472092565 . _:b472092517 . _:b472092387 . _:b472092265 . _:b472092140 . . _:b472092141 . _:b472092142 . _:b472092143 . _:b472092136 . _:b472092137 . _:b472092537 . _:b472092138 . _:b472092139 . _:b472092132 . _:b472092133 . _:b472092134 . _:b472092168 . _:b472092135 . . _:b472092128 . _:b472092129 . _:b472092480 . _:b472092130 . _:b472092131 . _:b472092156 . _:b472092157 . _:b472092158 . _:b472092159 . _:b472092152 . . _:b472092153 . _:b472092154 . . _:b472092155 . _:b472092148 . . _:b472092149 . _:b472092150 . . _:b472092151 . _:b472092144 . . _:b472092145 . _:b472092459 . _:b472092146 . _:b472092147 . _:b472092108 . _:b472092109 . . _:b472092110 . _:b472092428 . _:b472092111 . _:b472092104 . _:b472092105 . _:b472092106 . _:b472092107 . _:b472092100 . _:b472092101 . _:b472092102 . _:b472092103 . _:b472092096 . _:b472092398 . _:b472092097 . _:b472092608 . _:b472092098 . _:b472092268 . _:b472092099 . _:b472092124 . _:b472092125 . _:b472092126 . _:b472092127 . _:b472092120 . _:b472092121 . _:b472092122 . _:b472092123 . _:b472092116 . _:b472092117 . _:b472092118 . _:b472092119 . . _:b472092112 . . _:b472092113 . _:b472092114 . _:b472092115 . _:b472092076 . _:b472092077 . _:b472092078 . _:b472092079 . _:b472092072 . _:b472092073 . . _:b472092074 . . _:b472092075 . _:b472092068 . _:b472092069 . _:b472092070 . _:b472092071 . _:b472092064 . _:b472092065 . _:b472092066 . _:b472092067 . _:b472092092 . _:b472092093 . _:b472092094 . _:b472092450 . _:b472092095 . _:b472092088 . _:b472092089 . _:b472092090 . _:b472092091 . _:b472092084 . _:b472092085 . _:b472092086 . _:b472092087 . . _:b472092080 . _:b472092081 . _:b472092082 . _:b472092316 . _:b472092083 . _:b472092045 . _:b472092046 . _:b472092047 . . . . _:b472092503 . _:b472092060 . _:b472092061 . _:b472092062 . _:b472092063 . _:b472092514 . _:b472092056 . _:b472092057 . _:b472092058 . . _:b472092059 . _:b472092052 . . _:b472092053 . _:b472092054 . _:b12444243 . _:b472092055 . _:b472092048 . . _:b472092049 . _:b472092050 . _:b472092051 . _:b12444223 . _:b472092308 . _:b12444283 "Evaluation of implanted GL261 mouse gliomas by MR microimaging indicated blood-brain barrier disruption already in early-stage of tumors (1\u20132 week) [>>50<<]. Thus intraperitoneally administered CsA can easily penetrate brain parenchyma." . _:b472092303 . _:b472092061 . _:b12444246 . . _:b472092579 . . . _:b472092243 . . . _:b472092363 . _:b472092296 . . _:b472092184 . . _:b12444257 "[2], [28], [>>29<<]. Tumor-derived cytokines such as IL-4, IL-10, TGF-\u03B2, and M-CSF are believed to polarise tumor-infiltrating macrophages towards an M2 anti-inflammatory phenotype [30], [31]." . _:b12444253 . _:b472092188 . _:b12444286 . _:b472092118 . _:b472092156 . _:b472092241 . _:b472092164 . _:b472092064 . . . _:b472092606 . _:b472092568 . . . _:b472092153 . _:b472092182 . _:b472092364 . . _:b12444285 "Previous studies showed an important role of microglia-derived MT1-MMP in regulation of MMP-2 activity [21], [>>23<<]." . . _:b472092146 . _:b472092045 . . _:b472092506 . . . . _:b472092212 . . . _:b472092490 . . _:b472092244 . . . . . _:b472092283 . _:b472092319 . . _:b472092157 . _:b472092309 . _:b472092147 . . . _:b12444241 "Immunosuppressive properties of glioma cancer stem cells, producing CSF-1, TGF-\u03B21 and macrophage inhibitory cytokine, and inducing polarisation of recruited macrophages/microglia have been demonstrated [18], [19], [>>20<<]." . . _:b472092180 . _:b12444279 "A chemokine CXCL14 was identified as a chemoattractant for monocytes [46], and can induce dendritic cell migration and maturation [>>47<<], [48]. The enhanced expression of cxcl14 in glioma-infiltrating CD11b+ cells could be involved in macrophage infiltration or their differentiation. Down-regulation of cxcl14 expression in CsA-treated mice correlates with reduced CD11b+" . _:b472092508 . _:b472092456 . _:b472092051 . . . . _:b472092287 . . _:b472092535 . . _:b472092305 . _:b472092083 . . . _:b472092389 . _:b472092255 . _:b472092516 . _:b12444286 "Despite of developments of new therapeutics, glioblastomas are difficult to treat due to frequent dysfunctions of tumor suppressors and oncogenes; the mean survival of patients with glioblastomas ranges between 1\u20132 years [>>51<<], [52]. Counteracting of brain macrophage accumulation and activation should be taken into account when considering the development of more effective therapy against malignant gliomas." . . . . _:b12444261 "Several experimental studies demonstrated that microglia contribute to glioma progression by secreting growth factors, angiogenic molecules, extracellular matrix\u2013degrading enzymes, and immunosuppressive factors [21], [>>22<<], [23], [24]." . . _:b472092472 . _:b472092096 . . _:b12444274 "Cyclooxygenase-2 (COX-2) expression and prostaglandins (PGE) have been implicated in the development of many cancers [>>42<<] serving as pro-inflammatory mediators under some conditions, but having anti-inflammatory and immunosuppressive properties under other conditions [43]." . . _:b472092111 . _:b472092219 . _:b472092352 . . _:b472092591 . _:b472092585 . _:b472092376 . _:b472092422 . _:b472092310 . _:b472092301 . _:b12444250 "Arginase activity was determined in brain tissue extracts using a colorimetric method based on the conversion of L-arginine to L-ornithine as described [>>26<<]. Optical density of ornithine-ninhydrin complexes formed in the samples was measured using a microplate reader at 515 nm." . . . . _:b472092279 . _:b12444269 . _:b472092555 . . _:b472092082 . . _:b12444226 . _:b472092209 . _:b472092612 . . _:b472092613 . _:b472092614 . _:b472092249 . _:b472092608 . _:b472092609 . _:b472092610 . _:b472092611 . _:b472092284 . _:b472092588 . _:b472092589 . _:b472092590 . _:b472092591 . _:b472092584 . _:b472092585 . _:b472092586 . . _:b472092587 . . _:b472092580 . . _:b472092581 . _:b472092582 . _:b472092583 . _:b472092576 . _:b472092577 . _:b472092578 . _:b472092579 . _:b472092604 . _:b472092605 . _:b472092523 . _:b472092606 . . _:b472092607 . _:b472092600 . _:b472092601 . _:b472092602 . _:b472092603 . _:b472092596 . _:b472092266 . _:b472092597 . _:b472092414 . _:b472092598 . _:b472092599 . _:b472092592 . . _:b472092593 . . _:b472092594 . . _:b472092595 . _:b472092556 . _:b472092557 . _:b472092558 . _:b472092559 . _:b472092552 . _:b472092553 . _:b472092554 . _:b472092555 . _:b472092548 . _:b472092549 . _:b472092550 . _:b472092551 . _:b472092544 . _:b472092545 . _:b472092546 . _:b472092547 . _:b472092572 . . _:b472092573 . . _:b472092574 . _:b472092575 . _:b472092071 . _:b472092568 . _:b472092544 . _:b472092569 . _:b472092570 . . _:b472092276 . _:b472092571 . _:b472092564 . . _:b472092565 . _:b472092566 . _:b472092455 . _:b472092567 . _:b472092560 . _:b472092076 . _:b472092561 . _:b472092562 . _:b472092563 . _:b472092524 . _:b472092525 . _:b472092526 . _:b472092527 . _:b472092520 . _:b472092521 . _:b472092522 . _:b472092523 . _:b472092089 . _:b472092516 . _:b472092351 . _:b472092517 . _:b472092518 . _:b472092519 . _:b472092512 . _:b472092513 . _:b472092514 . _:b472092515 . _:b472092540 . _:b472092609 . _:b472092541 . _:b472092542 . _:b472092543 . _:b472092536 . _:b472092537 . _:b472092538 . _:b472092259 . _:b472092539 . _:b472092532 . _:b472092533 . . _:b472092534 . _:b472092535 . _:b472092528 . _:b472092529 . _:b472092530 . _:b472092531 . _:b472092492 . _:b472092493 . _:b472092494 . _:b472092495 . _:b472092488 . . _:b472092489 . _:b472092490 . _:b472092491 . _:b472092484 . _:b472092485 . _:b472092486 . _:b472092487 . _:b472092480 . _:b472092481 . _:b472092482 . _:b472092483 . _:b472092556 . _:b472092508 . _:b472092509 . _:b472092510 . _:b472092511 . . _:b472092504 . _:b472092505 . _:b472092506 . _:b472092507 . _:b472092500 . _:b472092501 . _:b472092502 . _:b472092503 . . _:b472092496 . _:b472092497 . _:b472092498 . _:b472092499 . _:b472092460 . _:b472092207 . _:b472092461 . _:b472092462 . _:b472092463 . . _:b472092456 . _:b472092457 . . _:b472092458 . _:b472092459 . _:b472092452 . _:b472092453 . _:b472092454 . _:b472092455 . _:b472092448 . _:b472092449 . . . _:b472092450 . _:b472092451 . _:b472092476 . _:b472092477 . _:b12444243 "Experimental studies using brain organotypic slices depleted of microglia, genetic models of microglia ablation and microglia-glioma co-cultures pinpoint a pro-invasive role of glioma-infiltrating microglia [21], [>>22<<]. Glioma-exposed microglia release metalloproteinase MT1-MMP which activates a latent metalloproteinase 2 (pro-MMP-2) produced by glioma cells that promotes tumor invasion, as was shown using brain slices from MT1-MMP-deficient mice and in" . _:b472092478 . _:b472092614 . _:b472092479 . _:b472092451 . _:b472092472 . _:b472092473 . _:b472092474 . _:b472092475 . _:b472092468 . _:b472092469 . _:b472092470 . _:b472092471 . _:b472092464 . _:b472092465 . _:b472092466 . . _:b472092467 . _:b472092381 . _:b472092428 . _:b472092429 . _:b472092439 . _:b472092430 . _:b472092431 . _:b472092112 . _:b472092424 . _:b472092425 . _:b472092426 . _:b472092427 . _:b472092420 . _:b472092421 . _:b472092422 . _:b472092423 . _:b472092416 . . _:b472092417 . _:b472092418 . _:b472092419 . _:b472092444 . _:b472092445 . _:b472092446 . _:b472092447 . _:b472092440 . _:b472092441 . _:b472092442 . _:b472092443 . . _:b472092436 . _:b472092437 . _:b472092438 . _:b472092439 . _:b472092432 . _:b472092433 . _:b472092434 . _:b472092573 . _:b472092435 . _:b472092165 "4"^^ . _:b472092396 . _:b472092397 . _:b472092398 . _:b472092399 . _:b472092164 "4"^^ . _:b472092392 . _:b472092393 . _:b472092394 . _:b472092395 . _:b472092167 "4"^^ . _:b472092388 . _:b472092389 . _:b472092390 . _:b472092391 . _:b472092166 "4"^^ . _:b472092384 . _:b472092385 . _:b472092386 . _:b472092387 . _:b472092161 "4"^^ . _:b472092412 . _:b472092413 . _:b472092414 . _:b472092415 . _:b472092160 "4"^^ . _:b472092408 . _:b472092533 . . _:b472092409 . _:b472092410 . _:b472092411 . _:b472092163 "4"^^ . _:b472092404 . _:b472092405 . _:b472092406 . _:b472092407 . _:b472092162 "4"^^ . . _:b472092400 . _:b472092401 . _:b472092402 . _:b472092173 "3"^^ . _:b472092403 . _:b472092364 . _:b12444280 . _:b472092365 . _:b472092366 . _:b472092172 "3"^^ . _:b472092575 . _:b472092367 . _:b472092194 . _:b472092360 . _:b472092361 . _:b472092149 . _:b472092362 . _:b472092175 "3"^^ . _:b472092363 . _:b472092418 . _:b472092356 . _:b12444237 . _:b472092357 . _:b472092358 . _:b472092174 "3"^^ . _:b472092359 . _:b472092352 . _:b472092353 . _:b472092354 . _:b472092169 "3"^^ . _:b472092355 . _:b472092380 . _:b472092381 . _:b472092382 . _:b472092383 . _:b472092168 "4"^^ . _:b472092376 . _:b472092377 . _:b472092378 . _:b472092171 "3"^^ . _:b472092379 . _:b472092372 . _:b472092373 . . . . . _:b472092374 . _:b472092170 "3"^^ . _:b472092375 . . _:b472092368 . _:b472092369 . _:b472092370 . _:b472092181 "3"^^ . _:b472092371 . _:b472092332 . _:b472092333 . . _:b472092334 . _:b472092180 "3"^^ . _:b472092335 . _:b472092433 . _:b472092328 . _:b472092371 . _:b472092329 . _:b472092330 . _:b472092183 "3"^^ . _:b472092331 . . _:b472092324 . _:b472092325 . _:b472092273 . . _:b472092182 "3"^^ . _:b472092326 . _:b472092327 . _:b472092320 . _:b472092321 . . _:b472092177 "3"^^ . _:b472092322 . _:b472092323 . _:b472092348 . _:b472092140 . _:b472092349 . _:b472092350 . _:b472092176 "3"^^ . _:b472092351 . _:b472092344 . _:b472092345 . _:b472092081 . _:b472092346 . _:b472092179 "3"^^ . _:b472092347 . _:b472092340 . _:b472092341 . _:b472092342 . _:b472092178 "3"^^ . _:b472092343 . _:b472092336 . _:b472092337 . _:b472092338 . _:b472092189 "3"^^ . _:b472092339 . _:b472092300 . _:b12444259 "Tumor-derived cytokines such as IL-4, IL-10, TGF-\u03B2, and M-CSF are believed to polarise tumor-infiltrating macrophages towards an M2 anti-inflammatory phenotype [30], [>>31<<]. Mechanisms of accumulation and a role of microglia/macrophages in glioma pathobiology are still poorly understood and controversial. Several experimental studies demonstrated that microglia contribute to glioma progression by secreting" . _:b472092333 . _:b472092301 . _:b472092302 . _:b472092350 . _:b472092188 "3"^^ . _:b472092303 . _:b472092296 . _:b472092297 . _:b472092298 . _:b472092191 "3"^^ . _:b472092299 . _:b472092292 . _:b472092293 . _:b12444266 "The relevance of this finding for human pathology is unclear, because although human astrocytoma and glioblastoma cell lines produce GM-CSF, no evidence of its production by glioblastoma cells was found in vivo [>>34<<]. Our findings suggest that GM-CSF and IL-10 could be important cytokines for establishment of a pro-invasive phenotype of glioma-infiltrating microglia/macrophages." . _:b472092294 . _:b472092190 "3"^^ . _:b472092295 . _:b472092302 . _:b472092288 . . _:b472092289 . . _:b472092185 "3"^^ . _:b472092290 . _:b472092291 . _:b472092175 . _:b472092316 . _:b472092317 . _:b472092318 . _:b472092184 "3"^^ . _:b472092319 . _:b472092312 . _:b472092313 . _:b472092314 . _:b472092187 "3"^^ . _:b472092315 . _:b472092308 . _:b472092365 . _:b472092309 . _:b472092310 . _:b472092186 "3"^^ . _:b472092311 . _:b472092304 . . _:b472092305 . _:b472092306 . _:b472092197 "3"^^ . _:b472092307 . _:b472092268 . _:b472092269 . _:b472092270 . _:b472092541 . _:b472092196 "3"^^ . _:b472092271 . _:b472092264 . _:b12444233 . _:b472092265 . . _:b472092266 . _:b472092487 . _:b472092199 "3"^^ . _:b472092267 . _:b472092260 . . _:b472092261 . _:b472092262 . _:b472092198 "3"^^ . _:b472092263 . . _:b472092256 . _:b472092257 . . _:b472092258 . _:b472092193 "3"^^ . _:b472092259 . _:b472092284 . _:b472092285 . _:b472092286 . _:b472092192 "3"^^ . _:b472092287 . . _:b472092280 . _:b472092281 . _:b472092282 . _:b472092195 "3"^^ . _:b472092283 . _:b472092048 . _:b472092276 . _:b472092349 . _:b472092454 . _:b472092277 . . _:b472092278 . _:b472092194 "3"^^ . _:b472092279 . _:b472092458 . _:b472092272 . _:b472092273 . _:b472092274 . _:b472092205 "3"^^ . _:b472092275 . _:b472092236 . _:b472092237 . _:b472092251 . _:b472092238 . _:b472092204 "3"^^ . _:b472092239 . _:b472092098 . _:b472092232 . _:b472092233 . _:b472092234 . _:b472092207 "3"^^ . _:b472092235 . _:b472092228 . _:b472092229 . _:b472092230 . _:b472092206 "3"^^ . _:b472092231 . _:b472092224 . _:b472092225 . _:b472092226 . _:b472092201 "3"^^ . _:b472092227 . _:b472092252 . _:b472092253 . . _:b472092254 . _:b472092200 "3"^^ . _:b472092255 . _:b472092248 . _:b12444281 . _:b472092432 . _:b472092249 . _:b472092250 . _:b472092203 "3"^^ . _:b472092251 . _:b472092116 . _:b472092519 . _:b472092244 . _:b472092245 . _:b472092246 . _:b472092202 "3"^^ . _:b472092247 . _:b472092213 . _:b472092240 . _:b472092241 . _:b472092242 . _:b472092469 . _:b472092213 "3"^^ . _:b472092243 . _:b472092204 . _:b472092205 . _:b472092206 . _:b472092212 "3"^^ . _:b472092207 . _:b472092330 . _:b472092200 . _:b472092201 . _:b472092202 . _:b472092215 "3"^^ . _:b472092203 . _:b472092196 . _:b472092197 . _:b472092093 . _:b472092513 . _:b472092214 "3"^^ . _:b472092198 . _:b472092199 . _:b472092192 . _:b472092193 . _:b472092220 . _:b472092194 . _:b472092209 "3"^^ . _:b472092195 . _:b472092298 . . _:b472092220 . _:b472092221 . _:b472092222 . _:b472092205 . _:b472092208 "3"^^ . _:b472092223 . _:b472092216 . _:b472092217 . _:b472092218 . _:b472092211 "3"^^ . . _:b472092219 . _:b472092212 . _:b472092213 . _:b472092214 . _:b472092210 "3"^^ . _:b472092215 . _:b472092208 . _:b472092370 . _:b472092258 . _:b472092209 . _:b472092210 . _:b472092221 "3"^^ . _:b472092211 . _:b472092172 . _:b472092055 . _:b472092217 . _:b472092173 . _:b472092174 . _:b472092220 "3"^^ . _:b472092175 . . _:b472092168 . . _:b472092169 . _:b472092170 . _:b472092223 "3"^^ . _:b472092171 . _:b472092164 . _:b472092165 . _:b472092166 . _:b472092545 . _:b472092222 "3"^^ . _:b472092167 . _:b472092160 . _:b472092256 . _:b472092161 . _:b472092162 . _:b472092217 "3"^^ . . _:b472092163 . _:b472092188 . _:b472092445 . _:b472092189 . _:b472092190 . _:b472092216 "3"^^ . _:b472092191 . . _:b472092184 . _:b472092185 . _:b472092186 . _:b472092219 "3"^^ . _:b472092187 . _:b472092180 . _:b472092181 . _:b472092426 . _:b472092182 . _:b472092218 "3"^^ . . _:b472092183 . _:b472092176 . _:b472092177 . _:b472092178 . _:b472092229 "3"^^ . _:b472092179 . _:b472092228 "3"^^ . . _:b472092231 "3"^^ . . _:b472092230 "3"^^ . _:b472092225 "3"^^ . _:b472092421 . _:b472092292 . _:b472092504 . . _:b472092420 . _:b472092224 "3"^^ . . _:b12444257 . _:b472092227 "3"^^ . _:b472092121 . _:b472092423 . . _:b12444275 . _:b472092148 . . _:b472092226 "3"^^ . _:b472092422 . _:b472092237 "3"^^ . _:b472092417 . . _:b472092434 . _:b472092236 "3"^^ . _:b472092416 . _:b472092239 "3"^^ . _:b472092419 . . _:b472092080 . _:b472092238 "3"^^ . _:b472092418 . . _:b472092262 . _:b472092429 . _:b472092233 "3"^^ . _:b472092232 "3"^^ . _:b472092428 . _:b472092369 . _:b472092431 . _:b472092235 "3"^^ . _:b472092572 . _:b12444219 "Recent experimental and pre-clinical studies show an important role of tumor-infiltrating macrophages in tumor growth, metastasis and response to cancer treatments [>>1<<], [2]. Tumor-associated macrophages are attracted by tumor-released molecules which induce reprogramming/differentiation of macrophages into anti-inflammatory cells known as alternatively activated, in contrast to inflammatory M1-type" . _:b472092234 "3"^^ . _:b472092430 . _:b472092245 "3"^^ . _:b472092425 . _:b472092244 "3"^^ . _:b472092424 . . . _:b472092247 "3"^^ . . _:b472092427 . . _:b472092246 "3"^^ . _:b472092426 . . . _:b12444242 "Experimental studies using brain organotypic slices depleted of microglia, genetic models of microglia ablation and microglia-glioma co-cultures pinpoint a pro-invasive role of glioma-infiltrating microglia [>>21<<], [22]. Glioma-exposed microglia release metalloproteinase MT1-MMP which activates a latent metalloproteinase 2 (pro-MMP-2) produced by glioma cells that promotes tumor invasion, as was shown using brain slices from MT1-MMP-deficient mice" . _:b472092241 "3"^^ . _:b472092437 . _:b472092240 "3"^^ . _:b472092436 . . _:b472092286 . . _:b472092243 "3"^^ . _:b472092439 . _:b472092204 . _:b472092238 . . _:b472092242 "3"^^ . _:b472092438 . _:b472092253 "2"^^ . _:b472092433 . _:b472092224 . _:b472092252 "2"^^ . _:b472092432 . _:b472092255 "2"^^ . _:b472092435 . . _:b472092254 "2"^^ . . _:b472092434 . _:b472092525 . _:b472092445 . _:b472092249 "3"^^ . _:b472092248 "3"^^ . _:b472092444 . _:b472092251 "2"^^ . _:b472092447 . _:b12444271 "Enhanced expression of Arg-1 associated with TAMs was found in 3LL murine lung carcinoma [>>39<<], in the human papillomavirus E6/E7-expressing murine tumors [40] and in CD11b+/CD14\u2212 myeloid cells from renal carcinoma patients [41]." . _:b472092280 . _:b472092250 "3"^^ . _:b472092446 . _:b472092360 . _:b472092211 . . _:b472092261 "2"^^ . _:b472092441 . . _:b472092260 "2"^^ . _:b472092440 . . _:b472092263 "2"^^ . _:b472092443 . _:b472092262 "2"^^ . _:b472092237 . _:b472092483 . _:b472092442 . . _:b472092453 . _:b472092257 "2"^^ . _:b472092453 . _:b472092598 . _:b472092256 "2"^^ . _:b472092452 . _:b472092110 . . _:b472092137 . _:b472092259 "2"^^ . _:b472092455 . _:b12444235 "Several glioma-secreted factors have been characterized as promoting microglial chemotaxis: macrophage colony-stimulating factor 1 [12], [>>14<<], granulocyte/macrophage colony-stimulating factor [15], hepatocyte growth factor [16] and monocyte chemotactic protein 3 [17]." . _:b472092258 "2"^^ . _:b472092454 . _:b472092402 . _:b472092557 . _:b472092269 "2"^^ . _:b472092449 . _:b472092341 . _:b472092268 "2"^^ . _:b472092448 . _:b472092271 "2"^^ . _:b472092451 . _:b472092467 . . _:b472092270 "2"^^ . _:b472092450 . _:b472092265 "2"^^ . _:b472092461 . . _:b472092264 "2"^^ . _:b472092460 . _:b472092267 "2"^^ . _:b472092463 . _:b12444225 "- IFN\u03B3) they are characterized by increased chemotaxis, production of inflammation mediators and cytokines, activation of the respiratory burst, and they become immune effector cells mediating both innate and adaptive responses [5], [>>6<<]. Histopathologic and flow cytometry studies of human glioma tissue have shown high intratumoral microglia density which correlates with the grade of malignancy [7], [8], [9]." . _:b472092266 "2"^^ . _:b472092462 . _:b472092526 . _:b472092277 "2"^^ . _:b472092457 . _:b472092477 . _:b472092276 "2"^^ . _:b472092571 . _:b472092456 . _:b472092425 . _:b472092279 "2"^^ . _:b472092459 . _:b472092261 . _:b472092278 "2"^^ . _:b472092458 . _:b472092273 "2"^^ . _:b472092469 . _:b472092272 "2"^^ . _:b472092468 . _:b472092275 "2"^^ . _:b472092471 . _:b12444232 "The presence of cells positively stained for CD163 and CD204, putative markers for \u201CM2\u201D macrophages [>>12<<], as well as myeloid-derived suppressor cell-like cells have been detected in glioma patients [13]." . _:b472092274 "2"^^ . . _:b472092470 . . _:b472092285 "2"^^ . _:b472092465 . _:b472092605 . _:b472092284 "2"^^ . _:b472092464 . _:b472092196 . _:b472092287 "2"^^ . _:b472092467 . _:b472092248 . _:b472092286 "2"^^ . _:b472092466 . _:b472092281 "2"^^ . _:b472092489 . _:b472092477 . _:b472092280 "2"^^ . _:b472092476 . _:b472092283 "2"^^ . . _:b472092479 . _:b12444278 . _:b472092368 . _:b472092282 "2"^^ . _:b472092478 . _:b12444254 "discussion" . _:b472092293 "2"^^ . . . _:b472092473 . _:b12444255 . _:b472092312 . _:b472092292 "2"^^ . _:b472092431 . _:b472092472 . . _:b472092295 "2"^^ . _:b472092475 . _:b472092294 "2"^^ . _:b472092474 . _:b472092154 . _:b472092289 "2"^^ . _:b472092485 . _:b472092417 . _:b472092288 "2"^^ . _:b472092593 . _:b472092484 . _:b472092291 "2"^^ . _:b472092487 . _:b472092290 "2"^^ . _:b472092486 . . _:b472092301 "2"^^ . _:b472092481 . . _:b472092300 "2"^^ . _:b472092480 . _:b12444282 "Numbers of infiltrating macrophages have been found to correlate with small vessel density and tumor grade [>>49<<]. We observed an increase in microglia/macrophage infiltration and the development of a dense vessel network in implanted gliomas (not shown). Furthermore, early treatment with CsA inhibited vessel network development in tumor-bearing mice." . _:b472092303 "2"^^ . _:b472092483 . . _:b472092302 "2"^^ . _:b472092482 . . _:b472092297 "2"^^ . _:b472092493 . . _:b472092296 "2"^^ . _:b472092492 . _:b472092299 "2"^^ . . _:b472092495 . _:b472092298 "2"^^ . _:b472092494 . _:b472092309 "2"^^ . _:b472092489 . _:b472092074 . _:b472092308 "2"^^ . _:b472092488 . _:b472092311 "2"^^ . _:b472092183 . _:b472092491 . _:b472092310 "2"^^ . _:b472092490 . _:b472092305 "2"^^ . _:b472092501 . _:b472092304 "2"^^ . _:b472092500 . _:b472092307 "2"^^ . _:b472092503 . _:b472092306 "2"^^ . _:b472092502 . _:b472092317 "2"^^ . _:b472092590 . _:b472092497 . _:b472092395 . _:b472092316 "2"^^ . _:b472092496 . . _:b472092319 "2"^^ . _:b472092499 . . . _:b472092318 "2"^^ . _:b472092498 . _:b472092313 "2"^^ . _:b472092509 . _:b472092312 "2"^^ . _:b472092508 . . _:b472092315 "2"^^ . _:b472092511 . _:b12444221 . . _:b472092314 "2"^^ . _:b472092510 . _:b12444220 . . . _:b472092325 "2"^^ . . _:b472092505 . _:b472092580 . _:b472092324 "2"^^ . _:b472092504 . _:b472092327 "2"^^ . _:b472092231 . _:b472092274 . _:b472092507 . _:b472092326 "2"^^ . _:b472092506 . _:b472092321 "2"^^ . _:b472092517 . . _:b472092320 "2"^^ . _:b472092516 . _:b472092100 . _:b472092323 "2"^^ . . _:b472092519 . _:b472092322 "2"^^ . _:b472092518 . _:b472092189 . _:b472092333 "2"^^ . _:b472092513 . _:b472092491 . . _:b472092332 "2"^^ . _:b472092512 . _:b472092335 "2"^^ . . _:b472092186 . . _:b472092515 . . _:b472092232 . _:b472092334 "2"^^ . _:b12444222 . . _:b472092514 . _:b472092329 "2"^^ . . _:b472092525 . _:b472092328 "2"^^ . _:b472092423 . _:b472092524 . _:b472092185 . . . _:b472092331 "2"^^ . . _:b472092527 . . _:b472092330 "2"^^ . _:b472092526 . _:b472092581 . _:b472092341 "2"^^ . _:b472092521 . _:b472092340 "2"^^ . _:b472092520 . . . _:b472092343 "2"^^ . _:b472092523 . . _:b472092342 "2"^^ . _:b472092522 . _:b472092337 "2"^^ . _:b472092533 . _:b472092336 "2"^^ . _:b472092532 . _:b472092354 . _:b472092339 "2"^^ . _:b12444272 . _:b472092535 . _:b472092338 "2"^^ . _:b472092534 . _:b472092349 "2"^^ . _:b472092529 . _:b12444224 . _:b472092348 "2"^^ . _:b472092277 . _:b472092528 . _:b472092351 "2"^^ . _:b472092531 . _:b472092350 "2"^^ . _:b472092530 . . . _:b472092345 "2"^^ . _:b472092541 . . . . _:b472092344 "2"^^ . _:b472092540 . . _:b472092347 "2"^^ . _:b472092119 . _:b472092543 . _:b472092346 "2"^^ . . _:b472092542 . _:b472092357 "2"^^ . _:b472092537 . _:b472092102 . _:b472092356 "2"^^ . _:b472092536 . _:b472092359 "2"^^ . _:b472092539 . . . _:b472092358 "2"^^ . _:b472092538 . . _:b472092353 "2"^^ . _:b472092549 . _:b472092352 "2"^^ . _:b472092548 . _:b472092355 "2"^^ . _:b472092551 . _:b472092354 "2"^^ . _:b472092088 . _:b472092550 . _:b472092365 "2"^^ . _:b472092545 . _:b472092364 "2"^^ . _:b472092544 . _:b12444248 . _:b12444240 . . _:b472092367 "2"^^ . . _:b472092547 . _:b472092366 "2"^^ . _:b472092546 . . _:b472092361 "2"^^ . _:b472092557 . _:b472092566 . _:b472092360 "2"^^ . _:b472092380 . _:b12444230 "Microglial cells in tumors do not secrete cytokines critical in developing effective innate immune responses and an anti-tumor immune response is suppressed in glioma patients [9], [>>10<<], [11]. The presence of cells positively stained for CD163 and CD204, putative markers for \u201CM2\u201D macrophages [12], as well as myeloid-derived suppressor cell-like cells have been detected in glioma patients [13]. Several glioma-secreted" . _:b472092556 . _:b472092363 "2"^^ . _:b472092075 . _:b472092559 . _:b472092362 "2"^^ . _:b472092558 . _:b12444242 . . _:b472092373 "2"^^ . _:b472092553 . _:b472092169 . _:b472092372 "2"^^ . _:b472092552 . _:b472092375 "2"^^ . . _:b472092555 . . _:b12444276 "Stimulation of PGE2 signalling in dendritic cells facilitates their migration and maturation, while in T cells potently suppresses activation and proliferation [>>44<<]. The observed up-regulation of cox2 mRNA in CD11b+ cells corroborates with a study showing the macrophagic expression of COX-2 and enhanced production of PGE1 by glioma-derived factors [45]. A chemokine CXCL14 was identified as a" . _:b472092374 "2"^^ . _:b472092554 . _:b472092369 "2"^^ . _:b472092565 . _:b472092368 "2"^^ . _:b472092564 . _:b472092371 "2"^^ . _:b472092567 . . _:b472092370 "2"^^ . _:b472092566 . _:b12444262 "Several experimental studies demonstrated that microglia contribute to glioma progression by secreting growth factors, angiogenic molecules, extracellular matrix\u2013degrading enzymes, and immunosuppressive factors [21], [22], [>>23<<], [24]. However, Galarneau et al. showed that ablation of CD11b cells (ganciclovir-treated B6 mice expressing a mutant form of HSV-1 TKmt-30 under CD11b promoter) increases glioma growth [32], a recent study demonstrated that ablation of" . _:b472092385 . _:b472092381 "2"^^ . . _:b472092561 . _:b472092073 . _:b472092380 "2"^^ . . _:b472092560 . _:b472092050 . _:b472092383 "2"^^ . _:b472092563 . . _:b472092382 "2"^^ . _:b472092562 . _:b472092278 . _:b472092377 "2"^^ . _:b472092573 . _:b472092463 . _:b472092376 "2"^^ . _:b472092572 . _:b472092090 . _:b472092222 . _:b472092379 "2"^^ . _:b472092575 . _:b472092378 "2"^^ . _:b472092574 . . _:b472092389 "2"^^ . _:b472092569 . _:b472092331 . _:b12444268 "L-arginine depletion due to extensive myeloid arginase activity may suppress T cell immune responses [>>36<<]. Expression of iNos and Arg-1 define classically and alternatively activated macrophages in the context of Th2-polarised immune responses [37], [38]. Enhanced expression of Arg-1 associated with TAMs was found in 3LL murine lung carcinoma" . _:b472092388 "2"^^ . _:b472092568 . _:b472092391 "2"^^ . _:b472092571 . _:b472092390 "2"^^ . _:b472092570 . _:b472092385 "2"^^ . _:b472092581 . _:b472092384 "2"^^ . _:b472092580 . _:b12444260 . . . _:b472092387 "2"^^ . _:b472092158 . _:b472092583 . . _:b472092386 "2"^^ . _:b472092582 . _:b12444241 . _:b472092397 "2"^^ . _:b472092415 . _:b472092577 . _:b472092396 "2"^^ . _:b472092576 . _:b472092399 "2"^^ . _:b472092579 . _:b472092398 "2"^^ . _:b472092136 . _:b472092578 . _:b472092393 "2"^^ . _:b472092448 . _:b472092589 . _:b12444222 "M2-type macrophages from experimental tumors and various types of cancers express arginase-1 (Arg1), IL-10 and transforming growth factor beta 1 (TGF-\u03B21), support tumor invasion, angiogenesis and matrix remodelling [2], [>>3<<], [4]. The stromal signals influencing glioma progression are poorly known and are likely distinct from those implicated in non-nervous system cancers. Microglia are brain resident macrophages, which respond to pathogens or injury in the" . _:b472092392 "2"^^ . _:b472092588 . _:b12444284 . . . . _:b472092395 "2"^^ . _:b472092356 . _:b472092591 . _:b472092198 . _:b472092394 "2"^^ . _:b472092590 . . _:b472092405 "2"^^ . _:b472092585 . _:b12444270 . . _:b472092404 "2"^^ . _:b472092584 . _:b472092407 "2"^^ . _:b472092587 . _:b472092406 "2"^^ . _:b472092586 . . . _:b472092401 "2"^^ . _:b472092543 . _:b472092597 . . . _:b472092400 "2"^^ . . _:b472092596 . _:b472092099 . _:b472092403 "2"^^ . . _:b472092599 . _:b472092160 . _:b472092402 "2"^^ . _:b472092598 . _:b472092413 "2"^^ . _:b472092593 . _:b472092412 "2"^^ . _:b472092592 . _:b472092282 . _:b472092386 . . _:b472092397 . _:b472092415 "2"^^ . _:b472092595 . _:b472092414 "2"^^ . . _:b472092594 . _:b472092409 "2"^^ . _:b472092605 . _:b12444265 "expressing a mutant form of HSV-1 TKmt-30 under CD11b promoter) increases glioma growth [32], a recent study demonstrated that ablation of CD11b in vivo (ganciclovir-treated CD11b-HSVTK mice) decreases tumor size and improves survival [>>33<<]." . _:b472092408 "2"^^ . _:b472092604 . _:b472092411 "2"^^ . _:b472092607 . _:b472092336 . _:b472092410 "2"^^ . _:b472092606 . . _:b472092421 "2"^^ . _:b472092289 . _:b472092601 . _:b472092420 "2"^^ . _:b472092600 . . _:b472092423 "2"^^ . . _:b472092603 . _:b472092422 "2"^^ . _:b472092602 . _:b472092417 "2"^^ . . _:b472092613 . _:b472092416 "2"^^ . _:b472092612 . _:b472092419 "2"^^ . _:b472092481 . _:b472092418 "2"^^ . . _:b472092614 . _:b472092429 "2"^^ . _:b472092609 . _:b472092329 . _:b472092428 "2"^^ . _:b472092608 . _:b472092095 . _:b472092431 "2"^^ . . _:b472092611 . . _:b472092430 "2"^^ . . _:b472092610 . _:b472092425 "2"^^ . _:b472092424 "2"^^ . _:b472092427 "2"^^ . _:b472092426 "2"^^ . _:b472092610 . _:b472092437 "2"^^ . _:b472092436 "2"^^ . _:b472092439 "2"^^ . _:b472092438 "2"^^ . _:b472092433 "2"^^ . _:b472092432 "2"^^ . _:b472092435 "2"^^ . . _:b472092434 "2"^^ . _:b472092445 "2"^^ . _:b472092403 . _:b472092444 "2"^^ . . _:b472092447 "2"^^ . _:b472092446 "2"^^ . _:b472092441 "2"^^ . . _:b472092440 "2"^^ . . _:b472092443 "2"^^ . . _:b472092442 "2"^^ . . _:b472092453 "2"^^ . _:b472092452 "2"^^ . . _:b472092455 "2"^^ . . _:b472092091 . _:b472092454 "2"^^ . _:b472092335 . _:b472092449 "2"^^ . _:b472092448 "2"^^ . _:b472092451 "2"^^ . _:b472092388 . _:b472092054 . _:b472092450 "2"^^ . _:b472092604 . _:b472092461 "2"^^ . . _:b472092460 "2"^^ . _:b472092463 "2"^^ . _:b472092462 "2"^^ . _:b472092457 "2"^^ . . _:b472092456 "2"^^ . _:b12444233 "The presence of cells positively stained for CD163 and CD204, putative markers for \u201CM2\u201D macrophages [12], as well as myeloid-derived suppressor cell-like cells have been detected in glioma patients [>>13<<]. Several glioma-secreted factors have been characterized as promoting microglial chemotaxis: macrophage colony-stimulating factor 1 [12], [14], granulocyte/macrophage colony-stimulating factor [15], hepatocyte growth factor [16] and" . . _:b472092459 "2"^^ . _:b472092498 . _:b472092458 "2"^^ . _:b472092056 . . _:b472092469 "2"^^ . _:b472092404 . _:b472092468 "2"^^ . _:b472092127 . _:b472092471 "2"^^ . _:b472092470 "2"^^ . _:b472092584 . _:b472092079 . _:b472092465 "2"^^ . _:b472092464 "2"^^ . _:b472092467 "2"^^ . _:b472092466 "2"^^ . _:b472092358 . _:b472092477 "2"^^ . _:b472092476 "2"^^ . _:b472092193 . _:b472092479 "2"^^ . . _:b472092478 "2"^^ . _:b472092473 "2"^^ . _:b472092518 . _:b472092472 "2"^^ . _:b472092304 . _:b472092475 "2"^^ . _:b12444235 . _:b472092474 "2"^^ . . _:b472092485 "2"^^ . _:b12444259 . _:b472092484 "2"^^ . _:b472092487 "2"^^ . _:b472092486 "2"^^ . . . _:b472092481 "2"^^ . _:b472092165 . _:b472092536 . _:b472092104 . _:b472092480 "2"^^ . _:b472092164 . _:b472092522 . _:b472092125 . _:b472092390 . _:b472092483 "2"^^ . _:b472092167 . . . _:b472092482 "2"^^ . _:b472092166 . . _:b472092493 "2"^^ . _:b472092161 . _:b472092492 "2"^^ . _:b472092160 . _:b12444265 . _:b472092495 "2"^^ . _:b472092163 . _:b472092285 . _:b472092494 "2"^^ . _:b472092162 . _:b472092489 "2"^^ . _:b472092173 . . _:b472092488 "2"^^ . _:b472092172 . . _:b472092491 "2"^^ . _:b472092175 . . _:b472092490 "2"^^ . _:b472092174 . . _:b472092501 "2"^^ . _:b472092169 . _:b472092500 "2"^^ . . _:b472092168 . . _:b472092503 "2"^^ . _:b472092171 . _:b472092502 "2"^^ . _:b472092170 . _:b472092497 "2"^^ . _:b472092181 . . _:b472092546 . _:b472092373 . _:b472092496 "2"^^ . _:b472092180 . _:b472092499 "2"^^ . _:b472092183 . _:b472092498 "2"^^ . _:b472092182 . _:b472092235 . _:b472092509 "2"^^ . _:b472092177 . _:b472092508 "2"^^ . _:b472092176 . _:b472092511 "2"^^ . _:b472092179 . _:b472092297 . _:b472092510 "2"^^ . _:b472092245 . . _:b472092178 . . _:b472092505 "2"^^ . _:b472092189 . _:b472092504 "2"^^ . _:b472092496 . _:b472092188 . _:b472092345 . _:b472092507 "2"^^ . _:b472092191 . _:b12444234 "Several glioma-secreted factors have been characterized as promoting microglial chemotaxis: macrophage colony-stimulating factor 1 [>>12<<], [14], granulocyte/macrophage colony-stimulating factor [15], hepatocyte growth factor [16] and monocyte chemotactic protein 3 [17]." . _:b472092506 "2"^^ . _:b472092190 . . _:b472092517 "2"^^ . _:b472092263 . _:b472092185 . _:b12444226 "Histopathologic and flow cytometry studies of human glioma tissue have shown high intratumoral microglia density which correlates with the grade of malignancy [>>7<<], [8], [9]." . _:b472092516 "2"^^ . _:b472092184 . _:b472092540 . _:b472092519 "2"^^ . _:b472092187 . _:b12444273 . . _:b472092518 "2"^^ . _:b472092186 . _:b12444278 "A chemokine CXCL14 was identified as a chemoattractant for monocytes [>>46<<], and can induce dendritic cell migration and maturation [47], [48]." . _:b472092513 "2"^^ . _:b472092197 . _:b472092512 "2"^^ . _:b472092196 . _:b472092325 . _:b472092576 . _:b472092515 "2"^^ . _:b472092199 . _:b472092187 . _:b472092424 . _:b472092514 "2"^^ . _:b472092460 . _:b472092198 . _:b472092511 . _:b472092527 . . _:b472092525 "2"^^ . _:b472092193 . _:b472092524 "2"^^ . . _:b472092192 . _:b472092527 "2"^^ . _:b472092195 . _:b472092526 "2"^^ . _:b472092194 . _:b472092521 "2"^^ . _:b472092205 . _:b472092520 "2"^^ . _:b472092204 . . _:b472092523 "2"^^ . _:b472092207 . _:b472092522 "2"^^ . _:b472092206 . . _:b472092497 . . . _:b472092533 "2"^^ . _:b472092201 . _:b472092532 "2"^^ . _:b472092200 . . _:b472092085 . _:b472092535 "2"^^ . _:b472092203 . _:b472092534 "2"^^ . _:b472092202 . . . _:b472092529 "2"^^ . _:b472092213 . . _:b472092528 "2"^^ . . _:b472092212 . _:b12444258 "Tumor-derived cytokines such as IL-4, IL-10, TGF-\u03B2, and M-CSF are believed to polarise tumor-infiltrating macrophages towards an M2 anti-inflammatory phenotype [>>30<<], [31]. Mechanisms of accumulation and a role of microglia/macrophages in glioma pathobiology are still poorly understood and controversial. Several experimental studies demonstrated that microglia contribute to glioma progression by" . _:b472092531 "2"^^ . _:b472092215 . . . _:b472092530 "2"^^ . _:b472092214 . _:b472092541 "2"^^ . _:b472092209 . _:b472092540 "2"^^ . _:b472092208 . _:b472092574 . . _:b472092543 "2"^^ . . _:b472092211 . . _:b472092542 "2"^^ . _:b472092210 . . _:b472092563 . _:b472092537 "2"^^ . _:b472092221 . . . . _:b472092464 . _:b472092536 "2"^^ . . _:b472092132 . _:b472092220 . . _:b472092539 "2"^^ . . . _:b472092223 . . _:b472092344 . _:b472092538 "2"^^ . _:b472092222 . _:b12444277 "The observed up-regulation of cox2 mRNA in CD11b+ cells corroborates with a study showing the macrophagic expression of COX-2 and enhanced production of PGE1 by glioma-derived factors [>>45<<]. A chemokine CXCL14 was identified as a chemoattractant for monocytes [46], and can induce dendritic cell migration and maturation [47], [48]. The enhanced expression of cxcl14 in glioma-infiltrating CD11b+ cells could be involved in" . _:b472092549 "2"^^ . _:b472092217 . _:b472092548 "2"^^ . _:b472092216 . _:b472092551 "2"^^ . _:b472092219 . _:b12444267 . _:b472092550 "2"^^ . _:b472092218 . _:b472092531 . _:b472092545 "2"^^ . _:b472092229 . _:b472092544 "2"^^ . _:b472092228 . _:b472092339 . _:b472092547 "2"^^ . _:b472092231 . _:b472092058 . . . _:b472092546 "2"^^ . _:b472092230 . _:b472092611 . _:b472092557 "2"^^ . _:b472092225 . . _:b472092413 . _:b472092556 "2"^^ . . _:b472092224 . _:b472092559 "2"^^ . _:b472092227 . _:b472092558 "2"^^ . _:b472092226 . _:b12444240 "Immunosuppressive properties of glioma cancer stem cells, producing CSF-1, TGF-\u03B21 and macrophage inhibitory cytokine, and inducing polarisation of recruited macrophages/microglia have been demonstrated [18], [>>19<<], [20]." . _:b472092553 "2"^^ . _:b472092237 . _:b472092552 "2"^^ . _:b472092236 . _:b472092548 . _:b472092555 "2"^^ . _:b472092239 . _:b472092554 "2"^^ . _:b472092238 . _:b472092565 "2"^^ . . . _:b472092233 . _:b472092564 "2"^^ . . _:b472092232 . _:b472092264 . _:b472092567 "2"^^ . _:b472092235 . _:b472092566 "2"^^ . _:b472092234 . _:b472092482 . _:b472092561 "2"^^ . _:b472092436 . _:b472092245 . _:b472092560 "2"^^ . _:b472092244 . _:b472092400 . _:b472092563 "2"^^ . _:b472092247 . _:b472092562 "2"^^ . _:b472092246 . . _:b12444275 "and prostaglandins (PGE) have been implicated in the development of many cancers [42] serving as pro-inflammatory mediators under some conditions, but having anti-inflammatory and immunosuppressive properties under other conditions [>>43<<]. Stimulation of PGE2 signalling in dendritic cells facilitates their migration and maturation, while in T cells potently suppresses activation and proliferation [44]." . _:b472092573 "2"^^ . _:b472092239 . _:b472092241 . _:b472092572 "2"^^ . _:b472092240 . _:b472092575 "2"^^ . _:b472092243 . _:b472092366 . _:b472092574 "2"^^ . _:b472092569 . _:b472092242 . . _:b472092569 "2"^^ . _:b472092253 . _:b472092568 "2"^^ . _:b472092252 . . _:b472092571 "2"^^ . _:b472092255 . _:b472092570 "2"^^ . _:b472092254 . _:b12444282 . _:b472092130 . _:b472092492 . _:b472092581 "2"^^ . _:b472092249 . _:b472092580 "2"^^ . _:b472092248 . _:b472092583 "2"^^ . _:b472092251 . _:b472092582 "2"^^ . _:b472092250 . _:b472092577 "2"^^ . _:b472092261 . _:b472092599 . _:b472092576 "2"^^ . _:b472092260 . _:b472092361 . _:b472092579 "2"^^ . . _:b472092263 . _:b472092578 "2"^^ . _:b472092262 . _:b472092165 . _:b472092589 "2"^^ . _:b472092223 . _:b472092257 . _:b472092588 "2"^^ . _:b472092256 . _:b472092591 "2"^^ . _:b472092259 . _:b12444246 "To interfere with glioma-microglia interactions, we used cyclosporine A (CsA) which has been shown to reduce microglia activation and invasion of glioma cells in vitro and in organotypic brain slices [>>22<<]. Systemically-applied CsA inhibits microglia/macrophage infiltration, induces cell death of infiltrating cells and blocks expression/activity of enzymes and cytokines, important for the establishment of a pro-invasive phenotype of" . . _:b472092590 "2"^^ . _:b472092258 . _:b472092585 "2"^^ . _:b472092269 . _:b472092584 "2"^^ . _:b472092166 . _:b472092268 . _:b472092486 . . _:b472092587 "2"^^ . _:b472092348 . _:b472092271 . _:b472092558 . _:b472092586 "2"^^ . _:b472092270 . _:b472092597 "2"^^ . _:b472092377 . _:b472092265 . _:b472092596 "2"^^ . _:b472092457 . . _:b472092264 . _:b472092599 "2"^^ . _:b472092267 . _:b472092598 "2"^^ . _:b472092266 . _:b472092593 "2"^^ . _:b472092277 . . _:b472092592 "2"^^ . . _:b472092276 . _:b472092595 "2"^^ . _:b472092279 . _:b472092594 "2"^^ . . _:b12444244 "metalloproteinase MT1-MMP which activates a latent metalloproteinase 2 (pro-MMP-2) produced by glioma cells that promotes tumor invasion, as was shown using brain slices from MT1-MMP-deficient mice and in a microglia depletion model [>>23<<]. Furthermore, microglial cells secrete active TGF-\u03B21, which stimulates glioblastoma invasion [24]." . _:b472092278 . _:b472092142 . _:b472092605 "2"^^ . _:b472092549 . _:b472092273 . _:b472092604 "2"^^ . . _:b472092272 . . _:b472092607 "2"^^ . _:b472092275 . _:b12444260 "Several experimental studies demonstrated that microglia contribute to glioma progression by secreting growth factors, angiogenic molecules, extracellular matrix\u2013degrading enzymes, and immunosuppressive factors [>>21<<], [22], [23], [24]." . _:b472092606 "2"^^ . . _:b472092274 . _:b472092505 . _:b472092601 "2"^^ . _:b472092285 . _:b472092600 "2"^^ . _:b472092284 . _:b472092603 "2"^^ . _:b472092461 . _:b472092287 . _:b472092171 . _:b472092300 . _:b472092602 "2"^^ . _:b472092286 . _:b472092613 "2"^^ . . _:b472092281 . _:b472092612 "2"^^ . _:b472092280 . . _:b472092430 . _:b472092283 . _:b472092614 "2"^^ . . _:b472092282 . _:b472092609 "2"^^ . _:b472092293 . _:b472092162 . _:b472092608 "2"^^ . . _:b472092292 . _:b472092611 "2"^^ . _:b472092465 . _:b472092295 . _:b472092610 "2"^^ . _:b472092294 . _:b472092046 . _:b472092289 . _:b472092288 . _:b472092338 . _:b472092291 . _:b472092500 . . _:b472092290 . _:b472092301 . _:b472092300 . _:b472092303 . . _:b472092302 . . _:b472092297 . . _:b472092296 . _:b472092267 . _:b472092108 . _:b472092299 . _:b472092298 . . _:b472092309 . _:b472092308 . _:b472092105 . _:b472092311 . _:b472092476 . _:b472092310 . _:b472092305 . . . _:b472092304 . _:b472092307 . _:b472092269 . _:b12444270 "Expression of iNos and Arg-1 define classically and alternatively activated macrophages in the context of Th2-polarised immune responses [37], [>>38<<]. Enhanced expression of Arg-1 associated with TAMs was found in 3LL murine lung carcinoma [39], in the human papillomavirus E6/E7-expressing murine tumors [40] and in CD11b+/CD14\u2212 myeloid cells from renal carcinoma patients [41]." . _:b472092306 . _:b472092317 . _:b12444280 "A chemokine CXCL14 was identified as a chemoattractant for monocytes [46], and can induce dendritic cell migration and maturation [47], [>>48<<]. The enhanced expression of cxcl14 in glioma-infiltrating CD11b+ cells could be involved in macrophage infiltration or their differentiation. Down-regulation of cxcl14 expression in CsA-treated mice correlates with reduced CD11b+ cell" . _:b472092293 . _:b472092316 . _:b472092319 . _:b472092407 . _:b472092318 . . _:b472092313 . _:b472092312 . _:b472092530 . _:b472092315 . _:b472092442 . _:b472092324 . _:b472092294 . _:b472092170 . _:b472092314 . _:b472092325 . . "PMC0" . . _:b472092324 . _:b472092327 . _:b472092441 . . . _:b472092326 . _:b472092228 . . _:b472092321 . _:b472092320 . _:b472092323 . _:b472092322 . _:b472092542 . . _:b472092333 . . _:b472092332 . _:b472092335 . _:b472092065 . _:b472092334 . . _:b472092329 . _:b472092328 . . _:b472092313 . _:b472092331 . _:b472092330 . _:b472092393 . _:b472092341 . . . _:b472092340 . _:b472092343 . _:b472092332 . _:b472092342 . _:b472092597 . _:b472092322 . _:b472092337 . _:b472092336 . _:b472092512 . _:b472092339 . . _:b12444238 "have been characterized as promoting microglial chemotaxis: macrophage colony-stimulating factor 1 [12], [14], granulocyte/macrophage colony-stimulating factor [15], hepatocyte growth factor [16] and monocyte chemotactic protein 3 [>>17<<]. Immunosuppressive properties of glioma cancer stem cells, producing CSF-1, TGF-\u03B21 and macrophage inhibitory cytokine, and inducing polarisation of recruited macrophages/microglia have been demonstrated [18], [19], [20]." . _:b472092338 . _:b472092067 . _:b472092349 . . _:b472092348 . _:b12444253 "CsA effectively impairs the pro-invasive activity of microglia in vitro and in organotypic brain slices [>>22<<]. As kinetic studies indicated different phases of microglia and macrophage accumulation, CsA was injected starting from the 2nd or 8th day after tumor implantation." . _:b472092351 . _:b472092350 . . _:b472092345 . . . _:b472092344 . _:b472092347 . _:b472092206 . . _:b472092346 . _:b472092357 . _:b472092356 . _:b472092359 . . _:b472092192 . _:b472092358 . _:b472092311 . _:b472092353 . _:b472092352 . _:b472092355 . . _:b472092354 . _:b472092365 . _:b472092210 . . _:b472092364 . . . _:b472092420 . _:b472092367 . . _:b472092366 . _:b472092361 . _:b472092613 . _:b472092360 . _:b472092260 . _:b472092363 . . _:b472092362 . . _:b472092373 . . . . _:b472092383 . . _:b472092372 . . _:b472092375 . . _:b472092374 . _:b472092369 . _:b472092368 . _:b12444245 . _:b472092114 . _:b472092371 . _:b472092370 . _:b472092381 . _:b472092342 . _:b472092380 . . _:b472092383 . . . _:b472092382 . . _:b472092059 . . _:b472092377 . _:b472092240 . . _:b472092551 . _:b472092376 . . _:b472092379 .