Tumour-derived CSF2/granulocyte macrophage colony stimulating factor controls myeloid cell accumulation and progression of gliomas

BACKGROUND: Malignant tumours release factors, which attract myeloid cells and induce their polarisation to pro-invasive, immunosuppressive phenotypes. Brain-resident microglia and peripheral macrophages accumulate in the tumour microenvironment of glioblastoma (GBM) and induce immunosuppression fostering tumour progression. Macrophage colony stimulating factors (CSFs) control the recruitment of myeloid cells during peripheral cancer progression, but it is disputable, which CSFs drive their accumulation in gliomas. METHODS: The expression of CSF2 (encoding granulocyte-macrophage colony stimulating factor) was determined in TCGA datasets and five human glioma cell lines. Effects of stable CSF2 knockdown in glioma cells or neutralising CSF2 or receptor CSF2Rα antibodies on glioma invasion were tested in vitro and in vivo. RESULTS: CSF2 knockdown or blockade of its signalling reduced microglia-dependent glioma invasion in microglia-glioma co-cultures. CSF2-deficient human glioma cells encapsulated in cell-impermeable hollow fibres and transplanted to mouse brains, failed to attract microglia, but stimulated astrocyte recruitment. CSF2-depleted gliomas were smaller, attracted less microglia and macrophages, and provided survival benefit in tumour-bearing mice. Apoptotic microglia/macrophages were detected in CSF2-depleted tumours. CONCLUSIONS: CSF2 is overexpressed in a subset of mesenchymal GBMs in association with high immune gene expression. Tumour-derived CSF2 attracts, supports survival and induces pro-tumorigenic polarisation of microglia and macrophages

Characteristics of the Alternative Phenotype of Microglia/Macrophages and its Modulation in Experimental Gliomas

Microglia (brain resident macrophages) accumulate in malignant gliomas and instead of initiating the anti-tumor response, they switch to a pro-invasive phenotype, support tumor growth, invasion, angiogenesis and immunosuppression by release of cytokines/chemokines and extracellular matrix proteases. Using immunofluorescence and flow cytometry, we demonstrate an early accumulation of activated microglia followed by accumulation of macrophages in experimental murine EGFP-GL261 gliomas. Those cells acquire the alternative phenotype, as evidenced by evaluation of the production of ten pro/anti-inflammatory cytokines and expression profiling of 28 genes in magnetically-sorted CD11b+ cells from tumor tissues. Furthermore, we show that infiltration of implanted gliomas by amoeboid, Iba1-positive cells can be reduced by a systematically injected cyclosporine A (CsA) two or eight days after cell inoculation. The up-regulated levels of IL-10 and GM-CSF, increased expression of genes characteristic for the alternative and pro-invasive phenotype (arg-1, mt1-mmp, cxcl14) in glioma-derived CD11b+ cells as well as enhanced angiogenesis and tumor growth were reduced in CsA-treated mice. Our findings define for the first time kinetics and biochemical characteristics of glioma-infiltrating microglia/macrophages. Inhibition of the alternative activation of tumor-infiltrating macrophages significantly reduced tumor growth. Thus, blockade of microglia/macrophage infiltration and their pro-invasive functions could be a novel therapeutic strategy in malignant gliomas

Neurogenne skostnienia heterotopowe – studium przypadku

The authors presented the case of a 30-year-old man in whom sudden cardiac arrest occurred as a result of high voltage electric shock. Starting from the 2nd week after the accident, rehabilitation was carried out in hospital conditions, designed to maintain range of motion in the joints, and from the 6th week, intensive rehabilitation was performed at the patient’s home. Despite the implemented treatment, total mobility restriction was observed in the hip joints, and based on spatial projection radiography and a CT, the patient was diagnosed with massive neurogenic heterotopic ossifi cation (NHO). Two surgeries were performed to remove the NHO: fi rst, from the left area (15th month after the accident), and then the right hip joint (18th month following the accident). After the intervention there was a signifi cant increase in mobility of both hips and a decrease in pain, which resulted in signifi cantly improved functional capabilities of the patient. In addition, prophylaxis to prevent the recurrence of NHO was implemented in order to maintain both passive and active range of motion, and the use of physical therapy treatments in the form of deep oscillation were performed. The results of the CT conducted in the 41st month following the accident revealed lesser NHO than the originally diagnosed. Rolka Ł., Browiński D., Kwiatek-Rolka K., Sielska M., Sielski G., Nyka W.M. Neurogenic heterotopic ossification – case study. Med Rehabil 2016; 20(4): 22-27. DOI: 10.5604/01.3001.0009.5482Obrzęki kończyn dolnych mogą być wynikiem nieprawidłowości budowy i funkcji układu chłonnego, urazów, zapalenia, mogą się też wiązać z chorobą nowotworową lub jej leczeniem, jednak coraz częściej są jednym z podstawowych objawów towarzyszących kobietom w III trymestrze ciąży, głównie na skutek zaburzeń w układzie żylnym. Celem pracy jest przedstawienie obecnego stanu wiedzy na temat czynników ryzyka, profilaktyki i leczenia obrzęków kończyn dolnych u kobiet w ciąży. Wśród czynników ryzyka obrzęku związanego z ciążą wymienia się: wzrost objętości krwi krążącej, powiększenie macicy, wzrost masy ciała oraz zmiany w gospodarce hormonalnej. Zaburzenia żylne powstają w wyniku nadciśnienia żylnego na skutek niewydolności pompy mięśniowej oraz niewydolności zastawek żylnych. Ciąża, wykonanie cięcia cesarskiego, okres połogu sprzyjają wystąpieniu zakrzepicy żylnej. Podstawową i niekwestionowaną metodą stosowaną w profilaktyce i leczeniu zaburzeń układu żylno-limfatycznego oraz ich powikłań jest kompresjoterapia, wykorzystująca bandażowanie kompresyjne oraz stosowanie produktów uciskowych. Ucisk może być stosowany samodzielnie lub w połączeniu z innymi metodami, np. z manualnym drenażem limfatycznym, przerywaną kompresją pneumatyczną, z ćwiczeniami fizycznymi i oddechowymi. Na podstawie badań naukowych oraz w oparciu o rekomendacje ekspertów, ucisk wydaje się też skutecznym rozwiązaniem w profilaktyce i leczeniu zakrzepicy żylnej i obrzęku kończyn dolnych u kobiet w ciąży, jednak wymaga dalszych badań zgodnych z zasadami evidence based medicine

Vascular niche IL-6 induces alternative macrophage activation in glioblastoma through HIF-2α

Macrophages in the tumour microenvironment (TME) acquire tumour-promoting functions upon M2 polarization. Here the authors show, in a mouse model of glioblastoma, that endothelial cells in the TME induce macrophage M2 polarization via IL-6 and that depletion of endothelial IL-6 improves survival