Glioblastoma and endothelial cells cross-talk, mediated by SDF-1, enhances tumour invasion and endothelial proliferation by increasing expression of cathepsins B, S, and MMP-9.
Malignant glioma is characterized by rapid proliferation, high invasiveness into the surrounding brain and increased vascularity. The aim of the study was to explain the observation that glioblastoma invasion often occurs along existing vasculature, suggesting interactions between the two types of cells. Using the in vitro model, we demonstrate that co-culturing of U87 (human glioblastoma) cells with HMEC-1 (human microvascular endothelial) cells increases the invasiveness of the U87 cells. The enhanced invasiveness correlates with increased expression of MMP-9 in both U87 and HMEC-1 cells, increased expression of cysteine cathepsins B and S and down-regulation of endogenous cell adhesion molecule NCAM in U87 cells. On the other hand, U87 tumour cells significantly enhance the proliferation of co-cultured endothelial cells by a mechanism involving cathepsin B, but not cathepsin S. Furthermore, we demonstrated that increased cell expression and activity of MMP-9 in cell microenvironment is mediated via secretion of SDF-1 by HMEC-1 cells. Selective SDF-1 inhibition impaired the enhanced U87 cell invasion, mostly via down-regulation of MMP-9, but did not alter cathepsin B, although the latter is more relevant for the invasion of U87 cells in mono-culture. Taken together, our study suggests that glioblastoma cells may be attracted by endothelial cells, enhancing their proliferation and underlines the importance of SDF-1, cathepsin B and MMP-9 in the cross-talk between these cells in normoxic conditions. This notion contributes to better understanding and suggests further investigations of the paracrine mechanisms, regulating glioma angiogenesis.
Kenig
Sasa
S
Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Vecna Pot 111, Ljubljana, Slovenia. sasa.kenig@nib.si
Alonso
María Beatriz Durán
MB
Mueller
Margareta M
MM
Lah
Tamara T
TT
D001483:Base Sequence; D002401:Cathepsin B / Q000378:metabolism*; D002403:Cathepsins / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D015971:Gene Expression Regulation, Enzymologic; D005909:Glioblastoma / Q000503:physiopathology*; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D019899:Paracrine Communication; D011480:Protease Inhibitors / Q000494:pharmacology; D015854:Up-Regulation
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D011480:Protease Inhibitors; D002403:Cathepsins; D002401:Cathepsin B; C028217:cathepsin S; D020780:Matrix Metalloproteinase 9