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

• Published in: Cancer letters Vol. 289; no. 1; pp. 53 - 61
• Main Authors: Kenig, Saša, Alonso, María Beatriz Durán, Mueller, Margareta M., Lah, Tamara T.
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 01.03.2010; Elsevier Limited
• Subjects: Angiogenesis; Base Sequence; Cancer; Cathepsin B - metabolism; Cathepsins - metabolism; Cell adhesion & migration; Cell culture; Cell Line, Tumor; Cell Proliferation - drug effects; Cells, Cultured; Chemokine CXCL12 - metabolism; Chemokines (CXCL12/SDF-1); Cysteine cathepsins; Endothelial Cells - cytology; Endothelial Cells - drug effects; Endothelial Cells - pathology; Enzyme-Linked Immunosorbent Assay; Enzymes; Gene expression; Gene Expression Regulation, Enzymologic; Glioblastoma - physiopathology; Glioblastoma invasion; Hematology, Oncology and Palliative Medicine; Humans; Matrix metalloproteases; Matrix Metalloproteinase 9 - metabolism; Molecular Sequence Data; Neoplasm Invasiveness; Paracrine Communication; Protease Inhibitors - pharmacology; Studies; Tumors; Up-Regulation; HIF; VEGF; SDF-1; Glioblastoma invasion; MIP1α; NGF; G-CSF; bFGF; Adhesion molecules: NCAM; Angiogenesis; Chemokines (CXCL12/SDF-1); GBM; Matrix metalloproteases; Cysteine cathepsins; GM-CSF; SF/HGF; TGFβ; Proteases and proteins: MMP; GAPDH; Cytokines: MCP-1; GF; TIMP; stromal-derived factor-1; transforming growth factor β; neural cell adhesion molecule; basic fibroblast growth factor; granulocyte-colony-stimulating factor; monocyte chemotactic protein-1; nerve growth factor; tissue inhibitor of metalloproteinases; growth factors; glyceraldehydes 3-phosphate dehydrogenise; scatter factor/hepatocyte growth factor; glioblastoma; vascular endothelial growth factor; hypoxia induced factor; granulocyte-macrophage colony-stimulating factor; matrix metalloproteinase; macrophage inflammatory protein 1alpha
• DOI: 10.1016/j.canlet.2009.07.014
• ISSN: 0304-3835; 1872-7980

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.