Identification and localization of the cytokine SDF1 and its receptor, CXCchemokine receptor 4, to regions of necrosis and angiogenesis in human glioblastoma

Glioblastoma multiforme (GBM) tumors display extensive histomorphological h eterogeneity, with great variability in the extent of invasiveness, angioge nesis, and necrosis, The identification of genes associated with these phen otypes should further the molecular characterization, permitting better def inition of glioma subsets that may ultimately lead to better treatment stra tegies. Therefore, we performed a differential mRNA display analysis compar ing six GBM-derived primary cell cultures from patients having tumors with varied histomorphological features, We identified stromal cell-derived fact or 1 (SDF1) as a gene with varied expression. SDF1 (cytokine) and CXC chemo kine receptor 4 (CXCR4) interactions are implicated in modulating cell migr ation. They are also implicated in modulating the immune response in AIDS p atients by macrophage-mediated T-cell apoptosis, GEM patients also fail to mount an immune response, although their tumors are seemingly exposed to im mune cells in regions of angiogenesis, where the blood-brain barrier is abs ent, or in areas of necrosis, To determine whether the expression and local ization of SDF1 and CXCR4 are consistent with such a role in these brain tu mors, immunohistochemical analyses of these proteins were performed on norm al brain and astrocytomas (grades II-IV). In normal brain tissue, low level s of SDF1 (0.5+) were observed in astrocytic processes, in neurons, and in the occasional phagocytic cells around vessels. CXCR4 expression was negati ve in brain tissue but was observed in phagocytic cells within the vessel l umen. In tumors, SDF1 and CXCR4 expression was colocalized when both were e xpressed, and SDF1 and CXCR4 expression increased with increasing tumor gra de (from 0.5+ to 6+), Additionally, CXCR4 was expressed in neovessel endoth elial cells. The proteins were expressed in regions of angiogenesis and deg enerative, necrotic, and microcystic changes. Those tumors displaying great er amounts of these features had greater staining intensity of the proteins . The expression of SDF1 and CXCR4 did not colocalize with the proliferatio n marker MIB-1, Thus, our data suggest that SDF1 and CXCR4 expressions: (a) increase with increasing grade; (b) colocalize to regions within these tum ors where their interaction may contribute to angiogenesis and/or modulatio n of the immune response; and (c) may serve to characterize subsets of GBMs .