Stem cell niches in glioblastoma: a neuropathological view

Abstract

Glioblastoma (GBM) stem cells (GSCs), responsible for tumor growth, recurrence, and resistance to therapies, are considered the real therapeutic target, if they had no molecular mechanisms of resistance, in comparison with the mass of more differentiated cells which are insensitive to therapies just because of being differentiated and nonproliferating. GSCs occur in tumor niches where both stemness status and angiogenesis are conditioned by the microenvironment. In both perivascular and perinecrotic niches, hypoxia plays a fundamental role. Fifteen glioblastomas have been studied by immunohistochemistry and immunofluorescence for stemness and differentiation antigens. It has been found that circumscribed necroses develop inside hyperproliferating areas that are characterized by high expression of stemness antigens. Necrosis developed inside them because of the imbalance between the proliferation of tumor cells and endothelial cells; it reduces the number of GSCs to a thin ring around the former hyperproliferating area. The perinecrotic GSCs are nothing else that the survivors remnants of those populating hyperproliferating areas. In the tumor, GSCs coincide with malignant areas so that the need to detect where they are located is not so urgent.

Figure 1

(a) Infiltration area with many positive cells on vessels of different size, Nestin, DAB, 200x. (b) Transition area: medium size vessels with no cell around, GFAP, DAB, 100x. (c) Same area with many positive cells around vessels, Nestin, DAB, 100x. (d) Proliferation area: cuffing of tumor cells around vessels; GFAP+ cells are in an external position, DAB, 200x. (e) Id Nestin+ cells prevail and are located in the inner layer of the cuffing, DAB, 200x. (f) Hyperproliferating area with a circumscribed necrosis: most cells do not express GFAP, DAB, 100x. (g) The same area: the cells strongly express Nestin, DAB, 100x. (h) Id for GFAP, DAB, 400x, and (i) Nestin, DAB, 400x.

Figure 2

(a) Hyperproliferating area with a circumscribed necrosis devoid of vessels, CD34, DAB, 100x. (b) Circumscribed necrosis in a hypercellular area, H&E, 100x. (c) Hyperproliferating area strongly positive for SOX2, DAB, 100x. (d) Id for REST, DAB, 100x. (e) Id in a hyperproliferating area with high Ki-67/MIB.1 LI, DAB, 100x. (f) HIF-1-positive cells near a circumscribed necrosis, DAB, 200x.

Figure 3

(a) Hyperproliferating area with few cells expressing GFAP, IF, 200x. (b) Id with many cells expressing Nestin, 200x. (c) Merge. (d) Hyperproliferating areas with omission of CD133 antibody, 400x. (e) Hyperproliferating area with CD133 antibody. (f) Id with Musashi.1, 400x.