Pseudopalisades in Glioblastoma Are Hypoxic, Express Extracellular Matrix Proteases, and Are Formed by an Actively Migrating Cell Population

Abstract

Necrosis and vascular proliferation are the pathologic features that distinguish the most malignant infiltrative astrocytoma, glioblastoma (GBM), from those of lower grades. In GBM, hypercellular zones called pseudopalisades typically surround necrotic foci. Although these cells are known to secrete high levels of proangiogenic factors that promote tumor growth, their origins are ill defined. We propose that pseudopalisades represent differing stages and histologic samplings of astrocytoma cells migrating away from a hypoxic/anoxic focus, often triggered by a central vaso-occlusive event. This proposition is based on our findings that pseudopalisading cells are 5-50% less proliferative and 6 -20 times more apoptotic than adjacent astrocytoma, indicating that cell accumulation does not result from increased proliferation or resistance to apoptosis. Coexisting inflammatory cells account for <2% of pseudopalisading cells and cannot account for hypercellularity. Pseudopalisading cells show nuclear expression of hypoxia-inducible factor 1␣, consistent with their hypoxic nature, and hypoxia induces a 20 -60% increase in glioma cell migration in vitro. Hypoxic cells in vitro and pseudopalisades in GBM specimens show enhanced gelatinase activity, typical of an invasive phenotype. These results suggest that pseudopalisading cells are migrating at the periphery of a hypoxic center. To uncover a potential source of hypoxia and sequence of structural events leading to pseudopalisade formation, we performed a morphometric analysis of 234 pseudopalisades from 85 pretreatment GBMs. We found distorted, degenerating, or thrombosed blood vessels within the center of more than half the pseudopalisades, suggesting that at least a subset of pseudopalisades are two-dimensional histologic representations of tumor cells migrating away from a vaso-occlusive event.

Accessibilome of Human Glioblastoma: Collagen-VI-alpha-1 Is a New Target and a Marker of Poor Outcome

“…32 They are in a state of organized migration away from necrotic areas, featuring increased expression of proangiogenic factors, for example, VEGF, HIF1/2, and MMPs. 33 The current findings indicate that COL6A1 may be expressed by this particular class of glioma cells that master the evasion of hostile conditions and are probably at the core of glioma's ability to adapt and survive all therapies available today. In support of this is the present correlation analysis of patientsurvival and COL6A1 gene-expression, demonstrating a significant positive correlation between high COL6A1 levels and poor outcome of glioma patients in general and glioblastoma in specific.…”

Hypoxia can induce c‐Met expression in glioma cells and enhance SF/HGF‐induced cell migration

“…Another transcription factor that can activate the c-Met promoter under normoxic as Previous studies suggested that hypoxia can stimulate glioma cell migration and invasion, although the responsible mechanisms have so far remained unclear. [18][19][20] In this study we analyzed 3 glioblastoma cell lines in which c-Met was inducible by hypoxia. We found that hypoxia by itself stimulated the migration of only 1 of these cell lines (U87), but enhanced the motogenic effects of SF/HGF on all 3 cell lines.…”

“…14 Hypoxia has been found to also increase the migration of glioma cells, although the mechanisms of this stimulation have so far remained unclear. [18][19][20] We hypothesized that the induction of cMet via HIF-1 might be one such mechanism. We therefore analyzed (i) whether c-Met protein and mRNA are inducible by hypoxia in glioma cells, (ii) whether the hypoxic induction of c-Met is mediated through HIF-1a and (iii) whether hypoxia can enhance the effect of SF/HGF on glioma cell migration in vitro.…”

Hypoxia stimulates breast carcinoma cell invasion through MT1-MMP and MMP-2 activation

“…Interestingly, many reports have linked hypoxia with the regulation of expression and/or activity of members of the MMP family, including MT1-MMP (Canning et al, 2001;Burke et al, 2003;Brat et al, 2004;Fahling et al, 2004;Ridgway et al, 2005). However, some of these reports are contradictory, and tumor-and cell type-specific constraints may exist.…”