Abstract
It is well established that the normal human brain contains populations of neural stem/progenitor cells. Recent studies suggest that they migrate toward a variety of CNS tissue injuries. In an investigation of the potential role of neural stem cells in the pathogenesis of primary CNS lymphomas (NHL-CNS), we observed that neural stem/progenitor cells appeared to accumulate at the border of the tumors with the brain and in the advancing edge of the tumors, in a pattern similar to that seen with reactive gliosis. We identified neural stem/progenitor cells using standard immunohistochemical markers thereof, including CD133, nestin, Group II Beta-tubulin, Musashi1, and the transcription factor Sox2, in neurosurgically obtained specimens of NHL-CNS metastatic carcinoma , and metastatic melanoma . We had similar results with each of these markers but found that Sox2 antibodies provided the clearest and most robust labeling of the cells at the borders of these non-glial tumors. To exclude that the immunoreactive cells were actually neoplastic, double-label immunohistochemistry for Sox2 and CD20 (for NHL-CNS), Sox2 and cytokeratin (CAM5.2, for carcinomas), or Sox2 and HMB45 (for melanomas) showed that in each tumor type, Sox2-immunoreactive cells adjacent to and among the tumor cells were separate from neoplastic cells. Sox2/GFAP double-labeling revealed a consistent pattern of Sox2 immunopositivity both in reactive GFAP-immunopositive astrocytes and in GFAP-negative cells, at the interface of tumor and non-neoplastic brain. These results suggest that neural stem/progenitor cells migrate to non-glial neoplasms in the CNS, are a source of reactive astrocytes, and that Sox2 is a reliable immunohistochemical marker for these cells.
Highlights
The cancer stem cell hypothesis has revolutionized studies of cancer biology, including those of primary brain tumors; it is widely accepted that there is a stem cell component in these as in most cancers
We show that neural stem/progenitor cells labeled by Sox2, Musashi1, nestin, CD133 or beta-tubulin antibodies accumulate at the borders of primary CNS B cell non-Hodkin lymphomas (NHL-CNS) and of metastatic non-neural neoplasms in the brain
These double-labeling experiments identified three different immunophenotypic cell populations, all in the gliotic brain adjacent to the neoplasms. These were: (Aboody et al 2000) astrocytes with Sox2-immunopositive nuclei and GFAP-immunopositive cytoplasm; (Aboody et al 2006) astrocytes with GFAP-immunopositive cytoplasm without Sox2 immunoreactivity in their nuclei; and (Alonso et al 2011) Sox2-immunopositive nuclei without any GFAP immunopositive cytoplasm (Figure 4). These results suggest that these non-neural tumors evoke a response by native neural stem/progenitor cells, which migrate into the zone adjacent to the tumor and among the tumor cells at the edges of the tumors, and which can mature into reactive astrocytes
Summary
The cancer stem cell hypothesis has revolutionized studies of cancer biology, including those of primary brain tumors; it is widely accepted that there is a stem cell component in these as in most cancers. Endogenous neural stem/progenitor cells distinct from tumor cells have an innate tropism for both gliomas (Aboody et al 2000) and non-glial CNS tumors metastatic to the CNS (Aboody et al 2006) and secrete antitumorigenic factors such as vanilloids and BMP-7 (Chirasani et al 2010; Stock et al 2012). The migration of neural stem cells into the region of a tumor in a mouse model was shown to be mediated by vascular endothelial growth factor (VEGF) secreted by tumor cells signaling through VEGF Receptor 2. Accurate characterization of the phenotype and function of endogenous neural stem/progenitor cells has clinical applications given that intracerebral injection of engineered neural stem/progenitor cells is being explored as treatment of neoplasms in the brain (Aboody et al 2006; Li et al 2005; Rath et al 2009; Sanson et al 2002). There is an ongoing clinical trial for recurrent high-grade gliomas with the latter strategy (ClinicalTrials.gov; Identifier: NCT01172964)
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