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CD90 is Identified as a Marker for Cancer Stem Cells in High-Grade Gliomas Using Tissue Microarrays

2012; Lippincott Williams & Wilkins; Volume: 70; Issue: 4 Linguagem: Inglês

10.1227/01.neu.0000413227.80467.92

1524-4040

Phillip V. Parry, Johnathan A. Engh,

Glioma Diagnosis and Treatment

Molecular characterization of tumors has revolutionized our ability to understand the genetic basis of cancer biology. It is well known that tumor cells have differential expression of surface proteins known as clusters of differentiation (CD) that are unique to a given cell line. Identifying the unique CDs amongst different tumor cells enables molecular fingerprinting of individual tumors.The well-known surface protein CD90 is considered a major marker for human stem cell pluripotency. It has been identified in many cancer stem cells (CSCs) including hematopoietic and mesenchymal lines.1,2 In gliomas, CSCs demonstrate increased resistance to both chemotherapy3 and radiation4; as a result, they are thought to be largely responsible for tumor recurrence. The presence of CSCs in gliomas has been demonstrated,5 however, the role of CD90 as a marker of glioma CSC has not been well studied to date. In recent work published by He et al from the University of Michigan, the investigators studied the variable expression patterns of CD90 in high and low grade gliomas vs normal brain tissue.6 Their work describes three extremely important aspects of CD90 in GBM tumorgenesis: (1) the role of CD90 as a marker for high grade glioma; (2) the role of CD90 in CSC formation; and (3) the location of CD90+ cells around vascular structures within GBM. In their experiments, glioma tissue was provided from 58 distinct donors whereby 15 samples were GBM, 19 were WHO grade III astrocytoma, 13 were WHO grade II astrocytoma, 3 were WHO grade I astrocytoma, and 8 were samples from normal subjects. Tissue microarrays permitted in situ identification of protein expression patterns using antihuman CD90 antibodies. The CD90 expression level in normal brain tissue and most low-grade astrocytomas was undetectable. In contrast, high-grade gliomas (WHO grade III and IV) demonstrated a dramatically higher expression level of CD90. Specifically, all normal brain tissue and WHO grade I samples showed no expression of CD90. In WHO grade II tumors, 10 of 13 samples (77%) demonstrated no detectable level of CD90, and of the 3 samples that did express CD90, it was present in less than 1% of cells. For WHO grade III astrocytomas, CD90 was detectable in all 19 samples (100%) with an average CD90 level of 7% (range: 2.8-12.3%). Additionally, all 15 GBM samples demonstrated CD90 positivity with an average CD90 level of 9% (range: 2.2-18.9%). There was no statistically significant difference in CD90 expression levels between WHO grades I and II (P < .05) or WHO grades III and IV (P < .05). However, the difference in the CD90 expression pattern between low-grade (WHO I and II) vs high-grade glioma (WHO III and IV) were significant (P < .0001). These data suggest that CD90 may therefore serve as a unique surface marker for high-grade gliomas.6 The authors further characterized the role of CD90 not only as a marker for high-grade glioma, but also as a marker of CSCs in GBM. Through a series of sophisticated experiments, undifferentiated GBM stem-like neurosphere cell lines were induced into differentiated cells and the levels of CD90 were measured before and after this process. The differentiated GBM cells showed a dramatically decreased expression of CD90 compared to their undifferentiated counterparts along with a loss of their stem-like quality to form neurospheres. Therefore, CD90+ cells have a much higher potential to participate in self-renewal and perpetuate tumor growth by serving as an endogenous source of CSCs. The authors also demonstrated the juxtaposition of the CD90+ cells to tumor vasculature using double immunoflourescence staining. Using antibodies to CD90 and CD31, a vascular endothelial cell marker, they were able to show co-localization or near co-localization of CD90+ cells in all 7 GBM tissue samples tested. The authors conclude that such a relationship to tumor vasculature provides CD90+ GBM CSCs the ability to nurture their self-renewal process. In conclusion, the researchers provide invaluable new information about the molecular characteristics of gliomas by demonstrating the role of CD90 as a marker of CSCs within high-grade gliomas. Additionally, they show that CD90 is important for the development of GBM CSCs, and that this process is localized near tumor vasculature. This research facilitates the effort to better characterize brain tumor-initiating cells. Future studies should shed light on whether CD 90 is an appropriate target for future anti-tumor therapies. undoubtedly assist in the development of GBM specific molecular therapies and sheds new hope on combating a most troublesome pathology for both the neurosurgeon and patient.Figure: Scatter plot of CD90 expression levels in 50 patients with different grades of astrocytomas and 8 normal subjects. The CD90 expression level of each tissue sample was represented by the percentage of CD90+ cells. Each point corresponds to the CD90 expression level of a single sample. CD90 expression levels were significantly elevated in patients with high-grade astrocytomas (WHO grade III and IV). Astro 1 = astrocytoma WHO grade I; Astro 2 = diffuse astrocytoma (WHO grade II); Astro 3 = anaplastic astrocytoma (WHO grade III); GBM=glioblastoma multiforme (WHO grade IV). Modified, from Molecular & Cellular Proteomics 2011 December 27 [Epub ahead of print].