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. 2017 May 1;19(5):660-668.
doi: 10.1093/neuonc/now239.

Percentage of mesenchymal stem cells in high-grade glioma tumor samples correlates with patient survival

Tal Shahar  1   2 , Uri Rozovski  3 , Kenneth R Hess  4 , Anwar Hossain  1   2 , Joy Gumin  1   2 , Feng Gao  1   2 , Gregory N Fuller  5 , Lindsey Goodman  6 , Erik P Sulman  6 , Frederick F Lang  1   2
Affiliations

Percentage of mesenchymal stem cells in high-grade glioma tumor samples correlates with patient survival

Tal Shahar et al. Neuro Oncol. .

Abstract

Background: Human mesenchymal stem cells (hMSCs) have been shown to reside as stromal cells in human gliomas as glioma-associated hMSCs (GA-hMSCs), but their biological role remains unclear. Because recent evidence indicates that GA-hMSCs drive tumor cell proliferation and stemness, we hypothesized that a higher percentage of GA-hMSCs in tumors predicts poor patient prognosis.

Method: We determined the percentage of cells coexpressing GA-hMSC markers CD105+/CD73+/CD90+ from patients with newly diagnosed high-grade glioma and analyzed the association between this percentage and overall survival (OS) in 3 independent cohorts: fresh surgical glioblastoma specimens (cohort 1, N = 9), cultured tumor specimens at passage 3 (cohort 2, N = 28), and The Cancer Genome Atlas (TCGA) database.

Results: In all cohorts, patient OS correlated with the percentages of GA-hMSCs in tumors. For cohort 1, the median OS of patients with tumors with a low percentage of triple-positive cells was 46 months, and for tumors with a high percentage of triple-positive cells, it was 12 months (hazard ratio [HR] = 0.24; 95% CI: 0.02-0.5, P = .02). For cohort 2, the median OS of patients with tumors with a low percentage of GA-hMSCs was 66 months, and for tumors with a high percentage, it was 11 months (HR = 0.38; 95% CI: 0.13-0.9, P = .04). In the database of TCGA, the median OS times in patients with high and low coexpression levels of CD105/CD73/CD90 were 8.4 months and 13.1 months (HR = 0.4; 95% CI: 0.1-0.88; P = .04), respectively.

Conclusions: The percentage of GA-MSCs inversely correlates with OS, suggesting a role for GA-MSCs in promoting aggressive behavior of gliomas.

Keywords: glioblastoma; mesenchymal stem cells; microenvironment; prognosis.

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Figures

Fig. 1
Fig. 1
High percentage of GA-MSCs in fresh surgical specimens predicts poor overall survival of patients with high-grade glioma. (A) A correlation between the percentage of triple-positive (CD105+/CD73+/CD90+) cells identified in high-grade glioma fresh surgical specimens and patients OS (Somer’s Dyx rank correlation coefficient = −0.39; 95% CI: −0.74 to −0.04). (B) Kaplan–Meier survival curves in patients with low (≤5.1%) and high percentage of triple-positive (CD105+/CD73+/CD90+) cells (log-rank test, P = .02).
Fig. 2
Fig. 2
A high percentage of GA-MSCs in the culture of surgical specimens predicts poor OS of patients with high-grade glioma. (A) A correlation between the percentage of triple-positive (CD105+/CD73+/CD90+) cells identified in high-grade glioma fresh surgical specimens and the percentage of triple-positive cells identified in culture (assayed at passage 3) derived from the specimen (r = 0.9). (B) A correlation between the percentage of triple-positive (CD105+/CD73+/CD90+) cells identified in high-grade glioma in culture and patients’ OS (Somer’s Dyx rank correlation coefficient = −0.24; 95% CI: −0.54 to 0.07). (C) Kaplan–Meier survival curves in patients with low (≤29%) and high percentage of triple-positive (CD105+/CD73+/CD90+) cells (log-rank test, P = 0.04).
Fig. 3
Fig. 3
Characterization of tumor-associated mesenchymal stem cells (MSCs) isolated from glioblastoma surgical specimens. (A) In culture, spindle-shape appearance of GA-MSCs. Bar, 50 µm. (B) Representative flow cytometry analysis for positive markers: CD73 (left field), CD90 (middle field), and CD105 (right field). (C) Triple-positive (CD105+/CD73+/CD90+) cells are shown in Fig. 1C. (D) Representative flow cytometry analysis for negative markers: CD45 (left field), CD34 (middle field), and CD133 (right field). Differentiation of GA-MSCs into osteocytes (E, calcium deposits in red; bar, 200 µm), adipocytes (F, fat droplets in red; bar, 200 µm), and chondrocytes (G, cartilage in purple; bar, 100 µm).
Fig. 4
Fig. 4
The distribution of patients represented in The Cancer Genome Atlas (TCGA) cohort, with gene expression levels at the lowest (A) or highest (B) quintile in Endoglin, NT5E, and THY1 genes separately and their overlaps. (C) Kaplan–Meier survival curves of patients having glioblastomas with high (upper quintile of gene expression) and low (lowest quintile of gene expression) levels of Endoglin, NT5E, and THY1 gene expression based on data from the database of TCGA.
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