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. 2009 Jun 15;69(9):991-1000.
doi: 10.1002/pros.20946.

Tumor-promoting phenotype of CD90hi prostate cancer-associated fibroblasts

Hongjuan Zhao  1 , Donna M Peehl
Affiliations

Tumor-promoting phenotype of CD90hi prostate cancer-associated fibroblasts

Hongjuan Zhao et al. Prostate. .

Abstract

Background: Cancer-associated stroma contributes to the malignant behavior of adenocarcinomas of the prostate and other organs. CD90 is a marker of mesenchymal stem cells (MSCs) and its expression is higher in prostate cancer stroma compared to normal tissue. Cultured prostate cancer-associated fibroblasts (CAFs) expressing high versus low levels of CD90 were analyzed for an MSC-like or tumor-promoting phenotype.

Methods: CD90(hi) and CD90(lo) cells were collected by fluorescence-activated cell sorting (FACS). Expression of genes associated with MSCs and/or tumor-promoting activities was measured by quantitative polymerase chain reaction (qPCR). Effects of stromal cell co-culture or conditioned media were tested on BPH-1 epithelial cells.

Results: The pattern of gene expression did not support the hypothesis that CD90(hi) cells were MSCs. However, CD90(hi) cells expressed higher levels of many genes associated with tumor promotion, including cytokines, angiogenic factors, hedgehog signaling components, and transforming growth factor (TGF)-beta. Co-culture or conditioned medium from CD90(hi) cells increased CXCR4 expression in BPH-1 cells, at least in part due to TGF-beta, and protected BPH-1 cells from apoptosis.

Conclusions: Our results suggest that the elevated expression of CD90 previously observed in the cancer-associated stroma of the human prostate is biologically significant. Although our results do not support the idea that CD90(hi) cells cultured from the cancer stroma are MSCs, our findings suggest that the phenotype of these cells is more tumor-promoting than that of cells expressing low CD90.

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Figures

Fig. 1
Fig. 1
Quantitation and collection of CD90hi versus CD90lo cells from F-CA-56 cells by FACS. A: F-CA-56 cells in suspension under phase contrast microscope. B: A subset of F-CA-56 cells in suspension stained with anti-CD90 showed intense fluorescent signal on cell membrane (arrows). C: Merged image of A and B. D: A histogram of CD90 expression in F-CA-56 cells by flow cytometry. Average intensity among cells defined by gates P5 and P6 is indicated. E: Acontour plot of cells defined by gates P5 and P6 showed two well-separated populations. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com].
Fig. 2
Fig. 2
Relative gene expression of MSC-associated stem cell markers in CD90hi versus CD90lo cells from F-CA-56 determined by qPCR. Error bars represent standard deviation. Asterisks indicate statistical significances by t-test (P < 0.05).
Fig. 3
Fig. 3
Relative gene expression of cancer-promoting factors in CD90hi versus CD90lo cells determined by qPCR. Two CAFs were used in the analysis shown in (A) (F-CA-56) and (B) (F-CA-85). For both A and B, error bars represent standard deviation. Asterisks indicate statistical significances by t-test (P < 0.05).
Fig. 4
Fig. 4
Relative expression of genes differentially expressed in prostate cancer-associated stromal cells in CD90hi versus CD90lo cells from F-CA-56 determined by qPCR. Error bars represent standard deviation. Asterisks indicate statistical significances by t-test (P < 0.05).
Fig. 5
Fig. 5
Relative gene expression of TGF-β isoforms in CD90hi versus CD90lo cells determined by qPCR. Two CAFs were used in the analysis shown in (A) (F-CA-56) and (B) (F-CA-85). For both A and B, error bars represent standard deviation. Asterisks indicate statistical significances by t-test (P < 0.05).
Fig. 6
Fig. 6
CXCR4 expression in BPH-1 epithelial cells in response to CD90hi versus CD90lo stromal cells. A: Histograms of CXCR4 expression in BPH-1 cells determined by flow cytometry. BPH-1 cells were cultured either in serum-free RPMI 1640, or serum-free RPMI 1640 conditioned by CD90hi/CD90lo cells from F-CA-56 with or without neutralizing antibody against TGF-β at 10 µg/ml. After 24 hr, cells were harvested and CXCR.4 expression was measured by FACS. B–E: Immunofluorescence staining of CXCR4 in BPH-1 cells. BPH-1 cells were cultured either in serum-free RPMI 1640 without TGF-β (B), with TGF-β (D), with CD90lo CAFs (C), or with CD90hi CAFs (E).CXCR4-expressing BPH-1 cells are indicated by arrows. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com].
Fig. 7
Fig. 7
Protection of BPH-1 epithelial cells from H2O2-induced cell death. BPH-1 cells were either cultured in serum-free RPMI 1640 without H2O2, with H2O2 (100 µM), with conditioned medium (CM) from CD90hi F-CA-56 cells and H2O2, or CM from CD90lo F-CA-56 cells and H2O2. Student’s t-test was used to determine statistical significance.
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