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Tumor-Stromal Interactions Influence Radiation Sensitivity in Epithelial- versus Mesenchymal-Like Prostate Cancer Cells.

Josson S, Sharp S, Sung SY, Johnstone PA, Aneja R, Wang R, Gururajan M, Turner T, Chung LW, Yates C - J Oncol (2010)

Bottom Line: Cocultured ARCaP(E) or ARCaP(M) cells with HS-27a, developed increased colony forming capacity and growth advantage, with ARCaP(E) exhibiting the most significant increases in presence of bone or prostate stroma cells.However pretreatment with anti-E-cadherin antibody (SHEP8-7) or anti-alpha v integrin blocking antibody (CNT095) significantly decreased stromal cell-induced radiation resistance in both ARCaP(E)- and ARCaP(M)-cocultured cells.Taken together the data suggest that mesenchymal-like cancer cells reverting to epithelial-like cells in the bone microenvironment through interaction with bone marrow stromal cells and reexpress E-cadherin.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Emory School of Medicine, Atlanta, GA 30311, USA.

ABSTRACT
HS-27a human bone stromal cells, in 2D or 3D coultures, induced cellular plasticity in human prostate cancer ARCaP(E) and ARCaP(M) cells in an EMT model. Cocultured ARCaP(E) or ARCaP(M) cells with HS-27a, developed increased colony forming capacity and growth advantage, with ARCaP(E) exhibiting the most significant increases in presence of bone or prostate stroma cells. Prostate (Pt-N or Pt-C) or bone (HS-27a) stromal cells induced significant resistance to radiation treatment in ARCaP(E) cells compared to ARCaP(M) cells. However pretreatment with anti-E-cadherin antibody (SHEP8-7) or anti-alpha v integrin blocking antibody (CNT095) significantly decreased stromal cell-induced radiation resistance in both ARCaP(E)- and ARCaP(M)-cocultured cells. Taken together the data suggest that mesenchymal-like cancer cells reverting to epithelial-like cells in the bone microenvironment through interaction with bone marrow stromal cells and reexpress E-cadherin. These cell adhesion molecules such as E-cadherin and integrin alpha v in cancer cells induce cell survival signals and mediate resistance to cancer treatments such as radiation.

No MeSH data available.


Related in: MedlinePlus

3D cocultures of ARCaPE or ARCaPM with HS-27a cells show E-cadherin expression. (a) 1 × 107 ARCaPE or ARCaPM were cocultured with HS-27a cells in RWV for 3 days. Immunohistochemistry of organoids was stained with anti-E-cadherin or N-cadherin antibody. (b) 2D Cocultures of HS-27a were preformed utilizing a total of 50,000 cm2/HS-27a fibroblasts, after which 20,000 cm2 ARCaPE   or ARCaPM were seeded on top of the fibroblast monolayer. The cocultures were maintained in serum-free medium for 1 or 4 days.  Immunocytochemistry of cocultures over these time periods was performed utilizing anti-E-cadherin and N-cadherin antibodies.  Shown are the EMT/MET of  ARCaPEcells (top panels) and MErT of  ARCaPMcells (bottom panels).
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fig1: 3D cocultures of ARCaPE or ARCaPM with HS-27a cells show E-cadherin expression. (a) 1 × 107 ARCaPE or ARCaPM were cocultured with HS-27a cells in RWV for 3 days. Immunohistochemistry of organoids was stained with anti-E-cadherin or N-cadherin antibody. (b) 2D Cocultures of HS-27a were preformed utilizing a total of 50,000 cm2/HS-27a fibroblasts, after which 20,000 cm2 ARCaPE or ARCaPM were seeded on top of the fibroblast monolayer. The cocultures were maintained in serum-free medium for 1 or 4 days. Immunocytochemistry of cocultures over these time periods was performed utilizing anti-E-cadherin and N-cadherin antibodies. Shown are the EMT/MET of ARCaPEcells (top panels) and MErT of ARCaPMcells (bottom panels).

Mentions: Previously, we have demonstrated a Mesenchymal to Epithelial reverse Transition (MErT) of metastatic prostate cancer cell lines within an experimental coculture model and confirmed in patients with liver metastasis [13, 28]. Our findings have recently been confirmed in prostate cancer bone metastasis where E-cadherin and β-catenin were robustly expressed in late stage carcinomas [29]. Therefore we sought to identify the significance of the bone microenvironment within the experimental ARCaP model. To assess cellular plasticity of the ARCaP EMT model, we coultured ARCaP cells with HS-27a cells in 3D RWV (rotary wall vessel) system for 3 days. ARCaPE cells formed larger prostate organoids than ARCaPM cells (data not shown). Upon immunohistochemical examination of organoids, we observed that both ARCaPE and ARCaPM express E-cadherin and lack N-cadherin expression (Figure 1(a)). To further examine the influence of tumor-stroma interactions over a multiday period we utilized a similar 2D cocultures method. Utilizing immunoctyochemical analysis, we observed a lack E-cadherin and robust N-cadherin staining after 1 day in both ARCAPE and ARCaPM cocultures. However by day 4, both ARCaPE and ARCaPM cells formed tumor nest that express E-cadherin and lack N-cadherin staining (Figure 1(b)). It is worthy to note that ARCaPM tumor nest appeared to develop at much smaller extent, compared to ARCaPE cocultures.


Tumor-Stromal Interactions Influence Radiation Sensitivity in Epithelial- versus Mesenchymal-Like Prostate Cancer Cells.

Josson S, Sharp S, Sung SY, Johnstone PA, Aneja R, Wang R, Gururajan M, Turner T, Chung LW, Yates C - J Oncol (2010)

3D cocultures of ARCaPE or ARCaPM with HS-27a cells show E-cadherin expression. (a) 1 × 107 ARCaPE or ARCaPM were cocultured with HS-27a cells in RWV for 3 days. Immunohistochemistry of organoids was stained with anti-E-cadherin or N-cadherin antibody. (b) 2D Cocultures of HS-27a were preformed utilizing a total of 50,000 cm2/HS-27a fibroblasts, after which 20,000 cm2 ARCaPE   or ARCaPM were seeded on top of the fibroblast monolayer. The cocultures were maintained in serum-free medium for 1 or 4 days.  Immunocytochemistry of cocultures over these time periods was performed utilizing anti-E-cadherin and N-cadherin antibodies.  Shown are the EMT/MET of  ARCaPEcells (top panels) and MErT of  ARCaPMcells (bottom panels).
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2926670&req=5

fig1: 3D cocultures of ARCaPE or ARCaPM with HS-27a cells show E-cadherin expression. (a) 1 × 107 ARCaPE or ARCaPM were cocultured with HS-27a cells in RWV for 3 days. Immunohistochemistry of organoids was stained with anti-E-cadherin or N-cadherin antibody. (b) 2D Cocultures of HS-27a were preformed utilizing a total of 50,000 cm2/HS-27a fibroblasts, after which 20,000 cm2 ARCaPE or ARCaPM were seeded on top of the fibroblast monolayer. The cocultures were maintained in serum-free medium for 1 or 4 days. Immunocytochemistry of cocultures over these time periods was performed utilizing anti-E-cadherin and N-cadherin antibodies. Shown are the EMT/MET of ARCaPEcells (top panels) and MErT of ARCaPMcells (bottom panels).
Mentions: Previously, we have demonstrated a Mesenchymal to Epithelial reverse Transition (MErT) of metastatic prostate cancer cell lines within an experimental coculture model and confirmed in patients with liver metastasis [13, 28]. Our findings have recently been confirmed in prostate cancer bone metastasis where E-cadherin and β-catenin were robustly expressed in late stage carcinomas [29]. Therefore we sought to identify the significance of the bone microenvironment within the experimental ARCaP model. To assess cellular plasticity of the ARCaP EMT model, we coultured ARCaP cells with HS-27a cells in 3D RWV (rotary wall vessel) system for 3 days. ARCaPE cells formed larger prostate organoids than ARCaPM cells (data not shown). Upon immunohistochemical examination of organoids, we observed that both ARCaPE and ARCaPM express E-cadherin and lack N-cadherin expression (Figure 1(a)). To further examine the influence of tumor-stroma interactions over a multiday period we utilized a similar 2D cocultures method. Utilizing immunoctyochemical analysis, we observed a lack E-cadherin and robust N-cadherin staining after 1 day in both ARCAPE and ARCaPM cocultures. However by day 4, both ARCaPE and ARCaPM cells formed tumor nest that express E-cadherin and lack N-cadherin staining (Figure 1(b)). It is worthy to note that ARCaPM tumor nest appeared to develop at much smaller extent, compared to ARCaPE cocultures.

Bottom Line: Cocultured ARCaP(E) or ARCaP(M) cells with HS-27a, developed increased colony forming capacity and growth advantage, with ARCaP(E) exhibiting the most significant increases in presence of bone or prostate stroma cells.However pretreatment with anti-E-cadherin antibody (SHEP8-7) or anti-alpha v integrin blocking antibody (CNT095) significantly decreased stromal cell-induced radiation resistance in both ARCaP(E)- and ARCaP(M)-cocultured cells.Taken together the data suggest that mesenchymal-like cancer cells reverting to epithelial-like cells in the bone microenvironment through interaction with bone marrow stromal cells and reexpress E-cadherin.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Emory School of Medicine, Atlanta, GA 30311, USA.

ABSTRACT
HS-27a human bone stromal cells, in 2D or 3D coultures, induced cellular plasticity in human prostate cancer ARCaP(E) and ARCaP(M) cells in an EMT model. Cocultured ARCaP(E) or ARCaP(M) cells with HS-27a, developed increased colony forming capacity and growth advantage, with ARCaP(E) exhibiting the most significant increases in presence of bone or prostate stroma cells. Prostate (Pt-N or Pt-C) or bone (HS-27a) stromal cells induced significant resistance to radiation treatment in ARCaP(E) cells compared to ARCaP(M) cells. However pretreatment with anti-E-cadherin antibody (SHEP8-7) or anti-alpha v integrin blocking antibody (CNT095) significantly decreased stromal cell-induced radiation resistance in both ARCaP(E)- and ARCaP(M)-cocultured cells. Taken together the data suggest that mesenchymal-like cancer cells reverting to epithelial-like cells in the bone microenvironment through interaction with bone marrow stromal cells and reexpress E-cadherin. These cell adhesion molecules such as E-cadherin and integrin alpha v in cancer cells induce cell survival signals and mediate resistance to cancer treatments such as radiation.

No MeSH data available.


Related in: MedlinePlus