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Prostaglandin E2 receptor EP4 as the common target on cancer cells and macrophages to abolish angiogenesis, lymphangiogenesis, metastasis, and stem-like cell functions.

Majumder M, Xin X, Liu L, Girish GV, Lala PK - Cancer Sci. (2014)

Bottom Line: Treating murine macrophage RAW 264.7 cell line with COX-2i celecoxib and EP4A significantly reduced VEGF-A/C/D production in vitro, measured with quantitative PCR and Western blots.Celecoxib or EP4A therapy at non-toxic doses abrogated tumor growth, lymphangiogenesis, and metastasis to lymph nodes and lungs.Knocking down COX-2 or EP4 in C3L5 cells or treating cells in vitro with celecoxib or EP4A and treating tumor-bearing mice in vivo with the same drug reduced SLC properties of tumor cells including preferential co-expression of COX-2 and SLC markers ALDH1A, CD44, OCT-3/4, β-catenin, and SOX-2.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.

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Related in: MedlinePlus

Tumor growth (a, b), lung colonies (c–e), and lymph metastasis (f, g) in a murine C3L5 breast cancer model. (a) Representative images of tumor-inclusive Matrigel or Matrigel only implants retrieved on day 16 (a scale in mm shown in the background). (b) Mean diameters of tumors were reduced significantly in mice treated with celecoxib or RQ-15986 (EP4A), compared to respective vehicle-treated controls. This reduction was significant at all time points for both therapies. Data represent means (n = 16/group/day) ± SE. *P < 0.05; **P < 0.005; ***P < 0.001. (c) Digital camera photographs of surface lung colonies at day 12 (black arrows) on left. (d) Representative images of micrometastases in H&E stained lung sections on days 8, 12, and 16. Scale bar = 200 μm. (e) Charts showing mean numbers of metastatic lung colonies were reduced with celecoxib (Cel) and EP4A therapies at all time points after tumor transplantation. Data represent mean ± SE (n = 8/group/day). *P < 0.05; **P < 0.01. (f) Histological pictures (H&E stained) of representative inguinal lymph nodes in control (vehicle-treated) and EP4A-treated mice on day 12, including low power views in the inset. Control lymph node (L) is nearly completely replaced by tumor cells (T). Lymph node treated with EP4A is tumor-free. Scale bar = 50 μm. (g) Column graphs show percent of lymph nodes (LN) with metastasis in control (Con) and treated mice at days 8, 12, and 16.
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fig01: Tumor growth (a, b), lung colonies (c–e), and lymph metastasis (f, g) in a murine C3L5 breast cancer model. (a) Representative images of tumor-inclusive Matrigel or Matrigel only implants retrieved on day 16 (a scale in mm shown in the background). (b) Mean diameters of tumors were reduced significantly in mice treated with celecoxib or RQ-15986 (EP4A), compared to respective vehicle-treated controls. This reduction was significant at all time points for both therapies. Data represent means (n = 16/group/day) ± SE. *P < 0.05; **P < 0.005; ***P < 0.001. (c) Digital camera photographs of surface lung colonies at day 12 (black arrows) on left. (d) Representative images of micrometastases in H&E stained lung sections on days 8, 12, and 16. Scale bar = 200 μm. (e) Charts showing mean numbers of metastatic lung colonies were reduced with celecoxib (Cel) and EP4A therapies at all time points after tumor transplantation. Data represent mean ± SE (n = 8/group/day). *P < 0.05; **P < 0.01. (f) Histological pictures (H&E stained) of representative inguinal lymph nodes in control (vehicle-treated) and EP4A-treated mice on day 12, including low power views in the inset. Control lymph node (L) is nearly completely replaced by tumor cells (T). Lymph node treated with EP4A is tumor-free. Scale bar = 50 μm. (g) Column graphs show percent of lymph nodes (LN) with metastasis in control (Con) and treated mice at days 8, 12, and 16.

Mentions: Implants of Matrigel alone appeared as clear avascular jelly beans (Fig.1a, shown for day 16) at all time points with no evidence of angiogenesis or lymphangiogenesis, as previously reported.10,38 Tumor growth was significantly blocked (at all time points) with both EP4A (as early as day 8) and celecoxib treatments (Fig.1b). Spontaneous lung metastases are shown in Figure1(c), as surface colonies and microscopic colonies (Fig.1d) on day 12. The incidence of microscopic colonies was high in vehicle-treated mice on day 8, with a further small increase on days 12 and 16. There was a significant reduction of lung colonies at all time points with celecoxib and EP4A treatments (Fig.1e).


Prostaglandin E2 receptor EP4 as the common target on cancer cells and macrophages to abolish angiogenesis, lymphangiogenesis, metastasis, and stem-like cell functions.

Majumder M, Xin X, Liu L, Girish GV, Lala PK - Cancer Sci. (2014)

Tumor growth (a, b), lung colonies (c–e), and lymph metastasis (f, g) in a murine C3L5 breast cancer model. (a) Representative images of tumor-inclusive Matrigel or Matrigel only implants retrieved on day 16 (a scale in mm shown in the background). (b) Mean diameters of tumors were reduced significantly in mice treated with celecoxib or RQ-15986 (EP4A), compared to respective vehicle-treated controls. This reduction was significant at all time points for both therapies. Data represent means (n = 16/group/day) ± SE. *P < 0.05; **P < 0.005; ***P < 0.001. (c) Digital camera photographs of surface lung colonies at day 12 (black arrows) on left. (d) Representative images of micrometastases in H&E stained lung sections on days 8, 12, and 16. Scale bar = 200 μm. (e) Charts showing mean numbers of metastatic lung colonies were reduced with celecoxib (Cel) and EP4A therapies at all time points after tumor transplantation. Data represent mean ± SE (n = 8/group/day). *P < 0.05; **P < 0.01. (f) Histological pictures (H&E stained) of representative inguinal lymph nodes in control (vehicle-treated) and EP4A-treated mice on day 12, including low power views in the inset. Control lymph node (L) is nearly completely replaced by tumor cells (T). Lymph node treated with EP4A is tumor-free. Scale bar = 50 μm. (g) Column graphs show percent of lymph nodes (LN) with metastasis in control (Con) and treated mice at days 8, 12, and 16.
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fig01: Tumor growth (a, b), lung colonies (c–e), and lymph metastasis (f, g) in a murine C3L5 breast cancer model. (a) Representative images of tumor-inclusive Matrigel or Matrigel only implants retrieved on day 16 (a scale in mm shown in the background). (b) Mean diameters of tumors were reduced significantly in mice treated with celecoxib or RQ-15986 (EP4A), compared to respective vehicle-treated controls. This reduction was significant at all time points for both therapies. Data represent means (n = 16/group/day) ± SE. *P < 0.05; **P < 0.005; ***P < 0.001. (c) Digital camera photographs of surface lung colonies at day 12 (black arrows) on left. (d) Representative images of micrometastases in H&E stained lung sections on days 8, 12, and 16. Scale bar = 200 μm. (e) Charts showing mean numbers of metastatic lung colonies were reduced with celecoxib (Cel) and EP4A therapies at all time points after tumor transplantation. Data represent mean ± SE (n = 8/group/day). *P < 0.05; **P < 0.01. (f) Histological pictures (H&E stained) of representative inguinal lymph nodes in control (vehicle-treated) and EP4A-treated mice on day 12, including low power views in the inset. Control lymph node (L) is nearly completely replaced by tumor cells (T). Lymph node treated with EP4A is tumor-free. Scale bar = 50 μm. (g) Column graphs show percent of lymph nodes (LN) with metastasis in control (Con) and treated mice at days 8, 12, and 16.
Mentions: Implants of Matrigel alone appeared as clear avascular jelly beans (Fig.1a, shown for day 16) at all time points with no evidence of angiogenesis or lymphangiogenesis, as previously reported.10,38 Tumor growth was significantly blocked (at all time points) with both EP4A (as early as day 8) and celecoxib treatments (Fig.1b). Spontaneous lung metastases are shown in Figure1(c), as surface colonies and microscopic colonies (Fig.1d) on day 12. The incidence of microscopic colonies was high in vehicle-treated mice on day 8, with a further small increase on days 12 and 16. There was a significant reduction of lung colonies at all time points with celecoxib and EP4A treatments (Fig.1e).

Bottom Line: Treating murine macrophage RAW 264.7 cell line with COX-2i celecoxib and EP4A significantly reduced VEGF-A/C/D production in vitro, measured with quantitative PCR and Western blots.Celecoxib or EP4A therapy at non-toxic doses abrogated tumor growth, lymphangiogenesis, and metastasis to lymph nodes and lungs.Knocking down COX-2 or EP4 in C3L5 cells or treating cells in vitro with celecoxib or EP4A and treating tumor-bearing mice in vivo with the same drug reduced SLC properties of tumor cells including preferential co-expression of COX-2 and SLC markers ALDH1A, CD44, OCT-3/4, β-catenin, and SOX-2.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.

Show MeSH
Related in: MedlinePlus