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Syngeneic Murine Ovarian Cancer Model Reveals That Ascites Enriches for Ovarian Cancer Stem-Like Cells Expressing Membrane GRP78.

Publication ,  Journal Article
Mo, L; Bachelder, RE; Kennedy, M; Chen, P-H; Chi, J-T; Berchuck, A; Cianciolo, G; Pizzo, SV
Published in: Mol Cancer Ther
March 2015

Patients with ovarian cancer are generally diagnosed at FIGO (International Federation of Gynecology and Obstetrics) stage III/IV, when ascites is common. The volume of ascites correlates positively with the extent of metastasis and negatively with prognosis. Membrane GRP78, a stress-inducible endoplasmic reticulum chaperone that is also expressed on the plasma membrane ((mem)GRP78) of aggressive cancer cells, plays a crucial role in the embryonic stem cell maintenance. We studied the effects of ascites on ovarian cancer stem-like cells using a syngeneic mouse model. Our study demonstrates that ascites-derived tumor cells from mice injected intraperitoneally with murine ovarian cancer cells (ID8) express increased (mem)GRP78 levels compared with ID8 cells from normal culture. We hypothesized that these ascites-associated (mem)GRP78(+) cells are cancer stem-like cells (CSC). Supporting this hypothesis, we show that (mem)GRP78(+) cells isolated from murine ascites exhibit increased sphere forming and tumor initiating abilities compared with (mem)GRP78(-) cells. When the tumor microenvironment is recapitulated by adding ascites fluid to cell culture, ID8 cells express more (mem)GRP78 and increased self-renewing ability compared with those cultured in medium alone. Moreover, compared with their counterparts cultured in normal medium, ID8 cells cultured in ascites, or isolated from ascites, show increased stem cell marker expression. Antibodies directed against the carboxy-terminal domain of GRP78: (i) reduce self-renewing ability of murine and human ovarian cancer cells preincubated with ascites and (ii) suppress a GSK3α-AKT/SNAI1 signaling axis in these cells. Based on these data, we suggest that (mem)GRP78 is a logical therapeutic target for late-stage ovarian cancer.

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Published In

Mol Cancer Ther

DOI

EISSN

1538-8514

Publication Date

March 2015

Volume

14

Issue

3

Start / End Page

747 / 756

Location

United States

Related Subject Headings

  • Tumor Microenvironment
  • Signal Transduction
  • Ovarian Neoplasms
  • Oncology & Carcinogenesis
  • Neoplastic Stem Cells
  • Mice, Inbred C57BL
  • Mice
  • Humans
  • Heat-Shock Proteins
  • Female
 

Citation

APA
Chicago
ICMJE
MLA
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Mo, L., Bachelder, R. E., Kennedy, M., Chen, P.-H., Chi, J.-T., Berchuck, A., … Pizzo, S. V. (2015). Syngeneic Murine Ovarian Cancer Model Reveals That Ascites Enriches for Ovarian Cancer Stem-Like Cells Expressing Membrane GRP78. Mol Cancer Ther, 14(3), 747–756. https://doi.org/10.1158/1535-7163.MCT-14-0579
Mo, Lihong, Robin E. Bachelder, Margaret Kennedy, Po-Han Chen, Jen-Tsan Chi, Andrew Berchuck, George Cianciolo, and Salvatore V. Pizzo. “Syngeneic Murine Ovarian Cancer Model Reveals That Ascites Enriches for Ovarian Cancer Stem-Like Cells Expressing Membrane GRP78.Mol Cancer Ther 14, no. 3 (March 2015): 747–56. https://doi.org/10.1158/1535-7163.MCT-14-0579.
Mo L, Bachelder RE, Kennedy M, Chen P-H, Chi J-T, Berchuck A, et al. Syngeneic Murine Ovarian Cancer Model Reveals That Ascites Enriches for Ovarian Cancer Stem-Like Cells Expressing Membrane GRP78. Mol Cancer Ther. 2015 Mar;14(3):747–56.
Mo, Lihong, et al. “Syngeneic Murine Ovarian Cancer Model Reveals That Ascites Enriches for Ovarian Cancer Stem-Like Cells Expressing Membrane GRP78.Mol Cancer Ther, vol. 14, no. 3, Mar. 2015, pp. 747–56. Pubmed, doi:10.1158/1535-7163.MCT-14-0579.
Mo L, Bachelder RE, Kennedy M, Chen P-H, Chi J-T, Berchuck A, Cianciolo G, Pizzo SV. Syngeneic Murine Ovarian Cancer Model Reveals That Ascites Enriches for Ovarian Cancer Stem-Like Cells Expressing Membrane GRP78. Mol Cancer Ther. 2015 Mar;14(3):747–756.

Published In

Mol Cancer Ther

DOI

EISSN

1538-8514

Publication Date

March 2015

Volume

14

Issue

3

Start / End Page

747 / 756

Location

United States

Related Subject Headings

  • Tumor Microenvironment
  • Signal Transduction
  • Ovarian Neoplasms
  • Oncology & Carcinogenesis
  • Neoplastic Stem Cells
  • Mice, Inbred C57BL
  • Mice
  • Humans
  • Heat-Shock Proteins
  • Female