Notch3 signaling promotes tumor cell adhesion and progression in a murine epithelial ovarian cancer model.

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  • Additional Information
    • Source:
      Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE
    • Publication Information:
      Original Publication: San Francisco, CA : Public Library of Science
    • Subject Terms:
      Carcinoma, Ovarian Epithelial/*secondary ; Cystadenocarcinoma, Serous/*secondary ; Ovarian Neoplasms/*pathology ; Peritoneal Neoplasms/*secondary ; Receptor, Notch3/*metabolism; Animals ; Carcinogenesis/metabolism ; Carcinoma, Ovarian Epithelial/metabolism ; Cell Adhesion ; Cell Line, Tumor ; Cystadenocarcinoma, Serous/metabolism ; Disease Progression ; Extracellular Matrix Proteins/metabolism ; Female ; Humans ; Mice ; Mice, Nude ; Ovarian Neoplasms/metabolism ; Peritoneal Neoplasms/metabolism ; Receptor, Notch3/genetics
    • Abstract:
      High grade serous ovarian cancer (HGSC) is the most common and deadly type of ovarian cancer, largely due to difficulties in early diagnosis and rapid metastasis throughout the peritoneal cavity. Previous studies have shown that expression of Notch3 correlates with worse prognosis and increased tumorigenic cell behaviors in HGSC. We investigated the mechanistic role of Notch3 in a model of metastatic ovarian cancer using the murine ovarian surface epithelial cell line, ID8 IP2. Notch3 was activated in ID8 IP2 cells via expression of the Notch3 intracellular domain (Notch3IC). Notch3IC ID8 IP2 cells injected intraperitoneally caused accelerated ascites and reduced survival compared to control ID8 IP2, particularly in early stages of disease. We interrogated downstream targets of Notch3IC in ID8 IP2 cells by RNA sequencing and found significant induction of genes that encode adhesion and extracellular matrix proteins. Notch3IC ID8 IP2 showed increased expression of ITGA1 mRNA and cell-surface protein. Notch3IC-mediated increase of ITGA1 was also seen in two human ovarian cancer cells. Notch3IC ID8 IP2 cells showed increased adhesion to collagens I and IV in vitro. We propose that Notch3 activation in ovarian cancer cells causes increased adherence to collagen-rich peritoneal surfaces. Thus, the correlation between increased Notch3 signaling and poor prognosis may be influenced by increased metastasis of HGSC via increased adherence of disseminating cells to new metastatic sites in the peritoneum.
      Competing Interests: The authors have declared that no competing interests exist.
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    • Grant Information:
      R01 CA164729 United States CA NCI NIH HHS; F31 CA192891 United States CA NCI NIH HHS; R00 CA230195 United States CA NCI NIH HHS; DP1 HD084071 United States HD NICHD NIH HHS; K99 CA230195 United States CA NCI NIH HHS; R01 HL112626 United States HL NHLBI NIH HHS; U54 CA209975 United States CA NCI NIH HHS; P30 CA008748 United States CA NCI NIH HHS; R01 CA142783 United States CA NCI NIH HHS
    • Accession Number:
      0 (Extracellular Matrix Proteins)
      0 (Notch3 protein, mouse)
      0 (Receptor, Notch3)
    • Publication Date:
      Date Created: 20200612 Date Completed: 20200824 Latest Revision: 20240426
    • Publication Date:
      20240426
    • Accession Number:
      PMC7289394
    • Accession Number:
      10.1371/journal.pone.0233962
    • Accession Number:
      32525899