A 3D tumor microenvironment regulates cell proliferation, peritoneal growth and expression patterns

Daniela Loessner, Anja Rockstroh, Ali Shokoohmand, Boris M. Holzapfel, Ferdinand Wagner, Jeremy Baldwin, Melanie Boxberg, Barbara Schmalfeldt, Ernst Lengyel, Judith A. Clements, Dietmar W. Hutmacher

Research output: Contribution to journalArticleResearchpeer-review

11 Citations (Scopus)

Abstract

Peritoneal invasion through the mesothelial cell layer is a hallmark of ovarian cancer metastasis. Using tissue engineering technologies, we recreated an ovarian tumor microenvironment replicating this aspect of disease progression. Ovarian cancer cell-laden hydrogels were combined with mesothelial cell-layered melt electrospun written scaffolds and characterized with proliferation and transcriptomic analyses and used as intraperitoneal xenografts. Here we show increased cancer cell proliferation in these 3D co-cultures, which we validated using patient-derived cells and linked to peritoneal tumor growth in vivo. Transcriptome-wide expression analysis identified IGFBP7, PTGS2, VEGFC and FGF2 as bidirectional factors deregulated in 3D co-cultures compared to 3D mono-cultures, which we confirmed by immunohistochemistry of xenograft and patient-derived tumor tissues and correlated with overall and progression-free survival. These factors were further increased upon expression of kallikrein-related proteases. This clinically predictive model allows us to mimic the complexity and processes of the metastatic disease that may lead to therapies that protect from peritoneal invasion or delay the development of metastasis.

Original languageEnglish
Pages (from-to)63-75
Number of pages13
JournalBiomaterials
Volume190-191
DOIs
Publication statusPublished - Jan 2019
Externally publishedYes

Keywords

  • Hydrogel
  • Mesothelial cells
  • Ovarian cancer
  • Scaffold
  • Tumor microenvironment

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