Normalization of the ovarian cancer microenvironment by SPARC

Neveen Said, Matthew J. Socha, Jeffrey J. Olearczyk, Ahmed A. Elmarakby, John D. Imig, Kouros Motamed

Research output: Contribution to journalArticle

67 Scopus citations

Abstract

Malignant ascites is a major source of morbidity and mortality in ovarian cancer patients. It functions as a permissive reactive tumor-host microenvironment and provides sustenance for the floating tumor cells through a plethora of survival/metastasis-associated molecules. Using a syngeneic, immunocompetent model of peritoneal ovarian carcinomatosis in SP-/- mice, we investigated the molecular mechanisms implicated in the interplay between host secreted protein acidic and rich in cysteine (SPARC) and ascitic fluid prosurvival/prometastasis factors that result in the significantly augmented levels of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMP). Ascitic fluid-enhanced ID8 invasiveness was mediated through VEGF via a positive feedback loop with MMP-2 and MMP-9 and through activation of αv and β1 integrins. Host SPARC down-regulated the VEGF-MMP axis at the transcriptional and posttranscriptional levels. In vitro, SPARC attenuated the basal as well as VEGF-induced integrin activation in tumor cells. SPARC inhibited the VEGF- and integrin-mediated ID8 proliferation in vitro and significantly suppressed their tumorigenicity in vivo. Relative to SP+/+, SP-/- ascitic fluid contained significantly higher levels of bioactive lipids and exerted stronger chemotactic, proinvasive, and mitogenic effects on ID8 cells in vitro. SP -/- ascites also contained high levels of interleukin-6, macrophage chemoattractant protein-1, and 8-isoprostane (prostaglandin F 2α) that were positively correlated with extensive infiltration of SP-/- ovarian tumors and ascites with macrophages. In summary, our findings strongly suggest that host SPARC normalizes the microenvironment of ovarian cancer malignant ascites through down-regulation of the VEGF-integrin-MMP axis, decreases the levels and activity of bioactive lipids, and ameliorates downstream inflammation.

Original languageEnglish (US)
Pages (from-to)1015-1030
Number of pages16
JournalMolecular Cancer Research
Volume5
Issue number10
DOIs
StatePublished - Oct 1 2007

    Fingerprint

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this