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

64 Citations (Scopus)

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

Tumor Microenvironment
Ovarian Neoplasms
Vascular Endothelial Growth Factor A
Cysteine
Ascites
Integrins
Ascitic Fluid
Matrix Metalloproteinases
Proteins
8-epi-prostaglandin F2alpha
Macrophages
Lipids
Neoplasms
Matrix Metalloproteinase 2
Chemotactic Factors
Matrix Metalloproteinase 9
Prostaglandins F
Interleukin-6
Down-Regulation
Neoplasm Metastasis

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Normalization of the ovarian cancer microenvironment by SPARC. / Said, Neveen; Socha, Matthew J.; Olearczyk, Jeffrey J.; Elmarakby, Ahmed A.; Imig, John D.; Motamed, Kouros.

In: Molecular Cancer Research, Vol. 5, No. 10, 01.10.2007, p. 1015-1030.

Research output: Contribution to journalArticle

Said, N, Socha, MJ, Olearczyk, JJ, Elmarakby, AA, Imig, JD & Motamed, K 2007, 'Normalization of the ovarian cancer microenvironment by SPARC', Molecular Cancer Research, vol. 5, no. 10, pp. 1015-1030. https://doi.org/10.1158/1541-7786.MCR-07-0001
Said, Neveen ; Socha, Matthew J. ; Olearczyk, Jeffrey J. ; Elmarakby, Ahmed A. ; Imig, John D. ; Motamed, Kouros. / Normalization of the ovarian cancer microenvironment by SPARC. In: Molecular Cancer Research. 2007 ; Vol. 5, No. 10. pp. 1015-1030.
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