Faculty Collaboration Database

Normalization of the ovarian cancer microenvironment by SPARC. Mol Cancer Res 2007 Oct;5(10):1015-30

Date

10/24/2007

Pubmed ID

17951402

DOI

10.1158/1541-7786.MCR-07-0001

Scopus ID

2-s2.0-35948982192 (requires institutional sign-in at Scopus site)   82 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 alpha(v) and beta(1) 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(2)alpha) 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.

Author List

Said N, Socha MJ, Olearczyk JJ, Elmarakby AA, Imig JD, Motamed K

MESH terms used to index this publication - Major topics in bold

Animals
Ascitic Fluid
Carcinoma
Cell Adhesion
Cell Proliferation
Cell Survival
Chemokine CCL2
Dinoprost
Female
Inflammation
Integrins
Interleukin-6
Metalloendopeptidases
Mice
Mice, Mutant Strains
Osteonectin
Ovarian Neoplasms
Peritoneal Neoplasms
Tissue Inhibitor of Metalloproteinases
Vascular Endothelial Growth Factor A