Normalization of the ovarian cancer microenvironment by SPARC.
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.
Said
Neveen
N
Vascular Biology Center, Medical College of Georgia, Augusta, Georgea 30912, USA.
Socha
Matthew J
MJ
Olearczyk
Jeffrey J
JJ
Elmarakby
Ahmed A
AA
Imig
John D
JD
Motamed
Kouros
K
D000818:Animals; D001202:Ascitic Fluid / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D002277:Carcinoma / Q000378:metabolism / Q000556:secondary*; D002448:Cell Adhesion; D049109:Cell Proliferation; D002470:Cell Survival; D018932:Chemokine CCL2 / Q000032:analysis; D015237:Dinoprost / Q000031:analogs & derivatives / Q000032:analysis; D005260:Female; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D016023:Integrins / Q000378:metabolism; D015850:Interleukin-6 / Q000032:analysis; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D015676:Osteonectin / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D010534:Peritoneal Neoplasms / Q000378:metabolism / Q000556:secondary*; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
D018932:Chemokine CCL2; D016023:Integrins; D015850:Interleukin-6; D015676:Osteonectin; D019714:Tissue Inhibitor of Metalloproteinases; D042461:Vascular Endothelial Growth Factor A; C075750:8-epi-prostaglandin F2alpha; D015237:Dinoprost; D008666:Metalloendopeptidases