Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Normalization of the ovarian cancer microenvironment by SPARC. 1795 2

We have recently identified that the role of secreted protein acidic and rich in cysteine (SPARC) in amelioration of peritoneal ovarian carcinomatosis is mediated, at least in part, through mesothelial cell/lysophosphatidic acid-induced inflammatory response in ovarian cancer cells. The aim of this study was to elucidate the molecular mechanisms of the interactions between tumor cells and the cellular components of the ovarian cancer peritoneal microenvironment, specifically, mesothelial cells and macrophages. We found that SPARC not only significantly reduced macrophage chemoattractant protein-1 production and its macrophage chemotactic effect, but also attenuated the response of ovarian cancer cells to the mitogenic and proinvasive effects of macrophage chemo-attractant protein-1 and decreased macrophage-induced cancer cell invasiveness. Overexpression of SPARC in ovarian cancer cells significantly attenuated macrophage- and mesothelial cell-induced production and activity of interleukin-6, prostanoids (prostaglandins E2 and 8-isoprostanes) as well as matrix metalloproteinases and urokinase plasminogen activator. Moreover, the effects of SPARC overexpression in ovarian cancer cells were mediated, in part, through inhibition of nuclear factor-kappaB promoter activation. These results indicate, for the first time, that the effects of tumor SPARC as a negative regulator of ovarian cancer are mediated through decreased recruitment of macrophages and downregulation of the associated inflammation.
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PMID:SPARC ameliorates ovarian cancer-associated inflammation. 1881 49

Peritoneal metastasis (PM) is a very serious complication of gastrointestinal and gynecological malignancies which is poorly documented. Modified mesothelial cell layer and their microenvironments can favor fibrin deposition for cancer cell adhesion. Scanning and transmission electron microscopy of peritoneal surface and cancer cell clusters from cancer patients was done. Ascites and its impact on mesothelial cells were assessed by cytokine array. Neprilysin, matrix metalloprotease, epithelial mesenchymal transition (EMT) related molecules (E-cadherin, Snail, Slug, Twist, Vimentin and Fibronectin), tissues factor (TF), endothelial protein C receptors (EPCR) were quantified by q-PCR. Fibrin in the simples were stained using anti fibrin F1E1 antibody. Migration ability was assessed by scratch assay. Cell viability and neprilysin activity were analyzed by bioluminescence. Cancer cells-fibrin interaction was investigated by scanning electron microscopy (SEM) and microcinematography (MCG). Mesothelial cells change their morphology after incubation with carcinomatosis peritoneal fluids in vitro. EMT associated with upregulation of neprilysin, matrix metalloproteinase-2, tissue factor and cytokines secretions such as interleukin-6, and 8, hepatocyte growth factor and granulocyte chemotactic protein-2 mRNA and protein were observed. EPCR expression as a natural anticoagulant was decreased. In parallel, carcinomatosis cell clusters extracted from peritoneal fluids were found to be associated with fibrin. Kinetic analysis of cancer cell-fibrin interaction in vitro studied by MCG showed that fiber filaments generated from clots inhibited cancer cell adhesion on fibrin clots. These results indicated that fibrin deposit on the peritoneal surface serve as niches for cancer expansion in carcinomatosis patients.
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PMID:Fibrin Deposit on the Peritoneal Surface Serves as a Niche for Cancer Expansion in Carcinomatosis Patients. 3173 30