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Variable inhibition of thrombospondin 1 against liver and lung metastases through differential activation of metalloproteinase ADAMTS1.

ABSTRACT: Metastasis relies on angiogenesis for tumor expansion. Tumor angiogenesis is restrained by a variety of endogenous inhibitors, including thrombospondin 1 (TSP1). The principal antiangiogenic activity of TSP1 resides in a domain containing three TSP1 repeats (3TSR), and TSP1 cleavage is regulated, in part, by the metalloproteinase ADAMTS1. In this study, we examined the role of TSP1 and ADAMTS1 in controlling metastatic disease in the liver and lung. TSP1 overexpression inhibited metastatic growth of colon or renal carcinoma cells in liver but not lung. Metastatic melanoma in liver grew more rapidly in Tsp1-null mice compared with controls, whereas in lung grew similarly in Tsp1-null mice or controls. Recombinant TSP1 was cleaved more efficiently in lysates from liver than lung. ADAMTS1 inhibition by neutralizing antibody, small interfering RNA, or genetic deletion abrogated cleavage activity. To confirm that lack of cleavage of TSP1 ablated its antiangiogenic function in the lung, we generated colon cancer cells stably secreting only the 3TSR domain and found that they inhibited formation of both liver and lung metastases. Collectively, our results indicate that the antiangiogenic activity of TSP1 is differentially regulated by ADAMTS1 in the liver and lung, emphasizing the concept that regulation of angiogenesis is varied in different tissue environments.

SUBMITTER: Lee YJ

PROVIDER: S-EPMC2934910 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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RETRACTED: Variable inhibition of thrombospondin 1 against liver and lung metastases through differential activation of metalloproteinase ADAMTS1.

Lee Yoon-Jin YJ Koch Moritz M Karl Daniel D Torres-Collado Antoni X AX Fernando Namali T NT Rothrock Courtney C Kuruppu Darshini D Ryeom Sandra S Iruela-Arispe M Luisa ML Yoon Sam S SS

Cancer research 20100126 3

Metastasis relies on angiogenesis for tumor expansion. Tumor angiogenesis is restrained by a variety of endogenous inhibitors, including thrombospondin 1 (TSP1). The principal antiangiogenic activity of TSP1 resides in a domain containing three TSP1 repeats (3TSR), and TSP1 cleavage is regulated, in part, by the metalloproteinase ADAMTS1. In this study, we examined the role of TSP1 and ADAMTS1 in controlling metastatic disease in the liver and lung. TSP1 overexpression inhibited metastatic growt ...[more]

PMID: 20103648

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Project description:Background and aimsThis study examined whether enhanced susceptibility of steatotic liver to ischemia-reperfusion (I/R) injury is due to impaired recruitment of bone marrow (BM) progenitors of liver sinusoidal endothelial cells (LSECs, also called sinusoidal endothelial cell progenitor cells [sprocs]) with diminished repair of injured LSECs and whether restoring signaling to recruit BM sprocs reduces I/R injury.Approach and resultsHepatic vessels were clamped for 1 hour in rats fed a high-fat, high-fructose (HFHF) diet for 5, 10, or 15 weeks. Matrix metalloproteinase 9 (MMP-9) antisense oligonucleotides (ASO) or an MMP inhibitor were used to induce liver-selective MMP-9 inhibition. HFHF rats had mild, moderate, and severe steatosis, respectively, at 5, 10, and 15 weeks. I/R injury was enhanced in HFHF rats; this was accompanied by complete absence of hepatic vascular endothelial growth factor (VEGF)-stromal cell-derived factor 1 (sdf1) signaling, leading to lack of BM sproc recruitment. Liver-selective MMP-9 inhibition to protect against proteolytic cleavage of hepatic VEGF using either MMP-9 ASO or intraportal MMP inhibitor in 5-week and 10-week HFHF rats enhanced hepatic VEGF-sdf1 signaling, increased BM sproc recruitment, and reduced alanine aminotransferase (ALT) by 92% and 77% at 5 weeks and by 80% and 64% at 10 weeks of the HFHF diet, respectively. After I/R injury in 15-week HFHF rats, the MMP inhibitor reduced active MMP-9 expression by 97%, ameliorated histologic evidence of injury, and reduced ALT by 58%, which is comparable to control rats sustaining I/R injury. Rescue therapy with intraportal MMP inhibitor, given after ischemia, in the 5-week HFHF rat reduced ALT by 71% and reduced necrosis.ConclusionsLack of signaling to recruit BM sprocs that repair injured LSECs renders steatotic liver more susceptible to I/R injury. Liver-selective MMP-9 inhibition enhances VEGF-sdf1 signaling and recruitment of BM sprocs, which markedly protects against I/R injury, even in severely steatotic rats.

Project description:PurposeLeukocyte adhesion to vascular and matrix Metalloproteinase-8 (MMP8) expression is increased in sepsis and associated with poor prognosis in sepsis patients. This study aimed to investigate the role of MMP8 in sepsis serum mediated leukocyte adhesion.MethodsBioinformatics analysis of GSE64457 and GSE65682 was performed to evaluate the role of MMP8 in the progression of sepsis. Expression of MMP8 in blood samples from patients with sepsis was detected by qRT-PCR and ELISA. Human umbilical vein endothelial cells (HUVECs) were treated with sepsis serum, control serum, and MMP8 inhibitor. Expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1) were detected by qRT-PCR and ELISA, respectively. The protein expression of total p38, phosphorylated-p38, ERK1/2, and p-ERK1/2 was detected by Western blotting. Peripheral blood mononuclear cells (PBMCs) and polymorphonuclear neutrophils (PMNs) were incubated with the treated HUVECs to calculate leukocyte adhesion.ResultsFour hundred and twenty-nine differentially expressed genes (DEGs) and seven hub genes between sepsis patients and healthy controls were identified. GO function analysis of DEGs and hub genes indicated that the DEGs and hub genes were mainly enriched in neutrophil activation. MMP8 was selected as a key gene with an unfavorable prognosis in sepsis patients. The mRNA and protein expression of MMP8 in blood from sepsis patients were significantly higher than controls. Leukocyte adhesion and mRNA and protein expression of VCAM-1 and ICAM-1 were significantly increased in the sepsis serum group compared to that in the control group, as was the protein expression of p-p38 and p-ERK1/2. However, the MMP8 inhibitor suppressed the leukocyte adhesion promoted by sepsis serum by decreasing the expression of VCAM-1, ICAM-1, p-p38, and p-ERK1/2.ConclusionOur study indicated that MMP8 acts as a key gene in the development of sepsis, and sepsis serum promotes leukocyte adhesion to HUVECs via MMP8, which suggest that MMP8 might be a potential therapeutic target for sepsis.

Dataset Information

Variable inhibition of thrombospondin 1 against liver and lung metastases through differential activation of metalloproteinase ADAMTS1.

Publications

RETRACTED: Variable inhibition of thrombospondin 1 against liver and lung metastases through differential activation of metalloproteinase ADAMTS1.

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