Proteolysis during Tumor Cell Extravasation In Vitro: Metalloproteinase Involvement across Tumor Cell Types

Voura, Evelyn B.; English, Jane L.; Yu, Hoi-Ying Elsie; Ho, Andrew T.; Subarsky, Patrick; Hill, Richard P.; Hojilla, Carlo V.; Khokha, Rama

doi:10.1371/journal.pone.0078413

Cited by 35 publications

(28 citation statements)

References 63 publications

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“…In addition to PSGL‐1 shedding, transmigration of tumor cells through the endothelial cell layer is promoted by proteolytic degradation of tight junction proteins. This particular step is likely mediated by proteolysis that requires MMPs such as MMP‐9. By regulating MMP‐9, ADAM8 could also regulate this step of metastasis via transcriptional mechanisms involving ERK1/2 and CREB signaling.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, integrin‐mediated signals can enhance extracellular activities of matrix metalloproteases . MMPs furthermore promote a loss of the integrity of the basement membrane and allow direct invasion of carcinoma cells via proteolytic breakdown of tight junctions and extracellular matrix proteins . In this context, MMP‐9 promotes transendothelial migration and it is likely that regulation of MMP‐9 together with de‐adhesion of tumor cells from the endothelium is essential for the metastatic process.…”

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confidence: 99%

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ADAM8 expression in breast cancer derived brain metastases: Functional implications on MMP‐9 expression and transendothelial migration in breast cancer cells

Conrad

Götte

Schlomann

et al. 2017

Intl Journal of Cancer

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Metastatic breast cancer affects long-term survival and is a major cause of cancer death for women worldwide. The Metalloprotease-Disintegrin ADAM8 promotes breast cancer development and brain metastasis in a mouse breast cancer model. Here, abundant ADAM8 expression was detected in primary human breast tumors and associated brain metastases. To investigate the function of ADAM8 in metastasis, MB-231 breast cancer cells with ADAM8 knockdown (MB-231_shA8) and scramble control cells (MB-231_shCtrl) were analyzed for their capability to develop metastases. In vitro, formation of metastatic complexes in hanging drops is dependent on ADAM8 and blocked by ADAM8 inhibition. MB-231_shA8 in contrast to MB-231_shCtrl cells were impaired in transmigration through an endothelial and a reconstituted blood-brain barrier. Out of 23 MMP and 22 ADAM genes, only the MMP-9 gene was affected by ADAM8 knockdown in MB-231_shA8 cells. Following re-expression of wild-type ADAM8 in contrast to ADAM8 lacking the cytoplasmic domain in MB-231_shA8 cells caused increased levels of activated pERK1/2 and pCREB (S133) that were associated with elevated MMP-9 transcription. Application of ADAM8 and MMP-9 antibodies reduced transmigration of MB-231 cells suggesting that ADAM8 affects transmigration of breast cancer cells by MMP-9 regulation. ADAM8-dependent transmigration was confirmed in Hs578t cells overexpressing ADAM8. Moreover, transmigration of MB-231 and Hs578t cells was significantly reduced for cells treated with an antibody directed against P-selectin glycoprotein ligand (PSGL-1), a substrate of ADAM8. From these data we conclude that ADAM8 promotes early metastatic processes such as transendothelial migration by upregulation of MMP-9 and shedding of PSGL-1 from breast cancer cells.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

ADAM8 expression in breast cancer derived brain metastases: Functional implications on MMP‐9 expression and transendothelial migration in breast cancer cells

Conrad

Götte

Schlomann

et al. 2017

Intl Journal of Cancer

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“…Their precursors needed to be cut by Furin before maturation and activation [16]. Therefore, we also have examined the expression of VEGF-C and VEGF-D protein in A549 cells which were treated by a1-PDX.…”

Section: Discussionmentioning

confidence: 99%

Effect of Furin inhibitor on lung adenocarcinoma cell growth and metastasis

Fan

Rao

et al. 2014

Cancer Cell Int

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BackgroundTo investigate the mechanisms of lung adenocarcinoma cell metastasis and provide a theoretical basis for the in-depth study of lung adenocarcinoma.MethodsA549 cells are incubated with different concentrations of Furin inhibitor for indicated times. The proliferation and migration were confirmed with MTT, colony formation, wound Healing and Transwell assayes. Hochest 33342 / PI double staining was used to detect apoptosis. Cell migration and apoptosis associated proteins were analysed by enzyme-linked immunosorbent assay (ELISA) and western blot.ResultsWe have found that Furin inhibitor play a significant role in inhibition A549 cell growth. And we also found cell migration was inhibited significantly upon Furin inhibitor treatment.ConclusionThe proliferration and migration of A549 cell were inhibited by Furin inbitor through down-regulation the expression of migration and apoptosis related proteins.

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“…Cytokines such as IL-17 induce MMP-9 expression which promotes invasiveness in colorectal cancer cells [149]. MMP-9 is important in promoting the extravasation of tumor cells in the microenvironment [150,151]. increased the metastatic activity of prostate cancer cells.…”

Section: Mmp-9 and Ngal And The Tumor Microenvironmentmentioning

confidence: 99%

Roles of NGAL and MMP-9 in the tumor microenvironment and sensitivity to targeted therapy

Candido

Abrams

Steelman

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Various, diverse molecules contribute to the tumor microenvironment and influence invasion and metastasis. In this review, the roles of neutrophil gelatinase-associated lipocalin (NGAL) and matrix metalloproteinase-9 (MMP-9) in the tumor microenvironment and sensitivity to therapy will be discussed. The lipocalin family of proteins has many important functions. For example when NGAL forms a complex with MMP-9 it increases its stability which is important in cancer metastasis. Small hydrophobic molecules are bound by NGAL which can alter their entry into and efflux from cells. Iron transport and storage are also influenced by NGAL activity. Regulation of iron levels is important for survival in the tumor microenvironment as well as metastasis. Innate immunity is also regulated by NGAL as it can have bacteriostatic properties. NGAL and MMP-9 expression may also affect the sensitivity of cancer cells to chemotherapy as well as targeted therapy. Thus NGAL and MMP-9 play important roles in key processes involved in metastasis as well as response to therapy. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis, Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza.

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Proteolysis during Tumor Cell Extravasation In Vitro: Metalloproteinase Involvement across Tumor Cell Types

Cited by 35 publications

References 63 publications

ADAM8 expression in breast cancer derived brain metastases: Functional implications on MMP‐9 expression and transendothelial migration in breast cancer cells

ADAM8 expression in breast cancer derived brain metastases: Functional implications on MMP‐9 expression and transendothelial migration in breast cancer cells

Effect of Furin inhibitor on lung adenocarcinoma cell growth and metastasis

Roles of NGAL and MMP-9 in the tumor microenvironment and sensitivity to targeted therapy

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