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By activating matrix metalloproteinase-7, shear stress promotes chondrosarcoma cell motility, invasion and lung colonization.

Guan PP, Yu X, Guo JJ, Wang Y, Wang T, Li JY, Konstantopoulos K, Wang ZY, Wang P - Oncotarget (2015)

Bottom Line: Interstitial fluid flow and associated shear stress are relevant mechanical signals in cartilage and bone (patho)physiology.However, their effects on chondrosarcoma cell motility, invasion and metastasis have yet to be delineated.Using human SW1353, HS.819.T and CH2879 chondrosarcoma cell lines as model systems, we found that fluid shear stress induces the accumulation of cyclic AMP (cAMP) and interleukin-1β (IL-1β), which in turn markedly enhance chondrosarcoma cell motility and invasion via the induction of matrix metalloproteinase-7 (MMP-7).

View Article: PubMed Central - PubMed

Affiliation: College of Life and Health Sciences, Northeastern University, Shenyang 110819, P. R. China.

ABSTRACT
Interstitial fluid flow and associated shear stress are relevant mechanical signals in cartilage and bone (patho)physiology. However, their effects on chondrosarcoma cell motility, invasion and metastasis have yet to be delineated. Using human SW1353, HS.819.T and CH2879 chondrosarcoma cell lines as model systems, we found that fluid shear stress induces the accumulation of cyclic AMP (cAMP) and interleukin-1β (IL-1β), which in turn markedly enhance chondrosarcoma cell motility and invasion via the induction of matrix metalloproteinase-7 (MMP-7). Specifically, shear-induced cAMP and IL-1β activate PI3-K, ERK1/2 and p38 signaling pathways, which lead to the synthesis of MMP-7 via transactivating NF-κB and c-Jun in human chondrosarcoma cells. Importantly, MMP-7 upregulation in response to shear stress exposure has the ability to promote lung colonization of chondrosarcomas in vivo. These findings offer a better understanding of the mechanisms underlying MMP-7 activation in shear-stimulated chondrosarcoma cells, and provide insights on designing new therapeutic strategies to interfere with chondrosarcoma invasion and metastasis.

No MeSH data available.


Related in: MedlinePlus

Signaling cascades involved in MMP-7 regulation in response to fluid shear stress, which in turn mediates chondrosarcoma metastasisFluid shear stress (2 dyn/cm2) induces cAMP and IL-1β production and release in human SW1353 chondrosarcoma cells. Elevated levels of cAMP and IL-1β stimulate the activity of PI3-K/AKT, p38 and ERK1/2 pathways, which in turn upregulate MMP-7 synthesis in a c-Jun- and NF-κB-dependent manner. Transactivation of MMP-7 mediates chondrosarcoma migration and invasion, thereby contributing to chondrosarcoma metastasis.
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Figure 7: Signaling cascades involved in MMP-7 regulation in response to fluid shear stress, which in turn mediates chondrosarcoma metastasisFluid shear stress (2 dyn/cm2) induces cAMP and IL-1β production and release in human SW1353 chondrosarcoma cells. Elevated levels of cAMP and IL-1β stimulate the activity of PI3-K/AKT, p38 and ERK1/2 pathways, which in turn upregulate MMP-7 synthesis in a c-Jun- and NF-κB-dependent manner. Transactivation of MMP-7 mediates chondrosarcoma migration and invasion, thereby contributing to chondrosarcoma metastasis.

Mentions: Prior work has suggested that MMP-7 correlates with the degree of malignancy in human chondrosarcoma [7]. We and others have reported the involvement of MMP-7 in the migration and invasion of different tumor cell types [7, 8, 21]. We herein sought to delineate the mechanism by which fluid shear stress potentiates chondrosarcoma cells motility and invasion. In view of our observations showing that endogenous cAMP and IL-1β regulate shear-induced MMP-7 activation, we examined the potential effects of exogenously added forskolin (10 μM) and IL-1β (100 ng/ml) on SW1353 cell motility and invasion. Both forskolin and IL-1β augmented SW1353 cell motility and invasion as shown in Transwell assays (Figs. 5A–5D). Interestingly, incubation of SW1353 cells with the PI3-K inhibitor LY294002 (10 μM), the ERK1/2 inhibitor U0126 (10 μM), the p38 inhibitor SB203580 (10 μM), the JNK inhibitor SP600125 (10 μM) or the NF-kB inhibitor QNZ (2 μM) abrogated the ability of forskolin or IL-1β (100 ng/ml) to augment SW1353 cells migration and invasion (Figs. 5A–5D). To further establish the relationship between shear stress and tumor migration and invasion, shear conditioned medium was collected and used as chemoatractant. The results reveal that sheared medium markedly increased the migration and invasion of human SW1353 cells (Figs. 5E, 5F). In light of these findings, we also assessed the potential contribution of MMP-7 to the migration and invasion of human chondrosarcoma cells. As a first step, we treated human SW1353 cells with rhMMP-7 (1 μg/ml). The results indicate that treatment of SW1353 cells with rhMMP-7 increased their motility and invasion in vitro (Figs. 5G, 5H). Of note, MMP-7 overexpression by MMP-7 cDNA plasmid transfection also enhanced the migration and invasion of human SW1353 cells. To extend these in vitro observations to the in vivo setting, mice were injected via tail vein with CH2879 chondrosarcoma cells treated with rhMMP-7 or transfected with either MMP-7 cDNA or the empty vector. rhMMP-7 treatment or ectopic expression of MMP-7 markedly increased lung colonization in vivo, as evidenced by the higher number of micrometastases and higher human DNA content in the lung of mice (Figs. 6A, 6B). To further support and confirm these in vivo data, live animal imaging experiments were carried out and CH2879 cells transfected with MMP-7 cDNA-mcherry plasmid were injected to mice via tail vein. The mice were anesthetized and scanned using Bruker in vivo imaging systems (MS FX PRO, Carestream, U.S.A). After 35 days injection, the cells migrated and colonized the lungs of NOD/SCID/IL2 receptor gamma knockout mice (Fig. 6C). Taken together, fluid shear stress induces the accumulation of cAMP- and IL-1β, which in turn activate PI3-K-, ERK1/2-, p38-dependent signaling pathways leading to MMP-7 induction via transactivation of NF-κB and c-Jun in human chondrosarcoma cells (Fig. 7); shear-induced MMP-7 promotes chondrosarcoma cell motility and invasion in vitro and in vivo.


By activating matrix metalloproteinase-7, shear stress promotes chondrosarcoma cell motility, invasion and lung colonization.

Guan PP, Yu X, Guo JJ, Wang Y, Wang T, Li JY, Konstantopoulos K, Wang ZY, Wang P - Oncotarget (2015)

Signaling cascades involved in MMP-7 regulation in response to fluid shear stress, which in turn mediates chondrosarcoma metastasisFluid shear stress (2 dyn/cm2) induces cAMP and IL-1β production and release in human SW1353 chondrosarcoma cells. Elevated levels of cAMP and IL-1β stimulate the activity of PI3-K/AKT, p38 and ERK1/2 pathways, which in turn upregulate MMP-7 synthesis in a c-Jun- and NF-κB-dependent manner. Transactivation of MMP-7 mediates chondrosarcoma migration and invasion, thereby contributing to chondrosarcoma metastasis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496208&req=5

Figure 7: Signaling cascades involved in MMP-7 regulation in response to fluid shear stress, which in turn mediates chondrosarcoma metastasisFluid shear stress (2 dyn/cm2) induces cAMP and IL-1β production and release in human SW1353 chondrosarcoma cells. Elevated levels of cAMP and IL-1β stimulate the activity of PI3-K/AKT, p38 and ERK1/2 pathways, which in turn upregulate MMP-7 synthesis in a c-Jun- and NF-κB-dependent manner. Transactivation of MMP-7 mediates chondrosarcoma migration and invasion, thereby contributing to chondrosarcoma metastasis.
Mentions: Prior work has suggested that MMP-7 correlates with the degree of malignancy in human chondrosarcoma [7]. We and others have reported the involvement of MMP-7 in the migration and invasion of different tumor cell types [7, 8, 21]. We herein sought to delineate the mechanism by which fluid shear stress potentiates chondrosarcoma cells motility and invasion. In view of our observations showing that endogenous cAMP and IL-1β regulate shear-induced MMP-7 activation, we examined the potential effects of exogenously added forskolin (10 μM) and IL-1β (100 ng/ml) on SW1353 cell motility and invasion. Both forskolin and IL-1β augmented SW1353 cell motility and invasion as shown in Transwell assays (Figs. 5A–5D). Interestingly, incubation of SW1353 cells with the PI3-K inhibitor LY294002 (10 μM), the ERK1/2 inhibitor U0126 (10 μM), the p38 inhibitor SB203580 (10 μM), the JNK inhibitor SP600125 (10 μM) or the NF-kB inhibitor QNZ (2 μM) abrogated the ability of forskolin or IL-1β (100 ng/ml) to augment SW1353 cells migration and invasion (Figs. 5A–5D). To further establish the relationship between shear stress and tumor migration and invasion, shear conditioned medium was collected and used as chemoatractant. The results reveal that sheared medium markedly increased the migration and invasion of human SW1353 cells (Figs. 5E, 5F). In light of these findings, we also assessed the potential contribution of MMP-7 to the migration and invasion of human chondrosarcoma cells. As a first step, we treated human SW1353 cells with rhMMP-7 (1 μg/ml). The results indicate that treatment of SW1353 cells with rhMMP-7 increased their motility and invasion in vitro (Figs. 5G, 5H). Of note, MMP-7 overexpression by MMP-7 cDNA plasmid transfection also enhanced the migration and invasion of human SW1353 cells. To extend these in vitro observations to the in vivo setting, mice were injected via tail vein with CH2879 chondrosarcoma cells treated with rhMMP-7 or transfected with either MMP-7 cDNA or the empty vector. rhMMP-7 treatment or ectopic expression of MMP-7 markedly increased lung colonization in vivo, as evidenced by the higher number of micrometastases and higher human DNA content in the lung of mice (Figs. 6A, 6B). To further support and confirm these in vivo data, live animal imaging experiments were carried out and CH2879 cells transfected with MMP-7 cDNA-mcherry plasmid were injected to mice via tail vein. The mice were anesthetized and scanned using Bruker in vivo imaging systems (MS FX PRO, Carestream, U.S.A). After 35 days injection, the cells migrated and colonized the lungs of NOD/SCID/IL2 receptor gamma knockout mice (Fig. 6C). Taken together, fluid shear stress induces the accumulation of cAMP- and IL-1β, which in turn activate PI3-K-, ERK1/2-, p38-dependent signaling pathways leading to MMP-7 induction via transactivation of NF-κB and c-Jun in human chondrosarcoma cells (Fig. 7); shear-induced MMP-7 promotes chondrosarcoma cell motility and invasion in vitro and in vivo.

Bottom Line: Interstitial fluid flow and associated shear stress are relevant mechanical signals in cartilage and bone (patho)physiology.However, their effects on chondrosarcoma cell motility, invasion and metastasis have yet to be delineated.Using human SW1353, HS.819.T and CH2879 chondrosarcoma cell lines as model systems, we found that fluid shear stress induces the accumulation of cyclic AMP (cAMP) and interleukin-1β (IL-1β), which in turn markedly enhance chondrosarcoma cell motility and invasion via the induction of matrix metalloproteinase-7 (MMP-7).

View Article: PubMed Central - PubMed

Affiliation: College of Life and Health Sciences, Northeastern University, Shenyang 110819, P. R. China.

ABSTRACT
Interstitial fluid flow and associated shear stress are relevant mechanical signals in cartilage and bone (patho)physiology. However, their effects on chondrosarcoma cell motility, invasion and metastasis have yet to be delineated. Using human SW1353, HS.819.T and CH2879 chondrosarcoma cell lines as model systems, we found that fluid shear stress induces the accumulation of cyclic AMP (cAMP) and interleukin-1β (IL-1β), which in turn markedly enhance chondrosarcoma cell motility and invasion via the induction of matrix metalloproteinase-7 (MMP-7). Specifically, shear-induced cAMP and IL-1β activate PI3-K, ERK1/2 and p38 signaling pathways, which lead to the synthesis of MMP-7 via transactivating NF-κB and c-Jun in human chondrosarcoma cells. Importantly, MMP-7 upregulation in response to shear stress exposure has the ability to promote lung colonization of chondrosarcomas in vivo. These findings offer a better understanding of the mechanisms underlying MMP-7 activation in shear-stimulated chondrosarcoma cells, and provide insights on designing new therapeutic strategies to interfere with chondrosarcoma invasion and metastasis.

No MeSH data available.


Related in: MedlinePlus