Topotecan inhibits cancer cell migration by down-regulation of chemokine CC motif receptor 7 and matrix metalloproteinases

Lin, Sensen; Sun, Li; Zhang, Yan-kai; Zhao, Renping; Liang, Wenlu; Yuan, Shengtao; Zhang, Luyong

doi:10.1038/aps.2009.32

Cited by 10 publications

(7 citation statements)

References 31 publications

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“…These results suggest that ethoxidine is able to differentially regulate events leading to angiogenesis. Similar results have been reported with topotecan, which mediates activation of transcription factors that regulate MMP2 expression both in tumor cells (29) and in endothelial cells (30) suggesting that it affects both tumor cells and endothelial cells for its therapeutic property when it is used at high concentration (10 À7 to 10 À6 M). Also, it is clear from the present study that ethoxidine at a concentration at which it had no reported effect on tumor cells (i.e.…”

Section: Discussionsupporting

confidence: 83%

Paradoxical effects of ethoxidine, a topoisomerase I inhibitor, in the cellular processes leading to angiogenesis on endothelial cells

Clere¹,

Faure²,

Hélesbeux

et al. 2010

Carcinogenesis

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Angiogenesis, a critical step in tumorigenesis, is defined by different processes leading to neovascularization. Topoisomerase I (Top I) is the target for some of the most successful anticancer drugs that decrease tumor cell proliferation. Ethoxidine, a benzo[c]phenanthridines derivative, camptothecin analogue, has been identified as a potent inhibitor of Top I in various cancer cell lines. This study was aimed to investigate the impact of ethoxidine on angiogenesis and cellular processes including migration, proliferation and adhesion since these processes play an important role in tumor progression. Ethoxidine was incubated for 24 h at low (10⁻⁹ M) and high (10⁻⁵ M) concentrations on two types of human endothelial cells: EaHy.926 and human umbilical endothelial cells. Vascular endothelial growth factor (VEGF, 20 ng/ml) was used as a positive control. Ethoxidine at low concentration increased cell proliferation and migration that was associated with enhanced metalloproteinase 2 expression and activity, whereas high concentration of ethoxidine inhibited all of these effects. The two concentrations of ethoxidine did not affect endothelial cell adhesion. Low concentration of ethoxidine increased VEGF expression and endothelial nitric oxide (NO) synthase expression, NO and superoxide anion productions, whereas high concentration of ethoxidine did not induce any effect. Taken together, the present results highlight paradoxical effects of ethoxidine on angiogenesis depending on the concentration used. This study underscores that in addition to its anti-proliferative properties, ethoxidine may affect the generation of vascular network in tumorigenesis.

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Section: Discussionsupporting

confidence: 83%

Paradoxical effects of ethoxidine, a topoisomerase I inhibitor, in the cellular processes leading to angiogenesis on endothelial cells

Clere¹,

Faure²,

Hélesbeux

et al. 2010

Carcinogenesis

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“…MDA-MB-231 cells are known to express CCR7 (23,24) and migrate toward increasing concentration of CCL21 when cultured in 2D and exposed to a CCL21 gradient (25). The system consists of two channels separated by a region containing single cells suspended in a collagen I gel (Fig.…”

Section: Resultsmentioning

confidence: 99%

Interstitial flow influences direction of tumor cell migration through competing mechanisms

Polacheck¹,

Charest

Kamm

2011

Proc. Natl. Acad. Sci. U.S.A.

432

434

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Interstitial flow is the convective transport of fluid through tissue extracellular matrix. This creeping fluid flow has been shown to affect the morphology and migration of cells such as fibroblasts, cancer cells, endothelial cells, and mesenchymal stem cells. A microfluidic cell culture system was designed to apply stable pressure gradients and fluid flow and allow direct visualization of transient responses of cells seeded in a 3D collagen type I scaffold. We used this system to examine the effects of interstitial flow on cancer cell morphology and migration and to extend previous studies showing that interstitial flow increases the metastatic potential of MDA-MB-435S melanoma cells [Shields J, et al. (2007) Cancer Cell 11:526-538]. Using a breast carcinoma line (MDA-MB-231) we also observed cell migration along streamlines in the presence of flow; however, we further demonstrated that the strength of the flow as well as the cell density determined directional bias of migration along the streamline. In particular, we found that cells either at high seeding density or with the CCR-7 receptor inhibited migration against, rather than with the flow. We provide further evidence that CCR7-dependent autologous chemotaxis is the mechanism that leads to migration with the flow, but also demonstrate a competing CCR7-independent mechanism that causes migration against the flow. Data from experiments investigating the effects of cell concentration, interstitial flow rate, receptor activity, and focal adhesion kinase phosphorylation support our hypothesis that the competing stimulus is integrin mediated. This mechanism may play an important role in development of metastatic disease. mechanobiology | computational model | signaling | cell mechanics T issues are composed of cells residing in an extracellular matrix (ECM) containing interstitial fluid that transports nutrients and signaling molecules (1, 2). Osmotic and hydrostatic pressure gradients across tissues resulting from physiologic processes such as drainage toward lymphatics, inflammation, locally elevated pressures due to tumor growth or leaky microvessels, and muscle contraction each drive fluid flow through the ECM (2, 3). This fluid flow is termed interstitial flow and has long been recognized to be instrumental in tissue transport and physiology (1, 4, 5). Chary and Jain used fluorescence recovery after photobleaching to directly observe fluid flow in the tissue interstitium and determined typical flow velocities to be on the order of 0.1-2.0 μm/s, and more recent studies have demonstrated that flow can reach velocities as high as 4.0 μm/s (6, 7).Interstitial flow is particularly important in driving transport in the vicinity of tumors, as neoplastic tissue is often characterized by localized increases in interstitial pressure, leading to high interstitial pressure gradients at the tumor margin (8). Interstitial flow has hence emerged as a possible stimulus for guiding tumor cell migration in the formation of metastases (9-12).Shields et al. observed increase...

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“…Furthermore, targeted delivery of the gene delivery system expressing CCR7 antagonistic proteins to the tumour site significantly inhibited CCL21/CCR7-mediated tumour cell lymphatic migration by blocking the binding of CCL21 to CCR7 in 4T1 and B16F10 30 . In addition, CCR7 can be downregulated by topotecan, a semi-synthetic analogue of camptothecin, thereby inhibiting metastasis in breast cancer 49 . In this study, PTX treatment could delay tumour growth but increase the risk of tumour metastasis, but inhibition of CCR7 could decrease the PTX-induced migration of B16F10 cells.…”

Section: Discussionmentioning

confidence: 99%

Paclitaxel treatment enhances lymphatic metastasis of B16F10 melanoma cells via CCL21/CCR7 axis

Zhang¹,

Zhu²,

Yao³

et al. 2022

Int. J. Biol. Sci.

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Chemotherapeutic drugs have been successfully used to treat several cancers, including melanoma. However, metastasis occasionally occurs after chemotherapy. Here, we reported that paclitaxel (PTX) treatment for B16F10 tumour in mice led to an enhanced lymphatic metastasis of the melanoma cells, although a significant inhibition of tumour growth at the injection site was observed. Further study demonstrated that PTX upregulated the expression of C-C chemokine receptor type 7 (CCR7) in B16F10 cells, enhancing their migration through the activation of JNK and p38 signalling pathways. Loss of CCR7 or blockade of C-C motif chemokine ligand 21 (CCL21)/CCR7 axis abolished the pro-migration effect of PTX on B16F10 melanoma cells. Importantly, combination of PTX and CCR7 mAb could simultaneously delay the tumour growth and reduce the lymphatic metastasis in B16F10 melanoma. The blockade of CCL21/CCR7 axis may collectively serve as a strategy for lymphatic metastasis in some melanoma after chemotherapy.

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Topotecan inhibits cancer cell migration by down-regulation of chemokine CC motif receptor 7 and matrix metalloproteinases

Cited by 10 publications

References 31 publications

Paradoxical effects of ethoxidine, a topoisomerase I inhibitor, in the cellular processes leading to angiogenesis on endothelial cells

Paradoxical effects of ethoxidine, a topoisomerase I inhibitor, in the cellular processes leading to angiogenesis on endothelial cells

Interstitial flow influences direction of tumor cell migration through competing mechanisms

Paclitaxel treatment enhances lymphatic metastasis of B16F10 melanoma cells via CCL21/CCR7 axis

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