Syngeneic lymph-node-targeting model of green fluorescent protein-expressing Lewis lung carcinoma

Bobek, Vladimír; Kološtová, Katarína; Pinterov, Daniela; Boubelı́k, Michael; Jiang, Ping; Yang, Meng; Hoffman, Robert M.

doi:10.1007/s10585-004-8118-8

Cited by 11 publications

(6 citation statements)

References 15 publications

(24 reference statements)

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“…Initially, mutant ( Ndst1 f/f TekCre + ) mice showed not only a reduction in LLC metastasis to regional lymph nodes, but also a reduction in CCL21 associated with metastatic tumor colonies (Figure 2B). Nodal metastasis in subcutaneous Lewis lung carcinoma models has been shown to occur via the afferent lymphatic conduit that intervenes between primary tumor and regional lymph nodes [45]. The findings support an important role for HS in mediating chemokine-dependent lymphatic-borne trafficking of tumor cells to the regional lymph nodes.…”

Section: Discussionmentioning

confidence: 68%

A critical role for lymphatic endothelial heparan sulfate in lymph node metastasis

et al. 2010

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BackgroundLymph node metastasis constitutes a key event in tumor progression. The molecular control of this process is poorly understood. Heparan sulfate is a linear polysaccharide consisting of unique sulfate-modified disaccharide repeats that allow the glycan to bind a variety of proteins, including chemokines. While some chemokines may drive lymphatic trafficking of tumor cells, the functional and genetic importance of heparan sulfate as a possible mediator of chemokine actions in lymphatic metastasis has not been reported.ResultsWe applied a loss-of-function genetic approach employing lymphatic endothelial conditional mutations in heparan sulfate biosynthesis to study the effects on tumor-lymphatic trafficking and lymph node metastasis. Lymphatic endothelial deficiency in N-deacetylase/N-sulfotransferase-1 (Ndst1), a key enzyme involved in sulfating nascent heparan sulfate chains, resulted in altered lymph node metastasis in tumor-bearing gene targeted mice. This occurred in mice harboring either a pan-endothelial Ndst1 mutation or an inducible lymphatic-endothelial specific mutation in Ndst1. In addition to a marked reduction in tumor metastases to the regional lymph nodes in mutant mice, specific immuno-localization of CCL21, a heparin-binding chemokine known to regulate leukocyte and possibly tumor-cell traffic, showed a marked reduction in its ability to associate with tumor cells in mutant lymph nodes. In vitro modified chemotaxis studies targeting heparan sulfate biosynthesis in lymphatic endothelial cells revealed that heparan sulfate secreted by lymphatic endothelium is required for CCL21-dependent directional migration of murine as well as human lung carcinoma cells toward the targeted lymphatic endothelium. Lymphatic heparan sulfate was also required for binding of CCL21 to its receptor CCR7 on tumor cells as well as the activation of migration signaling pathways in tumor cells exposed to lymphatic conditioned medium. Finally, lymphatic cell-surface heparan sulfate facilitated receptor-dependent binding and concentration of CCL21 on the lymphatic endothelium, thereby serving as a mechanism to generate lymphatic chemokine gradients.ConclusionsThis work demonstrates the genetic importance of host lymphatic heparan sulfate in mediating chemokine dependent tumor-cell traffic in the lymphatic microenvironment. The impact on chemokine dependent lymphatic metastasis may guide novel therapeutic strategies.

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Section: Discussionmentioning

confidence: 68%

A critical role for lymphatic endothelial heparan sulfate in lymph node metastasis

et al. 2010

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“…LLC cells (1 Â 10 6 ) mixed with or without various macrophages (3 Â 10 6 ) in 0.1 ml Hanks' Balanced Salt Solution were injected subcutaneouly into the dorsal side of the ear of female C57BL/6 mice as described previously [Bobek et al, 2004;Orimo et al, 2005] [Schoppmann et al, 2002]. The mean number of lymphatic microvessel density (LMVD) was counted and used in the statistical analysis.…”

Section: Implantation Of Tumors and Metastasis Analysismentioning

confidence: 99%

Alternatively activated RAW264.7 macrophages enhance tumor lymphangiogenesis in mouse lung adenocarcinoma

Zhang

Wang

Gao

et al. 2009

J of Cellular Biochemistry

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Tumor-associated macrophages (TAMs) have been implicated in promoting tumor progression and invasion. The onset and maintenance of tumor angiogenesis and lymphangiogenesis also seem to be partly driven by a group of polarized alternatively activated macrophages (aaMphi) in lung adenocarcinoma. Here, the aaMphi and classically activated macrophages (caMphi) were obtained using RAW264.7 cells via IL-4 and IFN-gamma + LPS treatment, respectively. Co-inoculation of aaMphi with Lewis lung carcinoma (LLC) cells promoted tumor growth, increased lymph node metastasis, and reduced the survival in C57BL/6 mice bearing LLC. Furthermore, the effects of the activated macrophages on the lymphangiogenesis-related properties of lymphatic endothelial cells (LECs) were investigated in vitro. When LECs were cultured in macrophages conditioned medium or in a co-culture system of macrophages and LECs, aaMphi significantly promoted proliferation, migration, and tube-like formation of LECs. We identified high VEGF-C expression in aaMphi and low expression in caMphi as well as unactivated macrophages by ELISA and Western blotting. In LECs, co-culture with aaMphi resulted in a significant increase of mRNA levels of specific lymphatic marker VEGF receptor-3 and the homeobox gene Prox-1, as well as lymphangiogenic factor VEGF-C rather than VEGF-D by quantitative RT-PCR. Furthermore, enhanced LECs migration and capillary formation by co-culture with aaMphi were significantly inhibited by rVEGF receptor-3/Fc chimera. In conclusion, these data show that aaMphi play a critical role in tumor-induced lymphangiogenesis through up-regulating VEGF-C and increasing lymphangiogenesis-related behavior of LECs, which may contribute to lymphatic invasion in lung adenocarcinoma.

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“…10 6 cells in 0.1 ml Hanks' balanced salt solution) were inoculated between the skin and cartilage on the dorsal side of the left ear, under deep inhalation anesthesia using ether as described previously [15] . Mice were randomized into a control group and a group that received ART treatment (10 mice/group).…”

Section: Llc Modelsmentioning

confidence: 99%

Artemisinin Inhibits Tumor Lymphangiogenesis by Suppression of Vascular Endothelial Growth Factor C

Wang

Zhang²,

Guo³

et al. 2008

Pharmacology

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We have previously reported that dihydroartemisinin is found to have a potent ability in influencing lymphatic endothelial cell migration and tube formation. In this study, we investigated the effect of artemisinin on tumor growth, lymphangiogenesis, metastasis and survival in mouse Lewis lung carcinoma (LLC) models. We found that orally administered artemisinin inhibited lymph node and lung metastasis and prolonged survival without retarding tumor growth. Consistent with the decrease in lymph node metastasis, tumor lymphangiogenesis and expression of vascular endothelial growth factor C (VEGF-C) was significantly decreased in artemisinin-treated mice, as compared to control mice. Furthermore, IL-1β-induced p38 mitogen-activated protein kinase (MAPK) activation and upregulation of VEGF-C mRNA and protein in LLC cells was also suppressed by artemisinin or by the p38 MAPK inhibitor SB-203580, suggesting that p38 MAPK could serve as a mediator of proinflammatory cytokine-induced VEGF-C expression. These data indicate that artemisinin may be useful for the prevention of lymph node metastasis by downregulating VEGF-C and reducing tumor lymphangiogenesis.

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Syngeneic lymph-node-targeting model of green fluorescent protein-expressing Lewis lung carcinoma

Cited by 11 publications

References 15 publications

A critical role for lymphatic endothelial heparan sulfate in lymph node metastasis

A critical role for lymphatic endothelial heparan sulfate in lymph node metastasis

Alternatively activated RAW264.7 macrophages enhance tumor lymphangiogenesis in mouse lung adenocarcinoma

Artemisinin Inhibits Tumor Lymphangiogenesis by Suppression of Vascular Endothelial Growth Factor C

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