Tumor cell entry into the lymph node is controlled by CCL1 chemokine expressed by lymph node lymphatic sinuses

Das, Suvendu; Sarrou, Eliana; Podgrabinska, Simona; Cassella, Melanie; Mungamuri, Sathish Kumar; Feirt, Nikki; Gordon, Ronald E.; Nagi, Chandandeep; Wang, Yarong; Entenberg, David; Condeelis, John S.; Skobe, Mihaela

doi:10.1084/jem.20111627

Cited by 165 publications

(178 citation statements)

References 87 publications

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“…This novel function significantly increases our understanding of the complex role of TNF-a and inflammatory macrophages in the tumour microenvironment in promoting tumour growth, invasion and metastasis. In addition to our findings, TNF-a-induced tumour cell migration and induction of CCL1 might also facilitate to lymph node metastasis 47,48 . Perhaps, these other mechanisms coordinate with lymphangiogenesis in promoting lymphatic metastasis.…”

Section: Discussionsupporting

confidence: 80%

TNFR1 mediates TNF-α-induced tumour lymphangiogenesis and metastasis by modulating VEGF-C-VEGFR3 signalling

et al. 2014

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Inflammation and lymphangiogenesis are two cohesively coupled processes that promote tumour growth and invasion. Here we report that TNF-a markedly promotes tumour lymphangiogenesis and lymphatic metastasis. The TNF-a-TNFR1 signalling pathway directly stimulates lymphatic endothelial cell activity through a VEGFR3-independent mechanism. However, VEGFR3-induced lymphatic endothelial cell tips are a prerequisite for lymphatic vessel growth in vivo, and a VEGFR3 blockade completely ablates TNF-a-induced lymphangiogenesis. Moreover, TNF-a-TNFR1-activated inflammatory macrophages produce high levels of VEGF-C to coordinately activate VEGFR3. Genetic deletion of TNFR1 (Tnfr1 À / À ) in mice or depletion of tumour-associated macrophages (TAMs) virtually eliminates TNF-a-induced lymphangiogenesis and lymphatic metastasis. Gain-of-function experiments show that reconstitution of Tnfr1 þ / þ macrophages in Tnfr1 À / À mice largely restores tumour lymphangiogenesis and lymphatic metastasis. These findings shed mechanistic light on the intimate interplay between inflammation and lymphangiogenesis in cancer metastasis, and propose therapeutic intervention of lymphatic metastasis by targeting the TNF-a-TNFR1 pathway.

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Section: Discussionsupporting

confidence: 80%

TNFR1 mediates TNF-α-induced tumour lymphangiogenesis and metastasis by modulating VEGF-C-VEGFR3 signalling

et al. 2014

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“…The CCR8 axis has been found to be activated in urothelial and renal carcinomas resulting in immune response impairment, and it is responsible for apoptosis inhibition in lymphoma [53,54]. Furthermore, CCR8 function in melanoma cells is essential for the entry of metastatic cells into lymph nodes [55]. We show the relevance of CCR8 on EV uptake in GBM8 cells by the dose-dependent reduction of uptake in the presence of increasing concentrations of MC148, a highly selective virus-encoded CCR8 antagonist [56] (Figure 2(c)).…”

Section: Resultsmentioning

confidence: 99%

“…Noteworthy, in melanoma, where EV-mediated communication has been shown to be key for metastasis [5,102], highly malignant cells express elevated levels of CCR8 and migrate to the lymph node in response to the secretion of the ligand by lymphatic endothelial cells. Blocking of the CCR8 axis resulted in strong reduction of metastatic transit through the lymph node in xenograft models [55], suggestive of a potential role of EV uptake via CCR8 during melanoma metastasis.…”

Section: Discussionmentioning

confidence: 99%

Glycosylated extracellular vesicles released by glioblastoma cells are decorated by CCL18 allowing for cellular uptake via chemokine receptor CCR8

Berenguer

Lagerweij

Zhao

et al. 2018

J of Extracellular Vesicle

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Cancer cells release extracellular vesicles (EVs) that contain functional biomolecules such as RNA and proteins. EVs are transferred to recipient cancer cells and can promote tumour progression and therapy resistance. Through RNAi screening, we identified a novel EV uptake mechanism involving a triple interaction between the chemokine receptor CCR8 on the cells, glycans exposed on EVs and the soluble ligand CCL18. This ligand acts as bridging molecule, connecting EVs to cancer cells. We show that glioblastoma EVs promote cell proliferation and resistance to the alkylating agent temozolomide (TMZ). Using in vitro and in vivo stem-like glioblastoma models, we demonstrate that EV-induced phenotypes are neutralised by a small molecule CCR8 inhibitor, R243. Interference with chemokine receptors may offer therapeutic opportunities against EV-mediated cross-talk in glioblastoma.

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“…CCL1, the natural cognate ligand of CCR8 that we identified in our angiosarcoma comparison, is known to be involved in cancerrelated inflammation, malignant progression, and control of tumor cell entry into the lymph node. 28 Just recently, ANGPTL7 was reported to be a hypoxia-driven proangiogenetic factor upregulated in cancer cells that can induce malignant behavior in human prostate cancer cells: it could be an interesting candidate to profile across many schwannomas, to determine if its expression levels correlate with malignant progression. 29,30 Many of the upregulated genes that we identified in our study have been functionally characterized as part of the inflammatory response, a hallmark enabling characteristic that can support multiple cancer capabilities.…”

Section: Discussionmentioning

confidence: 99%

Identification, by systematic RNA sequencing, of novel candidate biomarkers and therapeutic targets in human soft tissue tumors

Sarver

Thayanithy

et al. 2015

Laboratory Investigation

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Human sarcomas comprise a heterogeneous group of more than 50 subtypes broadly classified into two groups: bone and soft tissue sarcomas. Such heterogeneity and their relative rarity have made them challenging targets for classification, biomarker identification, and development of improved treatment strategies. In this study, we used RNA sequencing to analyze 35 primary human tissue samples representing 13 different sarcoma subtypes, along with benign schwannoma, and normal bone and muscle tissues. For each sarcoma subtype, we detected unique messenger RNA (mRNA) expression signatures, which we further subjected to bioinformatic functional analysis, upstream regulatory analysis, and microRNA (miRNA) targeting analysis. We found that, for each sarcoma subtype, significantly upregulated genes and their deduced upstream regulators included not only previously implicated known players but also novel candidates not previously reported to be associated with sarcoma. For example, the schwannoma samples were characterized by high expression of not only the known associated proteins GFAP and GAP43 but also the novel player GJB6. Further, when we integrated our expression profiles with miRNA expression data from each sarcoma subtype, we were able to deduce potential key miRNA-gene regulator relationships for each. In the Ewing's sarcoma and fibromatosis samples, two sarcomas where miR-182-5p is significantly downregulated, multiple predicted targets were significantly upregulated, including HMCN1, NKX2-2, SCNN1G, and SOX2. In conclusion, despite the small number of samples per sarcoma subtype, we were able to identify key known players; concurrently, we discovered novel genes that may prove to be important in the molecular classification of sarcomas and in the development of novel treatments.

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Tumor cell entry into the lymph node is controlled by CCL1 chemokine expressed by lymph node lymphatic sinuses

Abstract: Blocking CCR8 inhibits entry of metastases from the collecting lymphatic vessel into the lymph node.

Cited by 165 publications

References 87 publications

TNFR1 mediates TNF-α-induced tumour lymphangiogenesis and metastasis by modulating VEGF-C-VEGFR3 signalling

TNFR1 mediates TNF-α-induced tumour lymphangiogenesis and metastasis by modulating VEGF-C-VEGFR3 signalling

Glycosylated extracellular vesicles released by glioblastoma cells are decorated by CCL18 allowing for cellular uptake via chemokine receptor CCR8

Identification, by systematic RNA sequencing, of novel candidate biomarkers and therapeutic targets in human soft tissue tumors

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