Role of Extracellular Vesicles on Cancer Lymphangiogenesis and Lymph Node Metastasis

Wang, Linlin; Li, Ling; Zhu, Guiquan

doi:10.3389/fonc.2021.721785

Cited by 10 publications

(6 citation statements)

References 76 publications

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“…Currently, exosomes as cellular communication mediators have been shown to be involved in modulating sequential metastatic processes ( 22 ). Most studies have shown the importance of lymphangiogenesis contributing to LNM and exosome-mediated lymphangiogenesis ( 23 , 24 ) but the role of lymphangiogenesis in LNM is still controversial ( 25 ). Therefore, from a different perspective, we revealed a novel mechanism whereby lymphatic metastatic GC cell-exosomes directly conferred the LNM phenotype on primary GC cells depending on FAO reprogramming.…”

Section: Discussionmentioning

confidence: 99%

Exosomal CD44 Transmits Lymph Node Metastatic Capacity Between Gastric Cancer Cells via YAP-CPT1A-Mediated FAO Reprogramming

Wang

Cao

et al. 2022

Front. Oncol.

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BackgroundLymph node metastasis (LNM) commonly occurs in gastric cancer (GC) and is tightly associated with poor prognosis. Exosome-mediated lymphangiogenesis has been considered an important driver of LNM. Whether exosomes directly transmit the LNM phenotype between GC cells and its mechanisms remain elusive.MethodsA highly lymphatic metastatic GC cell line (HGC-27-L) was established by serial passage of parental HGC-27 cells in BALB/c nude mice. The capacities of migration, invasion and LNM; fatty acid oxidation (FAO) levels; and the role of exosome-transferred LNM phenotype were compared among HGC-27-L, HGC-27 and primary GC cell line AGS. Exosomes derived from GC cells and sera were separately isolated using ultracentrifugation and ExoQuick exosome precipitation solution, and were characterized by transmission electron microscopy, Nanosight and western blotting. Transwell assay and LNM models were conducted to evaluate the capacities of migration, invasion and LNM of GC cells in vitro and in vivo. β-oxidation rate and CPT1 activity were measured to assess FAO. CPT1A inhibitor etomoxir was used to determine the role of FAO. Label-free LC-MS/MS proteome analysis screened the differential protein profiling between HGC-27-exosomes and AGS-exosomes. Small interference RNAs and YAP inhibitor verteporfin were used to elucidate the role and mechanism of exosomal CD44. TCGA data analysis, immunochemistry staining and ELISA were performed to analyze the expression correlation and clinical significance of CD44/YAP/CPT1A.ResultsFAO was increased in lymphatic metastatic GC cells and indispensable for sustaining LNM capacity. Lymphatic metastatic GC cell-exosomes conferred LNM capacity on primary GC cells in an FAO-dependent way. Mechanistically, CD44 was identified to be enriched in HGC-27-exosomes and was a critical cargo protein regulating exosome-mediated transmission, possibly by modulating the RhoA/YAP/Prox1/CPT1A signaling axis. Abnormal expression of CD44/YAP/CPT1A in GC tissues was correlated with each other and associated with LNM status, stages, invasion and poor survival. Serum exosomal CD44 concentration was positively correlated with tumor burden in lymph nodes.ConclusionsWe uncovered a novel mechanism: exosomal CD44 transmits LNM capacity between GC cells via YAP-CPT1A-mediated FAO reprogramming from the perspective of exosomes-transferred LNM phenotype. This provides potential therapeutic targets and a non-invasive biomarker for GC patients with LNM.

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Section: Discussionmentioning

confidence: 99%

Exosomal CD44 Transmits Lymph Node Metastatic Capacity Between Gastric Cancer Cells via YAP-CPT1A-Mediated FAO Reprogramming

Wang

Cao

et al. 2022

Front. Oncol.

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“…The TDLN modifications mentioned above, induced by tumor-secreted factors, prepare the LN for the arrival of cancer cells, creating the pre-metastatic niche ( 16 ). Although signals involved in this TDLN preparation remain to be completely understood, tumor-derived extracellular vesicles (TEVs) can serve as carriers of multiple tumor-derived molecules (nucleic acids, proteins and metabolites) that play a key role in the remodeling of TDLNs ( 176 , 177 ). TEVs can be transported by LVs to TDLNs, where they may be retained.…”

Section: Cancer -Lymphatic- Immune Cell Crosstalk During Metastatic D...mentioning

confidence: 99%

Immunomodulatory properties of the lymphatic endothelium in the tumor microenvironment

Viúdez-Pareja,

Kreft,

García-Caballero

2023

Front. Immunol.

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The tumor microenvironment (TME) is an intricate complex and dynamic structure composed of various cell types, including tumor, stromal and immune cells. Within this complex network, lymphatic endothelial cells (LECs) play a crucial role in regulating immune responses and influencing tumor progression and metastatic dissemination to lymph node and distant organs. Interestingly, LECs possess unique immunomodulatory properties that can either promote or inhibit anti-tumor immune responses. In fact, tumor-associated lymphangiogenesis can facilitate tumor cell dissemination and metastasis supporting immunoevasion, but also, different molecular mechanisms involved in LEC-mediated anti-tumor immunity have been already described. In this context, the crosstalk between cancer cells, LECs and immune cells and how this communication can shape the immune landscape in the TME is gaining increased interest in recent years. In this review, we present a comprehensive and updated report about the immunomodulatory properties of the lymphatic endothelium within the TME, with special focus on primary tumors and tumor-draining lymph nodes. Furthermore, we outline emerging research investigating the potential therapeutic strategies targeting the lymphatic endothelium to enhance anti-tumor immune responses. Understanding the intricate mechanisms involved in LEC-mediated immune modulation in the TME opens up new possibilities for the development of innovative approaches to fight cancer.

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“…Given that lymphangiogenesis plays a critical role in LN metastasis, it may be viable to treat cancers using an anti-lymphangiogenesis strategy ( 104 ). Some receptor tyrosine kinase inhibitors may exert negative effects on tumor-related lymphangiogenesis (and LN and distant organ metastases) by targeting the VEGF-C–VEGFR3 signaling pathway ( 105 , 106 ).…”

Section: Therapy Based On Anti-lymphangiogenesis Strategymentioning

confidence: 99%

The Regulation of Lymph Node Pre-Metastatic Niche Formation in Head and Neck Squamous Cell Carcinoma

Huang

Sun

2022

Front. Oncol.

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In many distinct forms of malignancies, there is a close relationship between lymph node (LN) metastases and further dissemination to distant organs, and this is a critical prognostic factor. At the beginning of the process, the original tumor secretes soluble substances or releases extracellular vesicles (EVs) that are carried through lymphatic channels to draining (sentinel) LN. The tumor-derived factors then drive LN remodeling. These significant alterations occur prior to the emergence of the first metastatic cell, bringing about the development of a pre-metastatic niche that allows metastatic cells to survive and thrive. In this review, we discuss current information available about the regulation of lymph node pre-metastatic niche in head and neck squamous cell carcinoma (HNSCC), and the role of EVs in forming the pre-metastatic niche.

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Role of Extracellular Vesicles on Cancer Lymphangiogenesis and Lymph Node Metastasis

Cited by 10 publications

References 76 publications

Exosomal CD44 Transmits Lymph Node Metastatic Capacity Between Gastric Cancer Cells via YAP-CPT1A-Mediated FAO Reprogramming

Exosomal CD44 Transmits Lymph Node Metastatic Capacity Between Gastric Cancer Cells via YAP-CPT1A-Mediated FAO Reprogramming

Immunomodulatory properties of the lymphatic endothelium in the tumor microenvironment

The Regulation of Lymph Node Pre-Metastatic Niche Formation in Head and Neck Squamous Cell Carcinoma

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