Small extracellular vesicle-bound vascular endothelial growth factor secreted by carcinoma-associated fibroblasts promotes angiogenesis in a bevacizumab-resistant manner

Li, Jiao; Li, Xue; Zang, Shizhu; Zhou, Jiasheng; Zhang, Fuyin; Sun, Bo; Qi, Dongyuan; Li, Xiaojie; Kong, Jing; Jin, Dong Hoon; Yang, Xuesong; Luo, Yong; Lu, Yao; Lin, Bingcheng; Niu, Weidong; Liu, Tingjiao

doi:10.1016/j.canlet.2020.08.030

Cited by 43 publications

(26 citation statements)

References 57 publications

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“…In our previous study, it had been shown that CAFs can facilitate melanoma angiogenesis, and the expression of the angiogenic factor MMP9 in CAFs is upregulated compared with that in NFs (9). Research by Li et al confirmed that CAFs derived from OSCC can also promote the tube-forming ability of HUVECs (28). However, the role of lncRNAs in the proangiogenic effect of OSCC-derived CAFs is still unclear.…”

Section: Discussionmentioning

confidence: 96%

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LncRNA FENDRR in Carcinoma-Associated Fibroblasts Regulates the Angiogenesis of Oral Squamous Cell Carcinoma Through the PI3K/AKT Pathway

Jiang

Shao

et al. 2021

Front. Oncol.

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Angiogenesis is essential for the development of tumors. Studies have shown that carcinoma-associated fibroblasts (CAFs) are involved in regulating tumor angiogenesis, but the mechanism remains unclear. Recently, long noncoding RNAs (lncRNAs) have been proved to play an important role in the angiogenesis of various tumors. However, there is currently no research involving the regulation of CAFs on the angiogenesis of oral squamous cell carcinoma (OSCC) mediated by lncRNAs. By analyzing microarray data, we identified that the expression of lncRNA FOXF1 adjacent noncoding developmental regulatory RNA (FENDRR) in OSCC patients is downregulated, compared to that in normal tissues. Quantitative polymerase chain reaction (qPCR) results demonstrated that FENDRR expression is lower in CAFs compared to normal fibroblasts (NFs) of OSCC patients. KEGG pathway analysis revealed that some genes differentially expressed between CAFs and NFs of HNSCC patients are enriched to the PI3K/AKT pathway. Further experiments confirmed that the downregulation of FENDRR can activate the PI3K/AKT pathway in NFs and enhances the expression of matrix metalloproteinase 9 (MMP9). The overexpression of FENDRR had the opposite effect. Besides, we co-cultured human umbilical vein endothelial cells (HUVECs) with CAFs, and the tube-forming ability of HUVECs co-cultured with CAFs overexpressing FENDRR decreased significantly. However, activation of the AKT pathway of CAFs overexpressing FENDRR can weaken the inhibitory effect of FENDRR on angiogenesis. In summary, our experiments are focused on the influence of lncRNAs in CAFs on OSCC angiogenesis for the first time and prove that FENDRR mediates CAFs’ regulation of OSCC angiogenesis through the PI3K/AKT pathway.

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Section: Discussionmentioning

confidence: 96%

“…Research by Li et al. confirmed that CAFs derived from OSCC can also promote the tube-forming ability of HUVECs ( 28 ). However, the role of lncRNAs in the proangiogenic effect of OSCC-derived CAFs is still unclear.…”

Section: Discussionmentioning

confidence: 99%

LncRNA FENDRR in Carcinoma-Associated Fibroblasts Regulates the Angiogenesis of Oral Squamous Cell Carcinoma Through the PI3K/AKT Pathway

Jiang

Shao

et al. 2021

Front. Oncol.

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“…EVs play important roles in cell-cell communication by delivering their cargo to recipient cells [35,[42][43][44]. However, limited information is available regarding the interaction between EVs and the ECM.…”

Section: Discussionmentioning

confidence: 99%

Carcinoma-associated fibroblast-derived lysyl oxidase-rich extracellular vesicles mediate collagen crosslinking and promote epithelial-mesenchymal transition

Yang

et al. 2022

Preprint

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Background: Carcinoma-associated fibroblasts (CAFs) are the main cellular components of the tumor microenvironment and promote cancer progression by modifying the extracellular matrix (ECM). The tumor-associated ECM is characterized by collagen crosslinking catalyzed by lysyl oxidase (LOX). Small extracellular vesicles (sEVs) mediate cell-cell communication. However, the interactions between sEVs and the ECM remain unclear. Methods: sEVs separation was performed by differential ultracentrifugation. Normal fibroblasts (NFs) were treated with sEVs and the content of collagen crosslinking were performed by ELISA. Active LOX (αLOX) was enriched in sEVs were performed by western blot and ELISA. TCI-15 was used to inhibited sEVs bind to collagen I and triggered collagen crosslinking. CAF sEV-induced collagen crosslinking promoted the epithelial-mesenchymal transition (EMT) of OSCC cells was confirmed both in vitro and in vivo. Results: Here, we demonstrate, for the first time, that sEVs released from oral squamous cell carcinoma (OSCC)-derived CAFs induce collagen crosslinking, thereby promoting EMT. CAF sEVs preferably bound to the ECM rather than being taken up by fibroblasts and induced collagen crosslinking, and a LOX inhibitor or blocking antibody suppressed this effect. αLOX, but not the LOX precursor, was enriched in CAF sEVs and interacted with periostin, fibronectin, and bone morphogenetic protein-1 on the surface of sEVs. CAF sEV-associated integrin α2β1 mediated the binding of CAF sEVs to collagen I, and blocking integrin α2β1 inhibited collagen crosslinking by interfering with CAF sEV binding to collagen I. CAF sEV-induced collagen crosslinking promoted the EMT of OSCC cells in vitro and in vivo. Conclusions: This work reveals that CAF sEV-αLOX interacted with FN, POSTN, and BMP-1 on the surface of sEVs. Integrin α2β1 mediated the binding of CAF sEVs to collagen I, and αLOX triggered collagen crosslinking directly. Collagen crosslinking induced by CAF sEVs promoted the EMT of OSCC cells.

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“…Even after the completion of wound repair, the cancer-associated fibroblasts (CAFs), also termed as myofibroblasts, remain activated. The activated CAFs have a strong impact on tumorigenesis due to angiogenesis [41][42][43], inflammatory cell infiltration, and secretion of growth factors (GFs) and immunosuppressive cytokines [44,45]. The tumor cells secrete both immune-suppressive chemokines, such as IL8, GM-CSF, CCL-5,2,17 and CXCL12,17, and pro-inflammatory chemokines, such as CXCL9 and CXCL10.…”

Section: Tumor Microenvironment and Immune Suppressive Cellsmentioning

confidence: 99%

Metallic Nanoparticle-Mediated Immune Cell Regulation and Advanced Cancer Immunotherapy

2021

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Cancer immunotherapy strategies leveraging the body’s own immune system against cancer cells have gained significant attention due to their remarkable therapeutic efficacy. Several immune therapies have been approved for clinical use while expanding the modalities of cancer therapy. However, they are still not effective in a broad range of cancer patients because of the typical immunosuppressive microenvironment and limited antitumor immunity achieved with the current treatment. Novel approaches, such as nanoparticle-mediated cancer immunotherapies, are being developed to overcome these challenges. Various types of nanoparticles, including liposomal, polymeric, and metallic nanoparticles, are reported for the development of effective cancer therapeutics. Metallic nanoparticles (MNPs) are one of the promising candidates for anticancer therapy due to their unique theranostic properties and are thus explored as both imaging and therapeutic agents. In addition, MNPs offer a dense surface functionalization to target tumor tissue and deliver genetic, therapeutic, and immunomodulatory agents. Furthermore, MNPs interact with the tumor microenvironment (TME) and regulate the levels of tumor hypoxia, glutathione (GSH), and reactive oxygen species (ROS) for remodulation of TME for successful therapy. In this review, we discuss the role of nanoparticles in tumor microenvironment modulation and anticancer therapy. In particular, we evaluated the response of MNP-mediated immune cells, such as dendritic cells, macrophages, T cells and NK cells, against tumor cells and analyzed the role of MNP-based cancer therapies in regulating the immunosuppressive environment.

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Small extracellular vesicle-bound vascular endothelial growth factor secreted by carcinoma-associated fibroblasts promotes angiogenesis in a bevacizumab-resistant manner

Cited by 43 publications

References 57 publications

LncRNA FENDRR in Carcinoma-Associated Fibroblasts Regulates the Angiogenesis of Oral Squamous Cell Carcinoma Through the PI3K/AKT Pathway

LncRNA FENDRR in Carcinoma-Associated Fibroblasts Regulates the Angiogenesis of Oral Squamous Cell Carcinoma Through the PI3K/AKT Pathway

Carcinoma-associated fibroblast-derived lysyl oxidase-rich extracellular vesicles mediate collagen crosslinking and promote epithelial-mesenchymal transition

Metallic Nanoparticle-Mediated Immune Cell Regulation and Advanced Cancer Immunotherapy

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