Cancer-associated fibroblasts derived extracellular vesicles promote angiogenesis of colorectal adenocarcinoma cells through miR-135b-5p/FOXO1 axis

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ABSTRACT

Colorectal adenocarcinoma (COAD) is a prevalent malignant tumor. Cancer-associated fibroblasts (CAFs)-derived extracellular vesicles (EVs) (CAFs-EVs) are implicated in COAD treatment. This study explored the mechanism of CAFs-EVs in COAD. CAFs and normal fibroblast (NFs) were isolated from COAD tissues and adjacent normal tissues. Vimentin, α-SMA, and FAP expressions were detected. EVs were isolated from CAFs and identified. SW480 and HCT116 cells were co-incubated with EVs. The EV uptake and COAD cell malignant behaviors were assessed. EV-treated SW480 and HCT116 cells were co-cultured with human umbilical vein endothelial cells (HUVECs). Extensive analyses were conducted to examine HUVEC proliferation, migration, and angiogenesis, and miR-135b-5p expression in COAD cells, and SW480 and HCT116 cells. CAFs were transfected with the miR-135b-5p inhibitor. miR-135b-5p downstream targets were predicted. FOXO1 expression in the co-culture system was determined and then overexpressed to evaluate its role in HUVECs mediated by COAD cells. COAD mouse model was established by transplanting SW480 cells into nude mice and injecting with EVs. Tumor growth rate, volume, and weight were examined. Ki67, VEGF, CD34, FOXO1 expressions, and VEGF content were detected. CAFs-EVs promoted COAD cell malignant behaviors and COAD cells-mediated HUVEC proliferation, migration, and angiogenesis. CAFs-EVs delivered miR-135b-5p into COAD cells. miR-135b-5p targeted FOXO1. Inhibition of miR-135b-5p in EVs or overexpression of FOXO1 partially reversed the effect of EVs on promoting COAD-induced angiogenesis. CAFs-EVs promoted tumor proliferation and angiogenesis of COAD in vivo. CAFs-EVs delivered miR-135b-5p into COAD cells to downregulate FOXO1 and promote HUVECs proliferation, migration, and angiogenesis.

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Most cited references 28

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Exosomes

D Pegtel, Stephen Gould (2019)

Exosomes are small, single-membrane, secreted organelles of ∼30 to ∼200 nm in diameter that have the same topology as the cell and are enriched in selected proteins, lipids, nucleic acids, and glycoconjugates. Exosomes contain an array of membrane-associated, high-order oligomeric protein complexes, display pronounced molecular heterogeneity, and are created by budding at both plasma and endosome membranes. Exosome biogenesis is a mechanism of protein quality control, and once released, exosomes have activities as diverse as remodeling the extracellular matrix and transmitting signals and molecules to other cells. This pathway of intercellular vesicle traffic plays important roles in many aspects of human health and disease, including development, immunity, tissue homeostasis, cancer, and neurodegenerative diseases. In addition, viruses co-opt exosome biogenesis pathways both for assembling infectious particles and for establishing host permissiveness. On the basis of these and other properties, exosomes are being developed as therapeutic agents in multiple disease models.

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VEGF in Signaling and Disease: Beyond Discovery and Development

Rajendra Apte, Daniel S. Chen, Napoleone Ferrara (2019)

The discovery of vascular endothelial-derived growth factor (VEGF) has revolutionized our understanding of vasculogenesis and angiogenesis during development and physiological homeostasis. Over a short span of two decades, our understanding of the molecular mechanisms by which VEGF coordinates neurovascular homeostasis has become more sophisticated. The central role of VEGF in the pathogenesis of diverse cancers and blinding eye diseases has also become evident. Elucidation of the molecular regulation of VEGF and the transformative development of multiple therapeutic pathways targeting VEGF directly or indirectly is a powerful case study of how fundamental research can guide innovation and translation. It is also an elegant example of how agnostic discovery and can transform our understanding of human disease. This review will highlight critical nodal points in VEGF biology including recent developments in immunotherapy for cancer and multi-target approaches in neovascular eye disease.

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Is Open Access

Carcinoma-associated fibroblasts promote the stemness and chemoresistance of colorectal cancer by transferring exosomal lncRNA H19

Jing Ren, Liang Ding, Dongya Zhang … (2018)

Long non-coding RNAs (lncRNAs) are involved in the pathology of various tumors, including colorectal cancer (CRC). The crosstalk between carcinoma- associated fibroblasts (CAFs) and cancer cells in the tumor microenvironment promotes tumor development and confers chemoresistance. In this study, we further investigated the underlying tumor-promoting roles of CAFs and the molecular mediators involved in these processes. Methods: The AOM/DSS-induced colitis-associated cancer (CAC) mouse model was established, and RNA sequencing was performed. Small interfering RNA (siRNA) sequences were used to knock down H19. Cell apoptosis was measured by flow cytometry. SW480 cells with H19 stably knocked down were used to establish a xenograft model. The indicated protein levels in xenograft tumor tissues were confirmed by immunohistochemistry assay, and cell apoptosis was analyzed by TUNEL apoptosis assay. RNA-FISH and immunofluorescence assays were performed to assess the expression of H19 in tumor stroma and cancer nests. The AldeRed ALDH detection assay was performed to detect intracellular aldehyde dehydrogenase (ALDH) enzyme activity. Isolated exosomes were identified by transmission electron microscopy, nanoparticle tracking and Western blotting. Results: H19 was highly expressed in the tumor tissues of CAC mice compared with the expression in normal colon tissues. The up-regulation of H19 was also confirmed in CRC patient samples at different tumor node metastasis (TNM) stages. Moreover, H19 was associated with the stemness of colorectal cancer stem cells (CSCs) in CRC specimens. H19 promoted the stemness of CSCs and increased the frequency of tumor-initiating cells. RNA-FISH showed higher expression of H19 in tumor stroma than in cancer nests. Of note, H19 was enriched in CAF-derived conditioned medium and exosomes, which in turn promoted the stemness of CSCs and the chemoresistance of CRC cells in vitro and in vivo. Furthermore, H19 activated the β-catenin pathway via acting as a competing endogenous RNA sponge for miR-141 in CRC, while miR-141 significantly inhibited the stemness of CRC cells. Conclusion: CAFs promote the stemness and chemoresistance of CRC by transferring exosomal H19. H19 activated the β-catenin pathway via acting as a competing endogenous RNA sponge for miR-141, while miR-141 inhibited the stemness of CRC cells. Our findings indicate that H19 expressed by CAFs of the colorectal tumor stroma contributes to tumor development and chemoresistance.

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Author and article information

Journal

Journal ID (nlm-ta): Cancer Biol Ther

Journal ID (iso-abbrev): Cancer Biol Ther

Title: Cancer Biology & Therapy

Publisher: Taylor & Francis

ISSN (Print): 1538-4047

ISSN (Electronic): 1555-8576

Publication date (Electronic, pub): 31 January 2022

Publication date (Electronic, collection): 2022

Publication date PMC-release: 31 January 2022

Volume: 23

Issue: 1

Pages: 76-88

Affiliations

[a ]Department of Anus & Intestine Sugery, HwaMei Hospital, University of Chinese Academy of Sciences; , Ningbo City, Zhejiang, China

[b ]Pharmacy Department, Ningbo Eye Hospital; , Ningbo City, Zhejiang, China

Author notes

CONTACT Mingjun Dong MingjunD1113@ 123456163.com Department of Anus & Intestine Sugery, HwaMei Hospital, University of Chinese Academy of Sciences; , No. 41 Northwest Street, Haishu Zone, Ningbo City 315010, Zhejiang, China

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Mingjun Dong https://orcid.org/0000-0003-1672-8031

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Publisher ID: 2017222

DOI: 10.1080/15384047.2021.2017222

PMC ID: 8812748

PubMed ID: 35100092

SO-VID: 557fd091-3607-4133-b641-00a3a1ff529f

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This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License ( http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.

Cancer-associated fibroblasts derived extracellular vesicles promote angiogenesis of colorectal adenocarcinoma cells through miR-135b-5p/FOXO1 axis

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Most cited references 28

Exosomes

VEGF in Signaling and Disease: Beyond Discovery and Development

Carcinoma-associated fibroblasts promote the stemness and chemoresistance of colorectal cancer by transferring exosomal lncRNA H19

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