Exosomal microRNAs derived from colorectal cancer-associated fibroblasts: role in driving cancer progression

Bhome, Rahul; Goh, Rebecca W.; Bullock, Marc D.; Pillar, Nir; Thirdborough, Stephen M.; Mellone, Massimiliano; Mirnezami, Reza; Galea, Dieter; Veselkov, Kirill; Gu, Quan; Underwood, Timothy J.; Primrose, John N.; Wever, Olivier De; Shomron, Noam; Sayan, A. Emre; Mirnezami, Alex H.

doi:10.18632/aging.101355

Cited by 105 publications

(96 citation statements)

References 75 publications

(92 reference statements)

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“…Meanwhile, various cell types-derived exosomal miRNAs were found to be correlated with metastatic niche preparation and tumor growth interference [28]. Exosomes derived from CAFs containing abundant miR-21 could be transferred into CRC cells [11], which supports our findings that CAFs show elevated miR-93-5p expression and deliver it to CRC cells through exosomes.…”

Section: Discussionsupporting

confidence: 76%

“…Accumulating evidences have reported that stromal cells-secreted exosomes in the tumor microenvironment play a vital role in cancer progression through the transfer of their cargo, encompassing proteins, and messenger RNAs (mRNAs), and microRNAs (miRNAs), to cancer cells [9,10]. CAFs-derived exosomes (CAFs-exo) are transferred to CRC cells with elevation in miRNA levels, contributing to proliferation and chemoresistance of CRC cells [11]. miRNAs refer to small noncoding RNA molecules, which act as a regulator in cell proliferation, apoptosis and tumor growth [12].…”

Section: Introductionmentioning

confidence: 99%

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Exosome-mediated transfer of miR-93-5p from cancer-associated fibroblasts confer radioresistance in colorectal cancer cells by downregulating FOXA1 and upregulating TGFB3

Chen

Liu

Zhang

et al. 2020

J Exp Clin Cancer Res

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Background: Cancer-associated fibroblasts (CAFs) have been intensively studied in recent studies with aims of finding more concrete evidence on their mechanism of involvement in tumor progression, which is currently unknown. CAFs can secrete exosomes which are loaded with proteins, lipids and RNAs, all of which affect tumor microenvironment. The present study identified microRNA-93-5p (miR-93-5p) as a novel exosomal cargo responsible for the pro-tumorigenic effects of CAFs on colorectal cancer (CRC). Methods: CAFs and normal fibroblasts (NFs) were isolated from cancerous tissues and matched with paracancerous tissues that had been surgically resected from CRC patients. The interaction among miR-93-5p, forkhead box A1 (FOXA1) and TGFB3 was identified through ChIP and dual luciferase reporter assays. The proliferation and apoptosis of SW480 cells co-cultured with CAFs-derived exosomes under irradiation were evaluated by CCK-8, colony formation, and flow cytometric assays. Tumorigenesis of SW480 cells in nude mice was assessed under the irradiation. Results: FOXA1 was found to be associated with reduced radioresistance in CRC cells and was verified as a target of miR-93-5p. CAFs-derived exosomes contained higher miR-93-5p than those from NFs, which augmented SW480 cell proliferation and rescued them from radiation-induced apoptosis. miR-93-5p was identified as a mediator of the exosomal effects of CAFs on SW480 cells, possibly through downregulating FOXA1 and upregulating TGFB3. FOXA1 could bind to the promoter of TGFB3, thereby inhibiting nuclear accumulation of TGFB3. Also, CAFs-derived exosomes containing miR-93-5p increased the tumor growth of SW480 cells in irradiated nude mice. Conclusion: The present study identifies miR-93-5p as a specific exosomal cargo that rescues CRC cells against radiation-induced apoptosis.

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Section: Discussionsupporting

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Exosome-mediated transfer of miR-93-5p from cancer-associated fibroblasts confer radioresistance in colorectal cancer cells by downregulating FOXA1 and upregulating TGFB3

Chen

Liu

Zhang

et al. 2020

J Exp Clin Cancer Res

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“…CAFs are also a substantial source of growth factors, cytokines and exosomes that can promote tumour growth and modulate therapy responses 27,[106][107][108] . The production of TGFβ, leukaemia inhibitory factor (LIF), growth arrest-specific protein 6 (GAS6), fibroblast growth factor 5 (FGF5), growth differentiation factor 15 (GDF15) and hepatocyte growth factor (HGF) promotes invasive and proliferative behaviour in cancer cells 52,[109][110][111][112] .…”

Section: The Expanding Range Of Caf Functionsmentioning

confidence: 99%

A framework for advancing our understanding of cancer-associated fibroblasts

et al. 2020

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Cancer-associated fibroblasts (CAFs) are a key component of the tumour microenvironment with diverse functions, including matrix deposition and remodelling, extensive reciprocal signalling interactions with cancer cells and crosstalk with infiltrating leukocytes. As such, they are a potential target for optimizing therapeutic strategies against cancer. However, many challenges are present in ongoing attempts to modulate CAFs for therapeutic benefit. These include limitations in our understanding of the origin of CAFs and heterogeneity in CAF function, with it being desirable to retain some antitumorigenic functions. On the basis of a meeting of experts in the field of CAF biology, we summarize in this Consensus Statement our current knowledge and present a framework for advancing our understanding of this critical cell type within the tumour microenvironment. Extracellular matrix (ECM).The structural network of secreted proteins and glycosaminoglycans that provides structure to tissue. Angiogenesis The formation of new blood vessels. Mesenchyme A type of tissue composed of loosely associated cells surrounded by extracellular matrix. Mesoderm one of three fundamental layers of tissue formed early in development and the predominant source of fibroblastic lineages.

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“…Stromal remodeling can promote cancer progression. CAFs display an activated myofibroblast phenotype and expression of αSMA in many solid tumors is a marker of reduced disease free and overall survival 8, 35, 39-41 . The tumor-promoting biology of CAFs make them a target for novel cancer therapies.…”

Section: Discussionmentioning

confidence: 99%

Modulation of the tumour promoting functions of cancer associated fibroblasts by phosphodiesterase type 5 inhibition increases the efficacy of chemotherapy in human preclinical models of esophageal adenocarcinoma

Hayden

Manousopoulou

Cowie

et al. 2020

Preprint

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Background and aimsEsophageal adenocarcinoma (EAC) is chemoresistant in the majority of cases. The tumor-promoting biology of cancer associated fibroblasts (CAF) make them a target for novel therapies. Phosphodiesterase type 5 inhibitors (PDE5i) have been shown to regulate the activated fibroblast phenotype in benign disease. We investigated the potential for CAF modulation in EAC using PDE5i to enhance the efficacy of chemotherapy.MethodsEAC fibroblasts were treated with PDE5i and phenotypic effects examined using immunoblotting, immunohistochemistry, gel contraction, transwell invasion, organotypics, single cell RNAseq and shotgun proteomics. The combination of PDE5i with standard-of-care chemotherapy (Epirubicin, 5-Fluorouracil and Cisplatin) was tested for safety and efficacy in validated near-patient model systems (3D tumor growth assays (3D-TGAs) and patient derived xenograft (PDX) mouse models).ResultsPDE5i treatment reduced α–SMA expression in CAFs by 50% (p<0.05), associated with a significant reduction in the ability of CAFs to contract collagen-1 gels and induce cancer cell invasion, (p<0.05). RNAseq and proteomic analysis of CAF and EAC cell lines revealed PDE5i specific regulation of pathways related to fibroblast activation and tumor promotion. 3D-TGA assays confirmed the importance of stromal cells to chemoresistance in EAC, which could be attenuated by PDE5i. Chemotherapy+PDE5i in PDX-bearing mice was safe and significantly reduced PDX tumor volume (p<0.05).ConclusionPDE5 is a candidate for clinical trials to alter the fibroblast phenotype in esophageal cancer. We demonstrate the specificity of PDE5i for fibroblasts to prevent transdifferentiation and revert the CAF phenotype. Finally, we confirm the efficacy of PDE5i in combination with chemotherapy in close-to-patient in vitro and in vivo PDX-based model systems.

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Exosomal microRNAs derived from colorectal cancer-associated fibroblasts: role in driving cancer progression

Cited by 105 publications

References 75 publications

Exosome-mediated transfer of miR-93-5p from cancer-associated fibroblasts confer radioresistance in colorectal cancer cells by downregulating FOXA1 and upregulating TGFB3

Exosome-mediated transfer of miR-93-5p from cancer-associated fibroblasts confer radioresistance in colorectal cancer cells by downregulating FOXA1 and upregulating TGFB3

A framework for advancing our understanding of cancer-associated fibroblasts

Modulation of the tumour promoting functions of cancer associated fibroblasts by phosphodiesterase type 5 inhibition increases the efficacy of chemotherapy in human preclinical models of esophageal adenocarcinoma

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