Exosomes Induce Fibroblast Differentiation into Cancer-Associated Fibroblasts through TGFβ Signaling

Goulet, Cassandra Ringuette; Bernard, Geneviève; Tremblay, Sarah; Chabaud, Stéphane; Bolduc, Stéphane; Pouliot, Frédéric

doi:10.1158/1541-7786.mcr-17-0784

Cited by 236 publications

(161 citation statements)

References 38 publications

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“…This in turn results in enhanced production of Tregs from naive T cells [217]. Interestingly, most (up to 86%) of TGF-β1 secreted by bladder cancer cells is encapsulated in exosomes that target healthy fibroblasts and stimulate their differentiation into cancer-associated fibroblasts (CAFs) by triggering SMAD2 phosphorylation [218]. Interestingly, the expression of TGF-β1 and TGFBR1 in peripheral blood mononuclear cells (PBMNCs) of bladder cancer patients is increased compared with healthy individuals, which coincides with the role of TGF-β1 signaling in bladder cancer immunity.…”

Section: Bladder Cancermentioning

confidence: 99%

TGF-β and microRNA Interplay in Genitourinary Cancers

Bogusławska¹,

Kryst

Poletajew

et al. 2019

Cells

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Genitourinary cancers (GCs) include a large group of different types of tumors localizing to the kidney, bladder, prostate, testis, and penis. Despite highly divergent molecular patterns, most GCs share commonly disturbed signaling pathways that involve the activity of TGF-β (transforming growth factor beta). TGF-β is a pleiotropic cytokine that regulates key cancer-related molecular and cellular processes, including proliferation, migration, invasion, apoptosis, and chemoresistance. The understanding of the mechanisms of TGF-β actions in cancer is hindered by the “TGF-β paradox” in which early stages of cancerogenic process are suppressed by TGF-β while advanced stages are stimulated by its activity. A growing body of evidence suggests that these paradoxical TGF-β actions could result from the interplay with microRNAs: Short, non-coding RNAs that regulate gene expression by binding to target transcripts and inducing mRNA degradation or inhibition of translation. Here, we discuss the current knowledge of TGF-β signaling in GCs. Importantly, TGF-β signaling and microRNA-mediated regulation of gene expression often act in complicated feedback circuits that involve other crucial regulators of cancer progression (e.g., androgen receptor). Furthermore, recently published in vitro and in vivo studies clearly indicate that the interplay between microRNAs and the TGF-β signaling pathway offers new potential treatment options for GC patients.

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Section: Bladder Cancermentioning

confidence: 99%

TGF-β and microRNA Interplay in Genitourinary Cancers

Bogusławska¹,

Kryst

Poletajew

et al. 2019

Cells

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“…Interestingly, exosomes secreted by metastatic melanoma cells instigated a proinflammatory gene signature in lung fibroblasts but did not activate wound‐healing functions. Activation of a matrix‐remodeling myofibroblast phenotype in stromal fibroblasts by tumor‐secreted exosomes was previously demonstrated in various cancer types . In chronic lymphocytic leukemia (CLL), tumor‐derived exosomes were shown to induce both myofibroblast and proinflammatory gene expression in BM stromal cells .…”

Section: Discussionmentioning

confidence: 90%

Melanoma‐derived extracellular vesicles instigate proinflammatory signaling in the metastatic microenvironment

Lahav

Adler

Zait

et al. 2019

Intl Journal of Cancer

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The major cause of melanoma mortality is metastasis to distant organs, including lungs and brain. Reciprocal interactions of metastasizing tumor cells with stromal cells in secondary sites play a critical role in all stages of tumorigenesis and metastasis. Changes in the metastatic microenvironment were shown to precede clinically relevant metastases, and may occur prior to the arrival of disseminated tumor cells to the distant organ, thus creating a hospitable “premetastatic niche.” Exosomes secreted by tumor cells were demonstrated to play an important role in the preparation of a hospitable metastatic niche. However, the functional role of melanoma‐derived exosomes on metastatic niche formation, and the downstream pathways activated in stromal cells at the metastatic niche are largely unresolved. Here we show that extracellular vesicles (EVs) secreted by metastatic melanoma cells that spontaneously metastasize to lungs and to brain, activate proinflammatory signaling in lung fibroblasts and in astrocytes. Interestingly, unlike paracrine signaling by melanoma cells, EVs secreted by metastatic melanoma cells instigated a proinflammatory gene signature in lung fibroblasts but did not activate wound‐healing functions, suggesting that tumor cell‐secreted EVs activate distinct CAF characteristics and tumor‐promoting functions. Moreover, melanoma‐secreted EVs also activated proinflammatory signaling in astrocytes, indicating that EV‐mediated reprogramming of stromal cells is a general mechanism of modulating the metastatic niche in multiple distant organs. Thus, our study demonstrates that melanoma‐derived EVs reprogram tumor‐promoting functions in stromal cells in a distinct manner, implicating a central role for tumor‐derived EV signaling in promoting the formation of an inflammatory metastatic niche.

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“…The pro-metastatic miRNA-9 could stimulate the transformation of NFs to BCAFs to ultimatelypromote an aggressive BC phenotype [ 72 ]. Furthermore, the ability of TDEs to transport both TGF-β and IL-6 oncogenic factors may lead to BCAFs transdifferentiation [ 10 , 73 ].…”

Section: Epigenetic Regulation In Bcafsmentioning

confidence: 99%

Cancer-Associated Fibroblasts: Epigenetic Regulation and Therapeutic Intervention in Breast Cancer

Lee

Tan

Falasca

et al. 2020

Cancers

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Breast cancer is the leading cause of cancer-related mortality in women worldwide. Cancer-associated fibroblasts (CAFs) are a heterogeneous population of cells in the solid tumour microenvironment. These cells are positively linked to breast cancer progression. Breast CAFs can be categorised into distinct subtypes according to their roles in breast carcinogenesis. Epigenetic modifications change gene expression patterns as a consequence of altered chromatin configuration and DNA accessibility to transcriptional machinery, without affecting the primary structure of DNA. Epigenetic dysregulation in breast CAFs may enhance breast cancer cell survival and ultimately lead to therapeutic resistance. A growing body of evidence has described epigenetic modulators that target histones, DNA, and miRNA as a promising approach to treat cancer. This review aims to summarise the current findings on the mechanisms involved in the epigenetic regulation in breast CAFs and discusses the potential therapeutic strategies via targeting these factors.

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Exosomes Induce Fibroblast Differentiation into Cancer-Associated Fibroblasts through TGFβ Signaling

Cited by 236 publications

References 38 publications

TGF-β and microRNA Interplay in Genitourinary Cancers

TGF-β and microRNA Interplay in Genitourinary Cancers

Melanoma‐derived extracellular vesicles instigate proinflammatory signaling in the metastatic microenvironment

Cancer-Associated Fibroblasts: Epigenetic Regulation and Therapeutic Intervention in Breast Cancer

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