Colorectal cancer-derived extracellular vesicles induce transformation of fibroblasts into colon carcinoma cells

Abstract

Background We reported that horizontal transfer of malignant traits to target cells is a potential pathway to explain cancer dissemination. Although these results were encouraging, they were never corroborated by data showing the molecular mechanisms responsible for the observed phenomenon. Methods In the present study, we exposed BRCA1 -KO fibroblasts to extracellular vesicles (EVs) isolated from a colon cancer cell line (HT29) and from sera of patients with colorectal cancer. Three weeks after exposure, fibroblasts were injected subcutaneously into NOD-SCID mice. Whole genome sequencing, transcriptome analysis and RNA sequencing of cancer EVs and fibroblasts prior and after exposure to cancer EVs were performed. Results Phenotypical transformation of the fibroblasts into colon cancer cells was confirmed by histopathological study of the xenotransplants. We observed that EV-mediated transfer of cancer microRNAs was responsible for the transition from a mesenchymal to an epithelial phenotype (MET) in the treated fibroblasts as well as activation of cell cycle progression and cell survival pathways. DNA and RNA sequencing suggested that cancer DNA was transferred and possibly transcribed in target cells. Furthermore, injection of colon cancer EVs in the tail vein of NOD-SCID mice determined neoplastic transformation and metastases in the lungs of the mice confirming for the first time the hypothesis that transfer of malignant epithelial cancer traits to distant target cells is a concept applicable to in vivo models. Conclusions These discoveries shed new light into the molecular mechanisms behind the horizontal transfer of malignant traits and confirm the notion that metastatic disease might be reproduced through transfer of circulating genetic material. Electronic supplementary material The online version of this article (10.1186/s13046-019-1248-2) contains supplementary material, which is available to authorized users.

Uveal Melanoma-Derived Extracellular Vesicles Display Transforming Potential and Carry Protein Cargo Involved in Metastatic Niche Preparation

“…Cancer EVs have been reported to regulate cancer invasion and metastasis [ 52 , 55 , 56 , 57 , 58 , 59 ]. Furthermore, we have previously shown that cancer EVs carrying mutated DNA and RNA induced malignant transformation of Fibro-BKO [ 60 ]. We analyzed the transforming abilities of UM-EVs on Fibro-BKO cells: at the end of a 3-week exposure to culture medium without EVs (No-EVs), NCM-EVs or UM-EVs, Fibro-BKO cells were inoculated subcutaneously into NOD/SCID mice.…”

“…It was already known that circulating EV levels increase with advancing stages of cancer, suggesting potential roles in cancer progression and invasion [ 72 ]. Furthermore, we previously reported that EVs from different malignancies carry oncogenic factors that trigger malignant transformation in target cells [ 60 ]. In the present study, we wanted to verify whether EVs isolated from UM cell lines would trigger malignant transformation of Fibro BKO.…”

“…Moreover, factors carried by EVs belong to different molecular categories (i.e., DNA, mRNA, miRNA, proteins) and their roles in cancer biology have been extensively highlighted [ 32 , 74 , 75 , 76 , 77 ]. Recently, we provided evidence that cancer EVs actively transfer mutated cancer genes to target cells as well as a bulk of coding and non-coding RNAs acting as modulators of essential cellular pathways that impact cancer growth and progression [ 60 ]. Herein, we decided to deepen these analyses by focusing on UM-EV protein cargo.…”

Novel therapeutic targets for cancer metastasis

“…For example, the process of breast cancer metastasis-induction by miR-105 is due to this metastatic cancer cell-to-host cell or to nonmetastatic cancer cell crosstalk mediated by breast cancer cell miR-105-shedding EVs [11,33]. Recently, researchers were able to show evidence of in vivo horizontal transfer of malignant traits when they injected colorectal cancer cell-derived EVs into the bloodstream of NOD/SCID mice and found malignant transformation of distant cells [48].…”

Diffuse large B cell lymphoma‐derived extracellular vesicles educate macrophages to promote tumours progression by increasing PGC‐1β

“…They contain various components, such as maternal cell–derived proteins, miRNAs and mRNAs, and participate in intercellular substance and information exchange. Studies have found that tumour‐derived EVs can directly act on a variety of stromal cells, affecting the host's TME status, leading to tumour immune escape and progression . For example, tumour EVs contain a variety of proteins and RNAs that promote tumours by promoting polarization of M2 macrophages .…”