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

Mohamed Abdouh,Goffredo Orazio Arena,Zu-Hua Gao,Manuel Arena,Vincenzo Arena,Matteo Floris

doi:10.1186/s13046-019-1248-2

Abstract

BackgroundWe 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.MethodsIn 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.ResultsPhenotypical 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.ConclusionsThese 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.

Highlights

We reported that horizontal transfer of malignant traits to target cells is a potential pathway to explain cancer dissemination
Colorectal cancer extracellular vesicles increased BRCA1KO fibroblasts proliferation and reduced their apoptosis EVs are released into a variety of body fluids in vivo, and into the media of cultured cells in vitro, to accomplish important biological functions [15, 19, 23, 24]
We identified a list of 68,649 candidate allelic variants, which were found in the EVs desoxyribonucleic acid (DNA) sample and in the Breast cancer 1 (BRCA1)-Knock out (KO) fibroblasts exposed to the cancer EVs, but not found in the control BRCA1-KO fibroblast sample

Summary

Introduction

We reported that horizontal transfer of malignant traits to target cells is a potential pathway to explain cancer dissemination. According to the “seed to soil” hypothesis, the metastatic process initiated by the detachment of cells is followed by invasion into the neighboring tissues, penetration trough the basement membrane, dissemination via the blood flow and Abdouh et al Journal of Experimental & Clinical Cancer Research (2019) 38:257 of their epithelial state (MET) and would enable the malignant cells to escape the circulation and home to the target organs The legitimacy of this model has been strengthened by the accumulating evidence that downregulation of the expression of the epithelial marker Ecadherin (CDH1) is a crucial step in the progression from dysplasia to invasive carcinoma [6]. Increasing evidence of significant discrepancies between the genotype of the primary cancer cell and its metastatic counterpart [10, 11], coupled with conflicting explanations on the phenomenon of late metastases, have raised more doubts on the true identity of metastatic cells

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Conclusion