Abstract
Extracellular vesicles (EV), structures surrounded by a biological membrane, transport biologically active molecules, and represent a recently identified way of intercellular communication. Colorectal cancer (CRC), one of the most common cancer types in the Western countries, is composed of both tumor and stromal cells and the amount of stromal fibroblasts negatively correlates with patient survival. Here we show that normal colon fibroblasts (NCF) release EVs with a characteristic miRNA cargo profile when stimulated with TGFβ, one of the most important activating factors of fibroblasts, without a significant increase in the amount of secreted EVs. Importantly, fibroblast-derived EVs induce cell proliferation in epidermal growth factor (EGF)-dependent patient-derived organoids, one of the best current systems to model the intra-tumoral heterogeneity of human cancers. In contrast, fibroblast-derived EVs have no effect in 3D models where EGF is dispensible. This EV-induced cell proliferation did not depend on whether NCFs or cancer-associated fibroblasts were studied or on the pre-activation by TGFβ, suggesting that TGFβ-induced sorting of specific miRNAs into EVs does not play a major role in enhancing CRC proliferation. Mechanistically, we provide evidence that amphiregulin, transported by EVs, is a major factor in inducing CRC cell proliferation. We found that neutralization of EV-bound amphiregulin blocked the effects of the fibroblast-derived EVs. Collectively, our data suggest a novel mechanism for fibroblast-induced CRC cell proliferation, coupled to EV-associated amphiregulin.
Highlights
Extracellular vesicles (EV) are membrane-surrounded structures released by virtually all cell types
To study the effects of EVs released by activated fibroblasts on colorectal cancer (CRC) cells, first we used a widely accepted and reproducible, commercially available model system, normal human colonderived fibroblasts (NCF), and we activated them by TGFβ
In this study we prove that the TGFβ-induced activation of normal colon fibroblasts (NCF) modifies EV miRNA cargo and hsa-miR-101, 382, 424, and hsa-miR-642 are present only in EVs derived from activated NCFs
Summary
Extracellular vesicles (EV) are membrane-surrounded structures released by virtually all cell types. They transport biologically active molecules (such as nucleic acids, lipids and proteins) from the releasing to the target cells, participating in the recently identified way of intercellular communication (Tkach et al, 2018). Since EVs transport their cargo in a protected way in the Extracellular Vesicles and Amphiregulin in Colorectal Cancer tissues and body fluids, molecules specific for the releasing tumor cells are represented in them at a high concentration, they provide a promising tool for early cancer diagnostics. Despite the emerging evidence that EVs contribute to tumorigenesis and play a critical role in the communication among stromal and cancer cells (Maia et al, 2018), changes in their release intensity, cargo in different fibroblast populations, and mechanism of their action on colorectal cancer (CRC) cells is by far not yet understood
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