Intercellular crosstalk between cancer cells and cancer-associated fibroblasts via extracellular vesicles

Intercellular communication plays an important role in cancer initiation and progression through direct contact and indirect interactions, such as via secretory molecules. Cancer-associated fibroblasts (CAFs) are one of the principal components of such communication with cancer cells, modulating cancer metastasis and tumour mechanics and influencing angiogenesis, the immune system, and therapeutic resistance. Over the past few years, there has been a significant increase in research on extracellular vesicles (EVs) as regulatory agents in intercellular communication. EVs enable the transfer of functional molecules, including proteins, mRNAs and microRNAs (miRNAs), to recipient cells. Cancer cells utilize EVs to dictate the specific characteristics of CAFs within the tumour microenvironment, thereby promoting cancer progression. In response to such “education” by cancer cells, CAFs contribute to cancer progression via EVs. Researchers from the Tokyo Medical University summarize experimental data indicating the pivotal roles of EVs in intercellular communication between cancer cells and CAFs.

Summary of the intercellular crosstalk between cancer cells and CAFs via EVs

The interplay between cancer cells and cancer-associated fibroblasts (CAFs) generates a unique tumour microenvironment (TME) that supports cancer progression. Cancer cells utilize EVs to modify surrounding cells within the tumour microenvironment. Cancer cells secrete various bioactive molecules in EVs, which are transferred into the surrounding fibroblasts and CAFs; such molecules include transforming growth factor-beta (TGF-β), ITGB4, p53, mRNAs and miRNAs. These cancer-derived EVs confer specific phenotypes, such as mitophagy and glycolysis, myofibroblast features, matrix remodelling, and inflammatory gene expression (blue arrows), to support cancer progressions (broken arrows, the functions for cancer progression). Cancer-derived EVs also induce distinct CAF subtypes and contribute to the heterogeneity of CAFs. On the other hand, to support cancer progression, CAFs utilize EVs to transfer various functional molecules, such as CD81, CD9, FAP, miRNAs, lncRNAs, transposable RNAs and metabolites. These molecules confer aggressive phenotypes on cancer cells (red arrows). However, some molecules are downregulated in CAFs and thus their transfer to cancer cells is prevented. Interestingly, specific CAF subtype-derived EVs are also involved in cancer progression, suggesting that EV content may differ among CAF subtypes