Normoxic Tumour Extracellular Vesicles Modulate the Response of Hypoxic Cancer and Stromal Cells to Doxorubicin In Vitro.

Laura Patras,Pieter Vader,Arjan Barendrecht,Alina Sesarman,Manuela Banciu,Marcel H A M Fens,Raymond Schiffelers

doi:10.3390/ijms21175951

Laura Patras, Pieter Vader + Show 5 more

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https://doi.org/10.3390/ijms21175951

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Extracellular vesicles (EV) secreted in the tumour microenvironment (TME) are emerging as major antagonists of anticancer therapies by orchestrating the therapeutic outcome through altering the behaviour of recipient cells. Recent evidence suggested that chemotherapeutic drugs could be responsible for the EV-mediated tumour–stroma crosstalk associated with cancer cell drug resistance. Here, we investigated the capacity of tumour EV (TEV) secreted by normoxic and hypoxic (1% oxygen) C26 cancer cells after doxorubicin (DOX) treatment to alter the response of naïve C26 cells and RAW 264.7 macrophages to DOX. We observed that C26 cells were less responsive to DOX treatment under normoxia compared to hypoxia, and a minimally cytotoxic DOX concentration that mounted distinct effects on cell viability was selected for TEV harvesting. Homotypic and heterotypic pretreatment of naïve hypoxic cancer and macrophage-like cells with normoxic DOX-elicited TEV rendered these cells slightly less responsive to DOX treatment. The observed effects were associated with strong hypoxia-inducible factor 1-alpha (HIF-1α) induction and B-cell lymphoma–extra-large anti-apoptotic protein (Bcl-xL)-mediated anti-apoptotic response in normoxic DOX-treated TEV donor cells, being also tightly connected to the DOX-TEV-mediated HIF-1α induction, as well as Bcl-xL levels increasing in recipient cells. Altogether, our results could open new perspectives for investigating the role of chemotherapy-elicited TEV in the colorectal cancer TME and their modulatory actions on promoting drug resistance.

Highlights

The tumour microenvironment (TME) is shaped by the complex interactions between malignant cells and stromal cells
Among all cell types belonging to the TME, tumour-associated macrophages (TAM) are considered the most abundant and essential stromal cells for tumour growth through their capacity to coordinate angiogenesis, inflammation, oxidative stress, invasion, and metastatic capacity of tumour cells [5,6,7]
On the basis of these previous results, the aim of the present study was to investigate whether Tumour extracellular vesicles (EVs) (TEV) released from C26 colon carcinoma cells treated with doxorubicin (DOX) could influence the response of cancer cells as well as TME cells under normoxic and hypoxic conditions [23,24]

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Introduction

The tumour microenvironment (TME) is shaped by the complex interactions between malignant cells and stromal cells These stromal cells include resident cells (e.g., epithelial and mesenchymal cells, resident macrophages, cancer-associated fibroblasts) or infiltrating cells (e.g., immune cells, mesenchymal stem cells, endothelial progenitor cells) [1,2,3,4]. It is known that EVs are a heterogeneous group of membranous structures secreted by most cells, especially under pathological or cellular stress conditions [15] These vesicles can convey bioactive molecules (functional proteins, lipids, and nucleic acids) that can alter the behaviour of the recipient cells [15,16,17,18,19,20]. Tumour EVs (TEV) are able to shape a neoplastic TME that is favourable for cancer progression and to help define the therapeutic outcome of different cytotoxic drugs [17,21,22]

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