"My research activity has focused on the study of mesenchymal stem cell (MSC) function in cancer, and on how the interaction between malignant cells and MSCs promotes tumor progression. Through collaborations with multiple Departments at the hosting Institution and with international Institutions we developed a bioluminescent mouse model of osteosarcoma that enabled the study of the interactions between human OS cells and MSCs in vivo. The results of this investigation have been presented at international conferences and recently published in peer-reviewd journals (Baglio et al.,Clin Cancer Res 2017; Lagerweij et al., JoVE 2018; Bebelman et al., Pharmacology and Therapeutics 2018).
Exosomes are small extracellular vesicles (EVs) released by all cells that naturally function as communication devices by transferring proteins, lipids and regulatory RNAs between cells. We demonstrated that EVs released by OS cells trigger a prometastatic inflammatory loop by altering the behavior of MSCs. To investigate whether OS-released exosomes ""educate"" MSCs to support cancer progression, we developed a bioluminescent mouse model of osteosarcoma by inoculating osteosarcoma cells in the tibia of immunocompromised mice. We then educated human MSCs with exosomes released by OS cells, and injected tumor-educated (TEMSC) or non-educated MSCs into the tail vein of the osteosarcoma-bearing mice . We observed accelerated tumor growth in mice that received TEMSCs compared to the control groups. Moreover, we found MSCs in the tumor tissue and in the surrounding bone marrow, demonstrating that these cells can home to the tumor site . Importantly, administration of TEMSCs significantly increased the number of metastases compared to the control groups.
We showed that EVs released by the metastatic osteosarcoma cells instruct MSCs to produce increased levels of IL-6 and that this induction is dependent on a membrane-bound form of TGFβ specifically associated with the surface of the vesicles. We then asked whether we could inhibit tumor progression promoted by TEMSCs by using an IL-6 blocking agent. We found that administration of a clinically available anti-IL-6R antibody reduced tumor growth and metastasis formation in osteosarcoma-bearing mice receiving TEMSCs. Collectively, these data demonstrate that tumor EVs strongly influence MSCs behavior to promote cancer progression via the TGFβ-IL-6/STAT3 signaling axis and that we can interfere with this process using immunomodulatory drugs (Figure 1).
Finally, analysis of human osteosarcoma tissues revealed activation of IL-6/STAT3 signaling pathway and a strong TGFβ associated gene signature (Figure 4b) compared to normal bone tissue, confirming the clinical relevance of our pre-clinical findings. Moreover, we purified EVs from patient blood and showed that serum levels of EV-associated TGFβ are significantly higher in osteosarcoma patients compared to healthy control individuals. These data suggest that TGFβ-carrying vesicles of tumor origin act on stromal and tumor cells to sustain cancer progression, and could represent powerful biomarkers for disease monitoring.
The outcome of this project constitutes the basis of a new investigation that has recently received funding from the Dutch Cancer Society, in which we aim to further explore the communication between osteosarcoma and stromal immune cells and its clinical relevance. We are now setting up collaborations with pharmaceutical companies for testing specific combination of immunodulatory drugs, and with clinicians to evaluate the potential of EV-associated biomarkers to monitor cancer progression and treatment response.
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