• Doxorubicin or carboplatin treatment of differentiating mesenchymal stem cells resulted in increased numbers of mature lipid-containing adipocytes. • RNA-seq analysis suggested alterations in key pathways including the fibroblast growth factor (FGF) signaling pathway. • Inhibition of FGF2 ameliorated doxorubicin-enhanced adipogenesis. • Tumour cell growth was enhanced when exposed to conditioned media from doxorubicin-treated adipocyte cultures, which was abrogated when adipocyte FGF2 expression was inhibited. The bone marrow microenvironment is highly saturated with bone marrow adipocytes (BMA), which differentiate from their precursor, mesenchymal stem cells (MSC). Evidence from patient trials suggests that bone marrow adiposity is increased in patients following some forms of chemotherapy. Moreover, it has been suggested that BMA can confer chemotherapeutic resistance to tumour cells, thereby ascribing a tumour-supportive role to BMA. We investigated the effect of chemotherapy on adipogenesis of human mesenchymal stem cells in vitro, as well as potential underlying mechanisms leading to altered adipogenesis, and the effects in turn on tumour cell proliferation. Doxorubicin or carboplatin treatment of adipogenic differentiating MSC led to an increased percentage of mature BMA confirmed by increased gene expression of the adipocyte marker, PPARG . RNA-seq analysis identified significant increases in FGF pathway genes in doxorubicin treated adipogenic differentiated MSC, which were validated at the mRNA and protein level. Notably, endogenous and secreted FGF2 was significantly increased with doxorubicin treatment. Furthermore, siRNA-mediated targeting of FGF2 impeded the doxorubicin-enhanced formation of lipid-containing mature BMA returning it to levels similar to vehicle control treated BMA. As FGF2 is a secreted protein we tested and confirmed that transfer of conditioned media from doxorubicin-treated BMA enhanced proliferation of tumour cells in vitro , a phenotype that was abrogated when FGF2 was depleted from adipogenic differentiating MSC. Our findings suggest that chemotherapy actively promotes adipogenesis, in part by alteration of FGF2 in the context of doxorubicin treatment, which directly enhances adipogenesis and in turn leads to enhanced tumour cell growth as a result.
Kreps et al. (Sun,) studied this question.