Co-treatment of hyaluronan and doxorubicin in tumor cells affects endothelial cell behavior independently of VEGF expression

DAIANA VITALE; FIORELLA SPINELLI; DAIANA DEL DAGO; ANTONELLA ICARDI; GIANINA DEMARCHI; ILARIA CAON; MARIANA G. GARCIA; MARCELA BOLONTRADE; ALBERTO PASSI; CAROLINA CRISTINA; LAURA ALANIZ

Oncotarget

Impact Journals

Año: 2018

30 Hyaluronan is the major glycosaminoglycan of extracellular matrices, concentrated in31 tissues with high cell proliferation and migration rates. Hyaluronan expression is altered32 and it becomes fragmented into low molecular weight forms, affecting mechanisms33 associated with cell proliferation, invasion, angiogenesis and multidrug resistance in34 cancer. We analyzed the effect of low molecular weight hyaluronan on doxorubicin35 response in lymphoma T, osteosarcoma, and mammary adenocarcinoma cell lines.36 Besides, we analyzed whether tumor cells treated with hyaluronan and doxorubicin37 modified endothelial cells behavior. Our aim was to associate the hyaluronan38doxorubicin response to angiogenic alterations in these tumors. We observed that after39 hyaluronan and doxorubicin co-treatment, hyaluronan altered drug accumulation and40 modulated expression of ATP-binding cassette (ABC) transporters in lymphoma T41 cells. Contrasting, no changes in drug accumulation were observed in cells from solid42 tumors, indicating that hyaluronan might not affect drug efflux. However, when we43 evaluated the effect on angiogenic mechanisms, supernatant from tumor cells treated44 with doxorubicin exhibited a pro-angiogenic effect on endothelial cells. We observed45 that hyaluronan-doxorubicin co-treatment incremented migration and vessel formation46 ability in endothelial cells. This effect was independent of vascular endothelial growth47 factor but related to fibroblast growth factor-2 expression. Besides, we observed a pro48angiogenic effect on endothelial cells during hyaluronan and doxorubicin co-treatment49 in the in vivo murine model of lymphoma T. Our results demonstrate for the first time50 that hyaluronan is a potential modulator of doxorubicin response by mechanisms that51 involve not only drug efflux but also angiogenic process, conferring an adverse tumor52 stroma during chemotherapy.