Research Papers:

Co-treatment of tumor cells with hyaluronan plus doxorubicin affects endothelial cell behavior independently of VEGF expression

Daiana L. Vitale, Fiorella M. Spinelli, Daiana Del Dago, Antonella Icardi, Gianina Demarchi, Ilaria Caon, Mariana García, Marcela F. Bolontrade, Alberto Passi, Carolina Cristina and Laura Alaniz _

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Oncotarget. 2018; 9:36585-36602. https://doi.org/10.18632/oncotarget.26379

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Daiana L. Vitale1, Fiorella M. Spinelli1, Daiana Del Dago1, Antonella Icardi1, Gianina Demarchi2, Ilaria Caon5, Mariana García3, Marcela F. Bolontrade4, Alberto Passi5, Carolina Cristina2 and Laura Alaniz1

1Laboratorio de Microambiente Tumoral-Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires (CIT NOBA, UNNOBA-CONICET), Junín, Buenos Aires, Argentina

2Laboratorio de Fisiopatología de la Hipófisis-Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires (CIT NOBA, UNNOBA-CONICET), Junín, Buenos Aires, Argentina

3Laboratorio de Terapia Génica, IIMT–CONICET, Universidad Austral, Derqui-Pilar, Buenos Aires, Argentina

4Laboratorio de Células Madre-Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina

5Dipartimento di Medicina e Chirurgia, Universitá degli Studio dell’Insubria, Varese, Italia

Correspondence to:

Laura Alaniz, email: laualaniz@yahoo.com.ar, ldalaniz@comunidad.unnoba.edu.ar

Keywords: hyaluronan; cancer; doxorubicin; tumor microenvironment; angiogenesis

Received: December 13, 2017     Accepted: November 07, 2018     Published: November 27, 2018


Hyaluronan, the main glycosaminoglycan of extracellular matrices, is concentrated in tissues with high cell proliferation and migration rates. In cancer, hyaluronan expression is altered and it becomes fragmented into low-molecular-weight forms, affecting mechanisms associated with cell proliferation, invasion, angiogenesis and multidrug resistance. Here, we analyzed the effect of low-molecular-weight hyaluronan on the response of T lymphoma, osteosarcoma, and mammary adenocarcinoma cell lines to the antineoplastic drug doxorubicin, and whether co-treatment with hyaluronan and doxorubicin modified the behavior of endothelial cells. Our aim was to associate the hyaluronan-doxorubicin response with angiogenic alterations in these tumors. After hyaluronan and doxorubicin co-treatment, hyaluronan altered drug accumulation and modulated the expression of ATP-binding cassette transporters in T-cell lymphoma cells. In contrast, no changes in drug accumulation were observed in cells from solid tumors, indicating that hyaluronan might not affect drug efflux. However, when we evaluated the effect on angiogenic mechanisms, the supernatant from tumor cells treated with doxorubicin exhibited a pro-angiogenic effect on endothelial cells. Hyaluronan-doxorubicin co-treatment increased migration and vessel formation in endothelial cells. This effect was independent of vascular endothelial growth factor but related to fibroblast growth factor-2 expression. Besides, we observed a pro-angiogenic effect on endothelial cells during hyaluronan and doxorubicin co-treatment in the in vivo murine model of T-cell lymphoma. Our results demonstrate for the first time that hyaluronan is a potential modulator of doxorubicin response by mechanisms that involve not only drug efflux but also angiogenic processes, providing an adverse tumor stroma during chemotherapy.

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