THE ANTIANGIOGENIC ACTION OF SULFATED HYALURONAN ON MONOCYTES/MACROPHAGES IN BREAST TUMOR CONTEXT

FIORELLA SPINELLI; DAIANA VITALE; PAOLO ROSALES; ANTONELLA ICARDI; STEFANO PLUDA; CARLOS GUARESSI; DEVIS GALESSO; MARIANA G. GARCIA; INA SEVIC; ALANIZ LAURA

Florencia

Congreso; Matrix Biology Europe 2020 Congress; 2020

Society for Matrix Biology

Breast carcinoma is one the most frequent types of cancer. The potentiation of immune action again this tumor will be a promising therapeutic option. Monocytes/macrophages(Mo/MØ) are critical modulators of the tumor microenvironment¹. Chemically modified hyaluronan like sulfated hyaluronan (sHA) are biomaterials that can work as a possible adjuvant therapy because: (i) inhibits HAses², (ii) antitumor and antiangiogenic activity in cancer cells³,⁴, (iii) blocks VEGF action⁵. However, the action of sHA in Mo/MØ in tumor context it is not elucidated yet.Methods. sHA were synthesized from the tetrabutyl ammonium salt of HA in Fidia Farmaceuticis.p.a. (sHA1 MW=28,1 kDa and sHA3 MW=66,4 kDa). Human breast cancer cell line (MDA-MB- 231) was used to collect conditioned media (MCM). Mo/MØ were treated with MCM and sHA1 or 3. MTS assay was used to measure cell viability. TGFβ1 and IL1β biosynthesis were measured by ELISA. VEGF, FGF-2 and IL8 mRNA levels were measured by qPCR. EC migration was evaluated using a modified Boyden chamber. HA total levels were quantified by ELISA like assay. In vivo experiments: Mo/MØ pulsed with sHA were inoculated in MDA-MB-231 xenograft mice model. Tumors were fixed and stained with: i)Lectin GSLI-FITC for vasculature detection and ii)HA and TSG-6.Results. The treatments with sHA increased Mo/MØ viability. TGFβ1 decreased with the treatment of sHA3 plus MCM. sHA 1 or 3 plus MCM decreased the expression of angiogenic factors and EC migration. HA total levels diminished in the supernatant of Mo/MØ treated with sHA1 and MCM. Even more, Mo/MØ primed with sHA and inoculated breast tumor model incremented blood vessel formation and diminished TSG-6 and HA levels.Discussion. sHA could modulate immune activation by affecting the angiogenic and immune behavior of Mo/MØ. Further investigations are needed to understand the immune and angiogenic signals triggered by sHA in the context of the tumor microenvironment.References. ¹ Spinelli et al., Clin Transl Immunology, 2015. ²Spinelli et al., FEBS Journal, 2019. ³T. Isoyama, et al., Glycobiology, 2006. ⁴ A. Benitez, et al., Cancer research, 2011. ⁵ A. R. Jordan,et al., Oncotarget, 2016. ⁶ D. K. Lim, et al., Biomaterials, 2016.