Untangling Galectin-Mediated Circuits that Control Hypoxia-Driven Angiogenesis

Bannoud, Nadia; García, Pablo Andrés; Gambarte-Tudela, Julian; Sundblad, Victoria; Cagnoni, Alejandro J.; Bach, Camila A; Sáez, Juan M. Pérez; Blidner, Ada G.; Maller, Sebastián M.; Mariño, Karina; Salatino, Mariana; Cerliani, Juan P.; Rabinovich, Gabriel A.; Croci, Diego O.

doi:10.1007/978-1-0716-2055-7_34

Cited by 2 publications

(5 citation statements)

References 30 publications

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“…Primary human umbilical vein endothelial cells (HUVEC) were purified from human umbilical vein as previously reported (Bannoud et al., 2022 ). For tube formation assays, HUVEC were starved for 2 h in RPMI 1640 without FBS.…”

Section: Methodsmentioning

confidence: 99%

Extracellular vesicles from human plasma dampen inflammation and promote tissue repair functions in macrophages

Adamczyk

Leicaj

Fabiano

et al. 2023

J of Extracellular Vesicle

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Although inflammation is a vital defence response to infection, if left uncontrolled, it can lead to pathology. Macrophages are critical players both in driving the inflammatory response and in the subsequent events required for restoring tissue homeostasis. Extracellular vesicles (EVs) are membrane‐enclosed structures released by cells that mediate intercellular communication and are present in all biological fluids, including blood. Herein, we show that extracellular vesicles from plasma (pEVs) play a relevant role in the control of inflammation by counteracting PAMP‐induced macrophage activation. Indeed, pEV‐treatment of macrophages simultaneously with or prior to PAMP exposure reduced the secretion of pro‐inflammatory IL‐6 and TNF‐α and increased IL‐10 response. This anti‐inflammatory activity was associated with the promotion of tissue‐repair functions in macrophages, characterized by augmented efferocytosis and pro‐angiogenic capacity, and increased expression of VEGFa, CD300e, RGS2 and CD93, genes involved in cell growth and tissue remodelling. We also show that simultaneous stimulation of macrophages with a PAMP and pEVs promoted COX2 expression and CREB phosphorylation as well as the accumulation of higher concentrations of PGE2 in cell culture supernatants. Remarkably, the anti‐inflammatory activity of pEVs was abolished if cells were treated with a pharmacological inhibitor of COX2, indicating that pEV‐mediated induction of COX2 is critical for the pEV‐mediated inhibition of inflammation. Finally, we show that pEVs added to monocytes prior to their M‐CSF‐induced differentiation to macrophages increased efferocytosis and diminished pro‐inflammatory cytokine responses to PAMP stimulation. In conclusion, our results suggest that pEVs are endogenous homeostatic modulators of macrophages, activating the PGE2/CREB pathway, decreasing the production of inflammatory cytokines and promoting tissue repair functions.

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Section: Methodsmentioning

confidence: 99%

Extracellular vesicles from human plasma dampen inflammation and promote tissue repair functions in macrophages

Adamczyk

Leicaj

Fabiano

et al. 2023

J of Extracellular Vesicle

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“…Isolation of HUVECs from umbilical cords was performed essentially as described ( 77 ), following approval by the Ethics Committee from the Faculty of Medicine, National University of Cuyo (Mendoza, Argentina) (ref. EXP-CUY: 4693-2018).…”

Section: Methodsmentioning

confidence: 99%

“…The formation of capillary-like tubular structures was assessed in Geltrex-coated plates as described ( 77 ). In brief, HUVECs (1.5 × 10 4 cells) were mixed with plasma samples (5% RPMI 1640) from bevacizumab-treated patients at different time points, preincubated or not with anti-Gal1 mAb-42, and then plated on Geltrex-coated 96-well plates at 37 °C for 12 h or, alternatively, on Geltrex-coated µ-slide angiogenesis (Ibidi ® ) for 6 to 8 h. Capillary-like tubular structures were visualized by phase-contrast microscopy and recorded by counting the number of tubules (closed areas) per well in a phase-contrast microscope (Nikon E-100).…”

Section: Methodsmentioning

confidence: 99%

“…Tubulogenesis Assay. The formation of capillary-like tubular structures was assessed in Geltrex-coated plates as described (77). In brief, HUVECs (1.5 × 10 4 cells) were mixed with plasma samples (5% RPMI 1640) from bevacizumab-treated patients at different time points, preincubated or not with anti-Gal1 mAb-42, and then plated on Geltrex-coated 96-well plates at 37 °C for 12 h or, alternatively, on Geltrex-coated µ-slide angiogenesis (Ibidi ® ) for 6 to 8 h.…”

Section: Exp-cuy: 4693-2018)mentioning

confidence: 99%

“…Spheroid Sprouting Assay. To study angiogenesis in a 3D culture system, a HUVEC spheroid sprouting assay was performed as described (77). Briefly, HUVEC spheroids were obtained by seeding 400 to 500 HUVECs in 100 µL Methocel spheroid solution (Methocel, FBS, and RPMI 1640 medium in a 20:20:60 ratio and 15 ng/mL VEGF) for 2 to 3 d. Then, spheroids were harvested, washed with PBS, centrifuged (500 × g for 2 min), and resuspended in Methocel sprouting solution (Methocel and FBS in an 80:20 ratio).…”

Section: Pnasorgmentioning

confidence: 99%

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Circulating galectin-1 delineates response to bevacizumab in melanoma patients and reprograms endothelial cell biology

Bannoud

Stupirski

Cagnoni

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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Blockade of vascular endothelial growth factor (VEGF) signaling with bevacizumab, a humanized anti-VEGF monoclonal antibody (mAb), or with receptor tyrosine kinase inhibitors, has improved progression-free survival and, in some indications, overall survival across several types of cancers by interrupting tumor angiogenesis. However, the clinical benefit conferred by these therapies is variable, and tumors from treated patients eventually reinitiate growth. Previously we demonstrated, in mouse tumor models, that galectin-1 (Gal1), an endogenous glycan-binding protein, preserves angiogenesis in anti-VEGF–resistant tumors by co-opting the VEGF receptor (VEGFR)2 signaling pathway in the absence of VEGF. However, the relevance of these findings in clinical settings is uncertain. Here, we explored, in a cohort of melanoma patients from AVAST-M, a multicenter, open-label, randomized controlled phase 3 trial of adjuvant bevacizumab versus standard surveillance, the role of circulating plasma Gal1 as part of a compensatory mechanism that orchestrates endothelial cell programs in bevacizumab-treated melanoma patients. We found that increasing Gal1 levels over time in patients in the bevacizumab arm, but not in the observation arm, significantly increased their risks of recurrence and death. Remarkably, plasma Gal1 was functionally active as it was able to reprogram endothelial cell biology, promoting migration, tubulogenesis, and VEGFR2 phosphorylation. These effects were prevented by blockade of Gal1 using a newly developed fully human anti-Gal1 neutralizing mAb. Thus, using samples from a large-scale clinical trial from stage II and III melanoma patients, we validated the clinical relevance of Gal1 as a potential mechanism of resistance to bevacizumab treatment.

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Untangling Galectin-Mediated Circuits that Control Hypoxia-Driven Angiogenesis

Cited by 2 publications

References 30 publications

Extracellular vesicles from human plasma dampen inflammation and promote tissue repair functions in macrophages

Extracellular vesicles from human plasma dampen inflammation and promote tissue repair functions in macrophages

Circulating galectin-1 delineates response to bevacizumab in melanoma patients and reprograms endothelial cell biology

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