Anti-Tumor Effects of Biomimetic Sulfated Glycosaminoglycans on Lung Adenocarcinoma Cells in 2D and 3D In Vitro Models

Abstract

Lung cancer development relies on cell proliferation and migration, which in turn requires interaction with extracellular matrix (ECM) components such as glycosaminoglycans (GAGs). The mechanisms through which GAGs regulate cancer cell functions are not fully understood but they are, in part, mediated by controlled interactions with cytokines and growth factors (GFs). In order to mechanistically understand the effect of the degree of sulfation (DS) of GAGs on lung adenocarcinoma (LUAD) cells, we synthesized sulfated alginate (AlgSulf) as sulfated GAG mimics with DS = 0.0, 0.8, 2.0, and 2.7. Human (H1792) and mouse (MDA-F471) LUAD cell lines were treated with AlgSulf of various DSs at two concentrations 10 and 100 µg/mL and their anti-tumor properties were assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), trypan blue exclusion, and wound healing assays for 2D models and sphere formation assay for the 3D model. The proliferation and number of live MDA-F471 cells at the concentration of 100 µg/mL decreased significantly with the increase in the DS of biomimetic GAGs. In addition, the increase in the DS of biomimetic GAGs decreased cell migration (p < 0.001 for DS = 2.0 and 2.7 compared to control) and decreased the diameter and number of spheres formed (p < 0.001). The increased DS of biomimetic GAGs attenuated the expression of cancer stem cell (CSC)/progenitor markers in the 3D cultures. In conclusion, GAG-mimetic AlgSulf with increased DS exhibit enhanced anti-proliferative and migratory properties while also reducing growth of KRAS-mutant LUAD spheres in vitro. We suggest that these anti-tumor effects by GAG-mimetic AlgSulf are possibly due to differential binding to GFs and consequential decreased cell stemness. AlgSulf may be suitable for applications in cancer therapy after further in vivo validation.

Glycosaminoglycan from Ostrea rivularis attenuates hyperlipidemia and regulates gut microbiota in high‐cholesterol diet‐fed zebrafish

“…Glycosaminoglycans (GAGs) are long linear heteropolysaccharides widely present in the extracellular matrix of animal tissues (Naderer et al., 2015). These compounds display a variety of biological functions, including antioxidant (Bai et al., 2018), anticoagulant (Guan et al., 2019), hypolipidemic (Liu et al., 2002a), and antitumr activities (Al et al., 2020). Liu et al (Liu et al., 2002b) recently reported that GAGs extracted from sea cucumber reduce total cholesterol (TC) and LDL cholesterol levels in serum and the atherogenic index in rats fed with a high‐cholesterol diet.…”

Construction of a multiple-class classifier based on mRNAs and lncRNA FAM66A and PSORS1C3 for predicting distant metastasis in lung adenocarcinoma

“…Further clinical studies are needed, and an LUAD cell model should be validated in the observation experiment. Second, cytometric bead-array assay and additional histological descriptors were not available ( 67 ). Future research should include additional experiments to validate the conclusions.…”

Extracellular matrix sulfation in the tumor microenvironment stimulates cancer stemness and invasiveness

“…Although deregulation of sGAG biosynthesis and post-translational modification have been shown to correlate with poor prognosis, the effect of increase in sGAGs on tumor growth and invasion has been controversial [12][13][14][15] . Studies have reported both tumor promoting and inhibiting effects of sGAG supplementation [13][14][15][16][17][18] . The use of sGAGs has even been proposed as a therapeutic approach in cancer 19 .…”