Hyaluronan Oligosaccharides Inhibit Tumorigenicity of Osteosarcoma Cell Lines MG-63 and LM-8 in Vitro and in Vivo via Perturbation of Hyaluronan-Rich Pericellular Matrix of the Cells

Abstract

Numerous studies have demonstrated a correlation between hyaluronan expression and the malignant properties of various kinds of cancer, and inhibition of hyaluronan production causes decreased tumor growth. Hyaluronan oligosaccharides have been shown to inhibit several tumor cell types via disruption of receptor-hyaluronan interaction. However, few studies have addressed hyaluronan with respect to osteosarcoma. In this study, we examined the effects of exogenously added hyaluronan oligosaccharides on tumorigenicity of murine osteosarcoma cells, LM-8, and human osteoblastic osteosarcoma cells, MG-63. Moreover, the critical size of oligomers needed to inhibit malignant properties was defined. Fluorescent hyaluronan oligosaccharides accumulated both on the surface of cells and in the cytoplasm, and this retention was blocked by pretreatment with an anti-CD44 monoclonal antibody. Hyaluronan octasaccharides significantly inhibited cell viability and induced apoptosis as defined by cell proliferation and terminal deoxynucleotidyl transferase dUTP nick-end labeling assays, respectively. Octasaccharides also abrogated functional cell-associated matrices and significantly reduced the retention of endogenous hyaluronan. Further, octasaccharide treatment affected an inhibition of cell motility as well as cell invasiveness. Pretreatment of the cells with anti-CD44 antibody reduced the antitumor effect of the octasaccharides. In vivo, intratumoral injection of hyaluronan octasaccharides reduced the hyaluronan accumulation in local tumors, resulting in significant suppression of the formation of distant lung metastasis. Together these data suggest that hyaluronan oligosaccharides have potent antitumor effects functioning in part by the abrogation of hyaluronan-rich cell-associated matrices.

High-resolution microrheology in the pericellular matrix of prostate cancer cells

“…Motility and the invasive nature of osteosarcoma cells are abolished by the same treatment [9], which suggests an involvement of the PCM in cancer cell metastasis. Endothelial cells lose their ability to respond to fluid flow when HA is enzymatically removed [7].…”

Therapeutic potential of hyaluronan oligosaccharides for bone metastasis of breast cancer

“…Previous studies on chondrocytes and tumor cells had demonstrated that an effective concentration of 250 mg/ml of exogenous HA oligos was necessary to affect cell behavior. 20,26 The cells were cultured in the presence or absence of various-sized of 250 mg/ml HA oligos or HMWHA in chamber slides at a concentration of 2 Â HA Oligosaccharides HA oligos; tetrasaccharides (HA4), hexasaccharides (HA6), octasaccharides (HA8), decasaccharides (HA 10), and dodecasaccharides (HA12), were prepared by Seikagaku Co. as described previously. 27 The purity and size of each HA oligos were confirmed using high performance liquid chromatography analyses.…”

“…In these studies, an oligosaccharide length of more than octasaccharides was required for these effects. 20 A recent report showed HA-CD44 interaction plays an important role in the property of highly tumorigenic ovarian carcinoma cells and HA oligo is one of the therapeutic candidates to abrogate the properties of these cells. 21 However, no studies have ever investigated the effects of HA oligos on bone metastasis associated with several solid tumors/carcinomas.…”

Identification of a Novel Chondroitin Hydrolase in Caenorhabditis elegans

“…These oligosaccharides are most likely generated by digestion with Chnase in vivo because their reducing terminal sugar residues are GalNAc. Note that HA oligosaccharides liberated by digestion with hyaluronidases have biological activities, such as induction of the transcription of metalloproteases (37), enhancement of tumor cell motility (38), and inhibition of the tumorigenicity of cancer cells (39). A disaccharide derived from CS was also demonstrated to promote recovery of the central nervous system by modulating both neuronal and microglial behavior (40).…”