Inhibition of Functional Hyaluronan-CD44 Interactions in CD133-positive Primary Human Ovarian Carcinoma Cells by Small Hyaluronan Oligosaccharides

Abstract

Purpose: CD44 is one of the most common markers used for identification of highly tumorigenic subpopulations of human carcinoma cells, but little is known about the function of CD44 or its major ligand, hyaluronan, in these cells. The purpose of this study was to investigate the involvement of hyaluronan and its interaction with CD44 in the properties of a tumorigenic subpopulation of primary ovarian carcinoma cells. Experimental Design: A tumorigenic subpopulation was identified in ascites fluids from ovarian carcinoma patients by expression of high CD133 levels. Treatment with small hyaluronan oligosaccharides, which dissociate constitutive hyaluronan polymer-CD44 interactions, was used to test the importance of hyaluronan-CD44 interaction in assembly of multidrug and monocarboxylate transporters and receptor tyrosine kinases in the plasma membrane of cells with high CD133 levels, and in the tumorigenic capacity of the CD133-high subpopulation. Results: Although total CD44 levels were similar in cells with high or low CD133 expression, CD44 was present in close association with transporters, receptor tyrosine kinases, and emmprin (CD147) in the plasma membrane of cells with high CD133 levels. Treatment with small hyaluronan oligosaccharides reduced association of the transporters and receptor tyrosine kinases with CD44 in the plasma membrane, diminished drug transporter activity, and inhibited i.p. tumorigenesis in these cells. Conclusions: We conclude that hyaluronan-CD44 interaction plays an important role in the properties of highly tumorigenic cells by stabilizing oncogenic complexes in their plasma membrane, and that treatment with hyaluronan-CD44 antagonists provides a logical therapeutic approach for abrogating the properties of these cells. (Clin Cancer Res 2009;15(24):7593-601)

Ovarian cancer stem cells express ROR1, which can be targeted for anti–cancer-stem-cell therapy

“…Therefore, targeting such antigens with mAbs or small molecules also may affect the normal tissues that express these antigens (48,49). However, with few exceptions (50), the postpartum expression of ROR1 seems restricted to cancer cells.…”

ALDH1 in Combination with CD44 as Putative Cancer Stem Cell Markers are Correlated with Poor Prognosis in Urothelial Carcinoma of the Urinary Bladder

“…CD44, a specific receptor for hyaluronic acid and adhesion/homing molecule (Naor et al, 2008;Jaggupilli and Elkord, 2012), is a multifunctional class I transmembrane glycoprotein expressed in almost all normal and cancer cells (Naor et al, 2008;Jaggupilli and Elkord, 2012). In several previous studies, CD44 individually or in combination with other putative CSC markers has been applied to isolate CSCs in various solid tumors including breast (Al-Hajj et al, 2003), prostate, pancreas (Immervoll et al, 2011), ovarian, colorectal (Wielenga et al, 1993;Woodman et al, 1996;Choi et al, 2009), head and neck (Satpute et al, 2013) and bladder cancers (Yang and Chang, 2008;Chan et al, 2009;Slomiany et al, 2009;Lee et al, 2010;Su et al, 2010;Jaggupilli and Elkord, 2012). Both in vitro and in vivo studies have shown that CD44+ bladder cancer cells have higher tumorigenic potential compared to CD44-bladder cancer cells; whereas they have lower tumorigenic potential compared to ALDH1A1+ cells .…”

Serglycin Proteoglycan Is Required for Multiple Myeloma Cell Adhesion, in Vivo Growth, and Vascularization

“…To determine the involvement of CD44 in MM-BMSC interactions, adhesion assays were also performed in the presence of either an anti-CD44 ab (hermes-1) (Thermo Scientific) or hyaluronan oligosaccharides (o-HA) (100 g/ml). Hyaluronan oligosaccharides used in this study were a mixed fraction, with the average molecular weight of 2.5 ϫ 10 3 , composed of 2-10 disaccharide units that were fractionated from testicular hyaluronidase (Sigma, type 1-S) digests of hyaluronan polymer (Sigma, sodium salt), as described previously (20). For adhesion to collagen I, wells coated with collagen I were blocked with 1% BSA in serum-free culture medium for 1 h at room temperature.…”

“…These results clearly demonstrate the role of serglycin in mediating myeloma cell adhesion and further confirm that the decreased adhesion shown by serglycin knockdown cells is not an artifact of knockdown. To determine if CD44 is involved in this adhesion mechanism, the adhesion of MM cells to BMSCs was examined in the presence of antagonists of CD44-ligand interaction, either hyaluronan oligosaccharides (o-HA) (20,27) or anti-CD44 monoclonal antibodies (hermes-1). As shown in Fig.…”