Hyaluronan, CD44 and Emmprin: Partners in cancer cell chemoresistance

Abstract

Hyaluronan is not only an important structural component of extracellular matrices but also interacts with cells during dynamic cell processes such as occur in cancer. Consequently, interactions of hyaluronan with tumor cells play important cooperative roles in various aspects of malignancy. Hyaluronan binds to several cell surface receptors, including CD44, thus leading to co-regulation of signaling pathways that are important in regulation of multidrug resistance to anticancer drugs, in particular anti-apoptotic pathways induced by activation of receptor tyrosine kinases. Emmprin, a cell surface glycoprotein of the Ig superfamily, stimulates hyaluronan production and downstream signaling consequences. Emmprin and CD44 also interact with various multidrug transporters of the ABC family and monocarboxylate transporters associated with resistance to cancer therapies. Moreover, hyaluronan-CD44 interactions are critical to these properties in the highly malignant, chemotherapy-resistant cancer stem-like cells. Perturbations of the hyaluronan-CD44 interaction at the plasma membrane by various antagonists result in attenuation of receptor tyrosine kinase and transporter activities and inhibition of tumor progression in vivo. These antagonists, especially small hyaluronan oligomers, may be useful in therapeutic strategies aimed at preventing tumor refractoriness or recurrence due to drug-resistant sub-populations within malignant cancers.

Basigin/CD147 Promotes Renal Fibrosis after Unilateral Ureteral Obstruction

“…10 Previous reports and the present study have demonstrated that Bsg promotes hyaluronan production and subsequent ␣-SMA expression in fibroblasts. 25,49 In summary, Bsg is a multifunctional molecule engaged in hyaluronan production, MMP production, cell adhesion, and ␣-SMA induction in renal fibrosis. Intervention targeting Bsg would have multiple effects on the prevention of renal fibrosis.…”

“…Because it has been reported that Bsg promotes hyaluronan production in tumor cells and fibroblasts, [23][24][25]49 we asked whether or not Bsg deficiency would affect hyaluronan production by MEF. We found that the expression of hyaluronic acid synthase 2, which biosynthesizes hyaluronan, was lower in Bsg Ϫ/Ϫ MEF even in the steady state ( Figure 6A).…”

Extracellular Matrix Microenvironment in Glioma Progression

“…It should be pointed out that EMMPRIN levels have been shown to increase in glioma and correlate with tumor grade (Sameshima et al 2000). EMMPRIN has also been shown to increase hyaluronan and colocalizes with its receptor CD44 (Toole and Slomiany 2008). Given that Hyaluronan and CD44 are important players in the CNS and in gliomas (see section 3.4.1) EMMPRIN may play a significant role in glioma invasion.…”

Inhibition of Hyaluronan Synthesis Accelerates Murine Atherosclerosis

“…Because of these findings, the "hyaluronan system," including the synthases, hyaluronan receptors, and hyaluronidases, may indeed be developed into therapeutic strategies to treat cancer. 2,14 Of note, 4-MU is already used in patients as a musculotropic smooth muscle relaxant to treat nonspecific abdominal pain and as a cholagogue (Cholspasmin). Furthermore, 4-MU is advertised in the United States and Europe as a prescription-free "neutraceutical" product (Heparvit) for cancer patients.…”