Hyaluronan-CD44 Interactions in Cancer: Paradoxes and Possibilities

Abstract

Hyaluronan is a prominent component of the micro-environment in most malignant tumors and can be prognostic for tumor progression. Extensive experimental evidence in animal models implicates hyaluronan interactions in tumor growth and metastasis, but it is also evident that a balance of synthesis and turnover by hyaluronidases is critical. CD44, a major hyaluronan receptor, is commonly but not uniformly associated with malignancy, and is frequently used as a marker for cancer stem cells in human carcinomas. Multivalent interactions of hyaluronan with CD44 collaborate in driving numerous tumor-promoting signaling pathways and transporter activities. It is widely accepted that hyaluronan-CD44 interactions are crucial in both malignancy and resistance to therapy, but major challenges for future research in the field are the mechanism of activation of hyaluronan-CD44 signaling in cancer cells, the relative importance of variant forms of CD44 and other hyaluronan receptors, e.g., Rhamm, in different tumor contexts, and the role of stromal versus tumor cell production and turnover of hyaluronan. Despite these caveats, it is clear that hyaluronan-CD44 interactions are an important target for translation into the clinic. Among the approaches that show promise are antibodies and vaccines to specific variants of CD44 that are uniquely expressed at critical stages of progression of a particular cancer, hyaluronidase-mediated reduction of barriers to drug access, and small hyaluronan oligosaccharides that attenuate constitutive hyaluronan-receptor signaling and enhance chemosensitivity. In addition, hyaluronan is being used to tag drugs and delivery vehicles for targeting of anticancer agents to CD44-expressing tumor cells. (Clin Cancer Res 2009;15(24):7462-8)

N-cadherin and hyaluronan expression in head and neck squamous cell carcinoma, relation to patient outcomes

“…This difference could be explained by differences in immuno-histochemical procedures. [47] In the present study, we also found a significant (p = .04) association between high N-cadherin expression and neural invasion as 86.7% of cases that showed neural invasion exhibited high expression of N-cadherin. Kehagias et al also reported similar results in their series of salivary gland tumors as N-cadherin was not expressed in benign neoplasms, but was expressed in half of the malignant ones.…”

“…[46] HA acting through promoting cell adhesion and motility, proliferation, and differentiation. [47] Growth factors and chemokines produced in tumor microenvironment can induce HA production. [48] In the current study, HA was expressed in the proliferating tumor islands and in the surrounding stroma with variable intensity of the reaction.…”

Critical role for lysyl oxidase in mesenchymal stem cell-driven breast cancer malignancy

“…S1), in which HA is significantly represented. Third and most importantly, HA was shown to be a critical modulator of EMT phenotypes in normal and cancerous epithelial cells, and its abundance in the stromal environment of cancer cells causes their invasion and metastasis (30). Indeed, treatment of cocultures of MSCs and cancer cells with hyaluronidase inhibited MSC-induced LOX (and Twist) expression in BCC MSC (Fig.…”

“…HA acts through multiple receptors, with CD44 being its major partner in cancer (30). We, therefore, proceeded to explore whether it mediated the actions of MSCs on the LOX-Twist axis.…”

Interleukin-1β-induced Reduction of CD44 Ser-325 Phosphorylation in Human Epidermal Keratinocytes Promotes CD44 Homomeric Complexes, Binding to Ezrin, and Extended, Monocyte-adhesive Hyaluronan Coats

“…Due to the complexity of CD44 interactions, it has been assigned many functions, including lymphocyte homing, cell adhesion, migration, and proliferation. These functions are important in physiological and pathological processes like wound healing, inflammation, and cancer (1,2).…”