Hyaluronan (HA), a major component of the extracellular matrix (ECM), is enriched in many types of
tumors. In
cancer patients HA concentrations are usually higher in malignant
tumors than in corresponding benign or normal tissues, and in some
tumor types the level of HA is predictive of
malignancy. HA is often bound to CD44
isoforms which are ubiquitous, abundant, and functionally important
cell surface receptors. This article reviews the current evidence for HA/CD44-mediated activation of the
ankyrin-based cytoskeleton and RhoGTPase signaling during
tumor progression. A special focus is placed on the role of HA-mediated CD44 interaction with unique downstream effectors (e.g., the cytoskeletal
protein,
ankyrin and/or various
GTPases (e.g., RhoA, Rac1 and Cdc42)) in coordinating intracellular signaling pathways (e.g., Ca(2+) mobilization, Rho signaling,
PI3 kinase-AKT activation, NHE1-mediated cellular acidification, transcriptional upregulation and cytoskeletal function) and generating the concomitant onset of
tumor cell activities (e.g.,
tumor cell adhesion, growth, survival, migration and invasion) and
tumor progression. I believe this information will provide valuable new insights into poorly understood aspects of solid
tumor malignancy. Furthermore, the new knowledge concerning HA/CD44-mediated oncogenic signaling events will have potentially important clinical utility, and could establish CD44 and its associated signaling molecules as important
tumor markers for the early detection and evaluation of oncogenic potential. It could also serve as ground work for the future development of new
drug targets to inhibit HA/CD44-mediated
tumor metastasis and
cancer progression.