Hyaluronan and Hyaluronan Synthases: Potential Therapeutic Targets in Cancer

Abstract

Current models of oncogenesis describe cancer as a progression of genetic mutations in a tumor cell mass. However, tumors are more than a clonal expansion of malignant cells. Tumors are heterogeneous, with a complex 3D structure, analogous to organs comprised of different tissues. In a tumor mass, the component cell types interact with each other and with their microenvironment by exchanging information through cell-cell interactions and/or through interactions with the extracellular matrix (ECM). These synergetic interactions facilitate tumor progression. Furthermore, tumor invasion and metastatic development are accomplished through the breakdown of ECM. Disruption of ECM promotes abnormal inter- and/or intra- cellular signaling, leading to dysregulation of cell proliferation, growth and cytoskeleton reorganization. The disruption of the ECM in turn promotes the overproduction of growth factors, which induce elevated epithelial cell proliferation and other abnormalities including carcinogenesis. In this review we will demonstrate that hyaluronan (HA), a core component of ECM, contributes to certain types of cancer development. Additional to extracellular HA, intracellular and nuclear forms of HA have been detected. Intracellular HA is involved in cell signaling, whereas nuclear HA could promote chromatin condensation and thus facilitate mitosis. HA molecules are synthesized by hyaluronan synthases (HASs)-HAS1, HAS2 and HAS3 enzymes. Dysregulation of HAS genes results in abnormal production of HA and promotion of abnormal biological processes such as transformation and metastasis. The function of HASs appears to be cell and tissue specific. HAS1 maintains a low, basal level of HA. HAS2 is involved in embryonic and cardiac cushion morphogenesis and subsequent development through cell migration and invasion. HAS2 stimulates cell proliferation and angiogenesis. HAS3 appears to favor the malignant phenotype in many types of malignancies. However, the exact function of HAS isoenzymes and their role in cell signaling remains to be elucidated. A better understanding of HA and HASs may facilitate the design of novel therapeutic strategies to counter presumptive cancer-promoting effects of microenvironmental components.

A Rapid Transient Increase in Hyaluronan Synthase-2 mRNA Initiates Secretion of Hyaluronan by Corneal Keratocytes in Response to Transforming Growth Factor β

“…The rapidity, magnitude, and transient nature of the response of HAS2 suggest a functional role for HA in later events of the transdifferentiation of keratocytes to myofibroblasts. HA and HA fragments elicit motility and cell cycle entry from a number of cell types (6,39,40). It therefore seems likely that a burst of HA synthesis coupled with increased HA degradation could elicit a similar response from keratocytes as well.…”

Localisation and endocrine control of hyaluronan synthase (HAS) 2, HAS3 and CD44 expression in sheep granulosa cells

“…This specialised extracellular matrix (ECM) manages fluid dynamics and provides mechanical support. Hyaluronan (HA) is an important component of the ECM, present in various tissues of many species and contribute to cell signalling pathways as well as to the physical characteristics and stability of different cell types (Itano and Kimata 2002;Adamia et al 2005). In addition, HA actively participates in both intra-and extracellular pathways, influencing cellular behaviour such as migration, growth, motility, adhesion and differentiation (Toole 2001;Toole et al 2002;Bodevin-Authelet et al 2005;Itano 2008).…”

The Hyaluronan Receptors CD44 and Rhamm (CD168) Form Complexes with ERK1,2 That Sustain High Basal Motility in Breast Cancer Cells

“…Originally described as the principal cell surface receptor for HA (14), CD44 has since been shown to bind multiple ligands including fibronectin (15) and osteopontin (16); in general, the ligands for many of the CD44 variants are not yet known. However, a role for CD44std as a mediator of HA-promoted motility in breast cancer cell lines is well established on tissue culture plastic (two-dimensional cultures) (7,(17)(18)(19). CD44 isoforms containing variable exons v6 and v9 are also involved in HA-mediated signaling (e.g.…”

“…Cell surface Rhamm (CD168) is an HA-binding protein/receptor that is not highly expressed in normal tissues but is commonly overexpressed in many advanced cancers (18,19), including breast cancer (37,38). Rhamm was first identified as an HA-dependent motility cell surface receptor that can transform fibroblasts when overexpressed (39,40).…”