Hyaluronan in the Cancer Cells Microenvironment

Abstract

The presence of the glycosaminoglycan hyaluronan in the extracellular matrix of tissues is the result of the cooperative synthesis of several resident cells, that is, macrophages and tumor and stromal cells. Any change in hyaluronan concentration or dimension leads to a modification in stiffness and cellular response through receptors on the plasma membrane. Hyaluronan has an effect on all cancer cell behaviors, such as evasion of apoptosis, limitless replicative potential, sustained angiogenesis, and metastasis. It is noteworthy that hyaluronan metabolism can be dramatically altered by growth factors and matrikines during inflammation, as well as by the metabolic homeostasis of cells. The regulation of HA deposition and its dimensions are pivotal for tumor progression and cancer patient prognosis. Nevertheless, because of all the factors involved, modulating hyaluronan metabolism could be tough. Several commercial drugs have already been described as potential or effective modulators; however, deeper investigations are needed to study their possible side effects. Moreover, other matrix molecules could be identified and targeted as upstream regulators of synthetic or degrading enzymes. Finally, co-cultures of cancer, fibroblasts, and immune cells could reveal potential new targets among secreted factors.

Keywords: ECM-extracellular matrix; hyaluronan; soluble factors.

Figure 1

Summary of HA synthesis and its interaction with membrane receptors. The expression of the main synthetic enzyme HAS2 is controlled by various growth and transcription factors, as well as via epigenetic control of transcription by HAS2 antisense 1 (HAS2-AS1). Moreover, the HAS2 activity is also covalently regulated by ubiquitination, phosphorylation, O-GlcNAcylation (due to O-GlcNAc transferase, OGT). Several molecules such as 4-MU, metformin, 2-Deoxy-D-Glucose (2-DG), and the chemical AMPK-stimulating AICAR control HAS2 activity, as demonstrated in in vitro studies.

Figure 2

Schematic representation of the UDP-glucuronic acid (GlcUA) and UDP-N-acetylglucosamine (GlcNAc) biosynthetic pathways. Glucose (Glc) enters the cell through the GLUT transporters. Glucose 6-Phosphate (Glc6P) is transformed in UDP-glucose (UDP-Glc) and then in UDP-GlcUA. Fructose 6-phosphate (Fru6P) is directed to the synthesis of UDP-GlcNAc, by a complex metabolic way influenced by amino acids, lipids, and nucleotides availability. UDP-GlcUA and UDP-GlcNAc can be used for the synthesis of HA by HASes enzymes located at the plasma membrane, for glucuronidation and protein O-GlcNAcylation, respectively, or transported inside the ER/Golgi for the synthesis of GAGs and proteoglycans. 4-methylumbelliferone (4-MU) can act as a competitive inhibitor for HASes and decrease the UDP-GlcUA content.