Carcinoma Cell Hyaluronan as a "Portable" Cancerized Prometastatic Microenvironment

Abstract

Hyaluronan (HA) is a structurally simple polysaccharide, but its ability to act as a template for organizing pericellular matrices and its regulated synthesis and degradation are key to initiating repair responses. Importantly, these HA functions are usurped by tumor cells to facilitate progression and metastasis. Recent advances have identified the functional complexities associated with the synthesis and degradation of HA-rich matrices. Three enzymes synthesize large HA polymers while multiple hyaluronidases or tissue free radicals degrade these into smaller bioactive fragments. A family of extracellular and cell-associated HA-binding proteins/receptors translates the bioinformation encrypted in this complex polymer mixture to activate signaling networks required for cell survival, proliferation, and migration in an actively remodeling microenvironment. Changes in HA metabolism within both the peritumor stroma and parenchyma are linked to tumor initiation, progression, and poor clinical outcome. We review evidence that metastatic tumor cells must acquire the capability to autonomously synthesize, assemble, and process their own "portable" HA-rich microenvironments to survive in the circulation, metastasize to ectopic sites, and escape therapeutic intervention. Strategies to disrupt the HA machinery of primary tumor and circulating tumor cells may enhance the effectiveness of current conventional and targeted therapies. Cancer Res; 76(9); 2507-12. ©2016 AACR.

Figure 1. Autocrine Synthesis and Retention of a Hyaluronan Pericellular Matrix

The hyaluronan (HA) pericellular matrix is produced by extrusion of a growing HA chain into the microenvironment of the tumor cell. Cytoplasmic activated sugars (UDP-acetylglucosamine and UDP-B-glucuronic acid) are added to the polymer by the plasma membrane associated hyaluronan synthase (HAS). The extruded hyaluronan polymer is assembled into a pericellular coat by HA receptors such as CD44 and RHAMM and by extracellular HA binding proteins (not shown but mentioned in text). The pericellular coat captures and concentrates growth factors/cytokines required for circulating tumor cell survival. These, together with HA-clustered receptors, coordinate activation of signaling pathways via receptor tyrosine kinases (RTK). Two major pathways shown are the MAP kinase (MEK1, ERK1,2) and SRC/FAK pathways that promote expression of an oncogenic transcriptome required for tumor cell survival, migration/invasion, proliferation and resistance to apoptosis. RHAMM is an unusual regulator protein in this process that is required for binding of HA to the cell surface of unattached cells as well as playing key intracellular roles in signaling cascades and gene transcription.

Figure 2. Hyaluronan Pericellular Matrices as a Portable Pro-Metastatic Cancerized Microenvironment

Diagram of the stages of tumorigenesis that require HA pericellular matrices and fragments. Diagram shows that primary tumors are heterogeneous (symbolized by different colors) in terms of tumor cell subpopulations and are imbedded in an HA rich pericellular matrix (light green) containing HA fragments (dark green lines) that are produced by both host (grey shades) and tumor cells (colored). As tumors progress, subpopulations develop autocrine capability to synthesis HA matrices (blue) and fragments that promote invasion into the surrounding stroma and intravasation into vessels. The pericellular HA matrix (blue) is proposed to surround circulating tumor cells and to aid in extravasation at ectopic sites as well as growth of migrant colonies (surrounded by an HA-rich matrix) in these foreign microenvironments