Hyaluronan, Cancer-Associated Fibroblasts and the Tumor Microenvironment in Malignant Progression

Abstract

This review summarizes the roles of CAFs in forming a "cancerized" fibrotic stroma favorable to tumor initiation and dissemination, in particular highlighting the functions of the extracellular matrix component hyaluronan (HA) in these processes. The structural complexity of the tumor and its host microenvironment is now well appreciated to be an important contributing factor to malignant progression and resistance-to-therapy. There are multiple components of this complexity, which include an extensive remodeling of the extracellular matrix (ECM) and associated biomechanical changes in tumor stroma. Tumor stroma is often fibrotic and rich in fibrillar type I collagen and hyaluronan (HA). Cancer-associated fibroblasts (CAFs) are a major source of this fibrotic ECM. CAFs organize collagen fibrils and these biomechanical alterations provide highways for invading carcinoma cells either under the guidance of CAFs or following their epithelial to mesenchymal transition (EMT). The increased HA metabolism of a tumor microenvironment instructs carcinoma initiation and dissemination by performing multiple functions. The key effects of HA reviewed here are its role in activating CAFs in pre-malignant and malignant stroma, and facilitating invasion by promoting motility of both CAFs and tumor cells, thus facilitating their invasion. Circulating CAFs (cCAFs) also form heterotypic clusters with circulating tumor cells (CTC), which are considered to be pre-cursors of metastatic colonies. cCAFs are likely required for extravasation of tumors cells and to form a metastatic niche suitable for new tumor colony growth. Therapeutic interventions designed to target both HA and CAFs in order to limit tumor spread and increase response to current therapies are discussed.

Keywords: cancer-associated fibroblasts; circulating cancer-associated fibroblasts; hyaluronan; metastasis; migration; tumor initiation; tumor microenvironment.

Figure 1

Progression-Associated Fibrosis in Cancerized Stroma: Deregulated synthesis and deposition of ECM components, including HA and type I collagen, leads to tumor-associated fibrosis. HA, a major polysaccharide of provisional wound matrices, contributes to cancer initiation, progression and resistance-to-therapy. CAF activation sustains increased collagen synthesis, structurally oriented by fibroblast contractile forces. These provide structural and biochemical cues to enhance mechano-signaling for carcinoma motility and invasion.

Figure 2

Hyaluronan is a simple polysaccharide produced by cell membrane synthases. (A) Micrograph showing membrane localized hyaluronan synthase 2 in fibroblasts. (B) Hyaluronan synthase has multiple transmembrane domains that cluster to form pores in the cell membrane. UDP-sugars bind to the protein cytoplasmic face and growing polymer is extruded through the pore to the extracellular space.

Figure 3

Hyaluronan is a large polymer during tissue homeostasis and fragmented in wounds and tumors. In homeostasis, large hyaluronan polymers are decorated by proteins/proteoglycans, which contribute to normal tissue architecture. (A) Cartoon of a virgin mouse mammary gland. (B) Cartoon of a mouse mammary tumor (Blue, mammary tumor cells). During wounding, fragmented hyaluronan polymers produced by ROS/hyaluronidases activate fibroblasts and attract immune cells, which contribute to the loss of tissue architecture.

Figure 4

Circulating cCAF/circulating tumor cell (CTC) clusters and cCAF clusters in breast cancer patient blood. (A) cCAF/CTC co-cluster and (B) cCAF cluster. Red: FAP, Green: CK. From Ao et al. (2015).

Figure 5

Hyaluronan promotes CAFs motility toward tumor cells and tumor cell motility. CAF subsets produce hyaluronan as a motogenic stimulus for migrating toward tumor cells. Hyaluronan binds to tumor cell subsets via hyaluronan receptors (RHAMM and CD44) contributing to the migration and invasion of CAF-guided tumor cells.