Heparan sulfate and heparanase as modulators of breast cancer progression

Abstract

Breast cancer is defined as a cancer originating in tissues of the breast, frequently in ducts and lobules. During the last 30 years, studies to understand the biology and to treat breast tumor improved patients' survival rates. These studies have focused on genetic components involved in tumor progression and on tumor microenvironment. Heparan sulfate proteoglycans (HSPGs) are involved in cell signaling, adhesion, extracellular matrix assembly, and growth factors storage. As a central molecule, HSPG regulates cell behavior and tumor progression. HS accompanied by its glycosaminoglycan counterparts regulates tissue homeostasis and cancer development. These molecules present opposite effects according to tumor type or cancer model. Studies in this area may contribute to unveil glycosaminoglycan activities on cell dynamics during breast cancer exploring these polysaccharides as antitumor agents. Heparanase is a potent tumor modulator due to its protumorigenic, proangiogenic, and prometastatic activities. Several lines of evidence indicate that heparanase is upregulated in all human sarcomas and carcinomas. Heparanase seems to be related to several aspects regulating the potential of breast cancer metastasis. Due to its multiple roles, heparanase is seen as a target in cancer treatment. We will describe recent findings on the function of HSPGs and heparanase in breast cancer behavior and progression.

Figure 1

Heparan sulfate structure. Heparan sulfate glycosaminoglycan is linked to specific serine residues on heparan sulfate proteoglycans by a tetrasaccharide sequence of glucuronic acid, galactose, galactose, and xylose. The HS chains contain clusters of N-acetylated unmodified domains and N-sulfated modified domains. Specific sequences in the N-domains bind to different growth factors and their receptors, for example, fibroblast growth factor-2 (FGF-2) and its receptor (FGFR).

Figure 2

Model of how Heparan sulfate proteoglycans and heparanase participate in the epithelial-to-mesenchymal transition of a breast cancer cell. When a specific factor, such as TGF-β, stimulates its receptor on the tumor cell surface (1), the signaling cascade triggers transcriptional changes (2) that lead to a differential expression of specific receptors (3), which will allow the tumor cell to become responsive to other available factors that will culminate in the transition from an epithelial to a mesenchymal state (4). During this process, these transcriptional changes also lead to higher degree of sulfation of heparan sulfate chains (5), enhancing the cell ability to bind more extracellular molecules. Also, heparanase expression takes place (6), enhancing tumor angiogenesis (7) and degrading heparan sulfate chains (8) that will no longer be internalized, staying in the extracellular matrix bound with factors that also cooperate in the epithelial-to-mesenchymal transition process. Expression of extracellular matrix-degrading enzymes (9), such as metalloproteinases, promote extracellular matrix degradation (10) and heparan sulfate proteoglycans shedding (11). These processes altogether culminate in a complete transformation of an epithelial tumor cell into a mesenchymal phenotype (12) able to invade the neighboring tissue and circulation.

Figure 3

Cellular and molecular composition of premetastatic niche and metastatic microenvironment. premetastatic niche formation initiates by release of soluble factors, such as, VEGFA, TGF-beta, placental growth factor (PLGF), inflammatory chemokines S100, and Serum Amiloyd A3 (SAA3), as well as stromal-derived growth factor 1 (SDF1) by the primary tumor (1). As a result, bone marrow-derived hematopoietic progenitor cells (HPC) and immature myeloid cells are recruited to the premetastatic niche (2). Then, these bone marrow-derived cells start to populate the premetastatic niche with potent modified factors, such as tumor necrosis factor-α (TNFα), matrix metalloproteinase 9 (MMP9), and TGFβ, leading to stimulation of stromal cells that in turn modulate the extracellular matrix of the premetastatic microenvironment (3). For example, modified factors-mediated fibroblast activation initiates secretion of fibronectin, which constitutes an important adhesion protein in the niche. Additionally, other important extracellular matrix components such as hyaluronic acid, proteoglycans, glycosaminoglycan-modified enzymes, like heparanase and sulfatases are likely to be present (4), but it is yet to be confirmed and constitutes a new interesting area of research involving the premetastatic niche. Mature tumor microenvironment is composed by tumor cells, blood vessels, bone marrow-derived cells, proteoglycans, MMPs, hyaluronic acid, stromal cells, such as fibroblasts and several recruited cells like neutrophils, and macrophages. These cells, secrete several growth factors and cytokines that can drive epithelial to mesenchymal transition-mediated migration and invasion of tumor cells.