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.

1‐(2‐Hydroxyethyl)‐2‐imidazolidinone, a heparanase and matrix metalloproteinase inhibitor, improves epidermal basement membrane structure and epidermal barrier function

“…This is consistent with the fact that heparan sulfate contributes to the formation of BM structure by interacting with type IV collagen and laminins, and also with our previous findings that inhibitors of MMPs and heparanase promote the formation of BM ultra‐structures such as lamina densa, hemidesmosomes and anchoring fibrils in the SE model and UVB‐exposed human skin . In this connection, it is noteworthy that expression levels of MMP‐9 and heparanase are closely related to carcinogenesis and metastasis, and tumor cells secrete MMP‐9 and heparanase to generate a premetastatic microenvironment . Taken together, our findings indicate that the ability of HEI to inhibit MMP‐9 and heparanase activities and to prevent degradation of the BM structure synergistically, leads to a promoting of the formation of the BM structure.…”

Insights into the key roles of proteoglycans in breast cancer biology and translational medicine

“…Heparanase is a multifunctional molecule whose expression is closely associated with the aggressive behavior of many types of human cancers including breast cancer [250–254]. Heparanase binds to and enzymatically cleaves HS chains, thereby regulating HS availability and/or function both at the cell surface and within the ECM.…”

Complementing the Sugar Code: Role of GAGs and Sialic Acid in Complement Regulation

“…It is thought that increased surface levels of sialic acid confer protection against complement by recruiting FH ( 83 ) – removing sialic acid from cancer cells enhances their complement-mediated lysis ( 84 ) – and contributes to immune evasion from NK and other immune cells by non-complement-mediated mechanisms ( 78 ). Interestingly, many breast cancer cells have an increased amount of HS proteoglycans on their surfaces compared to normal mammary cells ( 85 ), and therefore, it is tempting to hypothesize that the up-regulation of this SAMP, like sialic acid, confers increased protection of cancer cells to complement by recruiting FH.…”