The action of hyaluronan in functional properties, morphology and expression of matrix effectors in mammary cancer cells depends on its molecular size

Abstract

Breast cancer constitutes a heterogeneous disease. The expression profiles of estrogen receptors (ERs), as well as the expression patterns of extracellular matrix (ECM) macromolecules, determine its development and progression. Hyaluronan (HA) is an ECM molecule that regulates breast cancer cells' properties in a molecular size-dependent way. Previous studies have shown that 200-kDa HA fragments modulate the functional properties, morphology, and expression of several matrix mediators of the highly metastatic ERα − /ERβ + MDA-MB-231 cells. In order to evaluate the effects of HA fragments (< 10, 30 and 200-kDa) in ERβ-suppressed breast cancer cells, the shERβ MDA-MB-231 cells were used. These cells are less aggressive when compared with MDA-MB-231 cells. To this end, the functional properties, the morphology, and the expression of the molecules associated with breast cancer cells metastatic potential were studied. Notably, both cell proliferation and invasion were significantly reduced after treatment with 200-kDa HA. Moreover, as assessed by scanning electron microscopy, 200-kDa HA affected cellular morphology, and as assessed by qPCR, upregulated the epithelial marker Ε-cadherin. The expression profiles of ECM mediators, such as HAS2, CD44, and MMP7, were also altered. On the other hand, cellular migration and the expression levels of syndecan-4 (SDC-4) were not significantly affected in contrast to our observations regarding MDA-MB-231 cells. These novel data demonstrate that the molecular size of the HA determines its effects on ERβ-suppressed breast cancer cells and that 200-kDa HA exhibits antiproliferative effects on these cells. A deeper understanding of this mechanism may contribute to the development of therapeutic strategies against breast cancer.

Sulfated Hyaluronan Modulates the Functional Properties and Matrix Effectors Expression of Breast Cancer Cells with Different Estrogen Receptor Status

“…Through its binding to the receptor CD44, HA regulates intracellular signaling pathways and cell functional properties in a size-dependent manner [ 26 ]. Recent studies have shown the role of HA fragments of different molecular size in modulating breast cancer cells proliferation, migration, and invasion [ 24 , 25 ]. Furthermore, treatment with such HA fragments results in significant alterations in the morphology and aggressive phenotype of breast cancer cells.…”

“…Depending on its molecular size, HA exerts different biological functions and regulates specific cellular behavior. For instance, HA fragments of <10, 30, and 200 kDa affect breast cancer cells’ functional properties and morphology, as well as the expression patterns of several molecules in a size-dependent manner [ 24 , 25 ]. Moreover, high molecular weight (HMW) HA is known for its anti-inflammatory, anti-angiogenic, and anti-proliferative properties [ 26 ].…”

A guide to the composition and functions of the extracellular matrix

“…HMWHA shows anti‐angiogenic, immune suppressive, and anti‐inflammatory activities, and induces tissue reparative processes as described in wound healing [242]. In an opposite fashion, the fragments of HA, called oligosaccharides when < 200 kDa, show the capacity to modify the expression of a variety of genes (such as MMPs, syndecan‐4, HPSE) to induce inflammatory processes as well as angiogenesis throughout their interactions with specific receptors [29,243–245] (Fig. 3).…”

Extracellular matrix-based cancer targeting

“…HA oligosaccharides promote angiogenesis which brings more nutrients to the tumor and facilitates systemic spread. Indeed, it has been demonstrated that the effects of HA in mammary cancer depend on its molecular size as well as the type of estrogen receptor (ERα/β) expressed [19][20][21].…”